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1
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Hasballa I, Maggi D. MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants. Int J Mol Sci 2024; 25:8790. [PMID: 39201476 PMCID: PMC11354648 DOI: 10.3390/ijms25168790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/26/2024] [Accepted: 08/12/2024] [Indexed: 09/02/2024] Open
Abstract
Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype-phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients.
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Affiliation(s)
- Iderina Hasballa
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132 Genoa, Italy
| | - Davide Maggi
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
- Diabetes Clinic, IRCCS Ospedale Policlinico San Martino Genoa, 16132 Genoa, Italy
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2
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Hammad MM, Abu-Farha M, Hebbar P, Anoop E, Chandy B, Melhem M, Channanath A, Al-Mulla F, Thanaraj TA, Abubaker J. The miR-668 binding site variant rs1046322 on WFS1 is associated with obesity in Southeast Asians. Front Endocrinol (Lausanne) 2023; 14:1185956. [PMID: 37859980 PMCID: PMC10583568 DOI: 10.3389/fendo.2023.1185956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 09/11/2023] [Indexed: 10/21/2023] Open
Abstract
The Wolfram syndrome 1 gene (WFS1) is the main causative locus for Wolfram syndrome, an inherited condition characterized by childhood-onset diabetes mellitus, optic atrophy, and deafness. Global genome-wide association studies have listed at least 19 WFS1 variants that are associated with type 2 diabetes (T2D) and metabolic traits. It has been suggested that miRNA binding sites on WFS1 play a critical role in the regulation of the wolframin protein, and loss of WFS1 function may lead to the pathogenesis of diabetes. In the Hungarian population, it was observed that a 3' UTR variant from WFS1, namely rs1046322, influenced the affinity of miR-668 to WFS1 mRNA, and showed a strong association with T2D. In this study, we genotyped a large cohort of 2067 individuals of different ethnicities residing in Kuwait for the WFS1 rs1046322 polymorphism. The cohort included 362 Southeast Asians (SEA), 1045 Arabs, and 660 South Asians (SA). Upon performing genetic association tests, we observed significant associations between the rs1046322 SNP and obesity traits in the SEA population, but not in the Arab or SA populations. The associated traits in SEA cohort were body mass index, BMI (β=1.562, P-value=0.0035, Pemp=0.0072), waist circumference, WC (β=3.163, P-value=0.0197, Pemp=0.0388) and triglyceride, TGL (β=0.224, P-value=0.0340). The association with BMI remained statistically significant even after multiple testing correction. Among the SEA individuals, carriers of the effect allele at the SNP had significantly higher BMI [mean of 27.63 (3.6) Kg/m2], WC [mean of 89.9 (8.1) cm], and TGL levels [mean of 1.672 (0.8) mmol/l] than non-carriers of the effect allele. Our findings suggest a role for WFS1 in obesity, which is a risk factor for diabetes. The study also emphasizes the significant role the ethnic background may play in determining the effect of genetic variants on susceptibility to metabolic diseases.
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Affiliation(s)
- Maha M. Hammad
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait, Kuwait
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait, Kuwait
| | - Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait, Kuwait
| | - Prashantha Hebbar
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait, Kuwait
| | - Emil Anoop
- Special Service Facility Department, Dasman Diabetes Institute, Kuwait, Kuwait
| | - Betty Chandy
- Special Service Facility Department, Dasman Diabetes Institute, Kuwait, Kuwait
| | - Motasem Melhem
- Special Service Facility Department, Dasman Diabetes Institute, Kuwait, Kuwait
| | - Arshad Channanath
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait, Kuwait
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait, Kuwait
| | | | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait, Kuwait
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3
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Rigoli L, Caruso V, Aloi C, Salina A, Maghnie M, d’Annunzio G, Lamacchia O, Salzano G, Lombardo F, Picca G. An Atypical Case of Late-Onset Wolfram Syndrome 1 without Diabetes Insipidus. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:2473. [PMID: 35206658 PMCID: PMC8872384 DOI: 10.3390/ijerph19042473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 12/04/2022]
Abstract
Wolfram syndrome 1, a rare autosomal recessive neurodegenerative disease, is caused by mutations in the WFS1 gene. It is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD), and other clinical manifestations such as urological and neurological disorders. Here we described the case of a patient with an atypical late-onset Wolfram syndrome 1 without DI. Our WS1 patient was a c.1620_1622delGTG (p.Trp540del)/c.124 C > T (p.Arg42*) heterozygous compound. The p.Arg42* nonsense mutation was also found in heterozygosity in his sister and niece, both suffering from psychiatric disorders. The p.Arg42* nonsense mutation has never been found in WS1 and its pathogenicity is unclear so far. Our study underlined the need to study a greater number of WS1 cases in order to better understand the clinical significance of many WFS1 variants.
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Affiliation(s)
- Luciana Rigoli
- Department of Human Pathology of Adulthood and Childhood G. Barresi, University of Messina, 98125 Messina, Italy; (G.S.); (F.L.)
| | - Valerio Caruso
- Psychiatry 2 Unit, Clinical and Experimental Medicine Department, University of Pisa, 56126 Pisa, Italy;
| | - Concetta Aloi
- Pediatric Clinic, LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), IRCCS Institute Giannina Gaslini, 16147 Genoa, Italy; (C.A.); (A.S.); (M.M.); (G.d.)
| | - Alessandro Salina
- Pediatric Clinic, LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), IRCCS Institute Giannina Gaslini, 16147 Genoa, Italy; (C.A.); (A.S.); (M.M.); (G.d.)
| | - Mohamad Maghnie
- Pediatric Clinic, LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), IRCCS Institute Giannina Gaslini, 16147 Genoa, Italy; (C.A.); (A.S.); (M.M.); (G.d.)
| | - Giuseppe d’Annunzio
- Pediatric Clinic, LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), IRCCS Institute Giannina Gaslini, 16147 Genoa, Italy; (C.A.); (A.S.); (M.M.); (G.d.)
| | - Olga Lamacchia
- Unit of Endocrinology and Diabetology, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; (O.L.); (G.P.)
| | - Giuseppina Salzano
- Department of Human Pathology of Adulthood and Childhood G. Barresi, University of Messina, 98125 Messina, Italy; (G.S.); (F.L.)
| | - Fortunato Lombardo
- Department of Human Pathology of Adulthood and Childhood G. Barresi, University of Messina, 98125 Messina, Italy; (G.S.); (F.L.)
| | - Giuseppe Picca
- Unit of Endocrinology and Diabetology, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy; (O.L.); (G.P.)
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4
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Ustianowski P, Malinowski D, Safranow K, Dziedziejko V, Tarnowski M, Pawlik A. PPARG, TMEM163, UBE2E2 and WFS1 Gene Polymorphisms Are Not Significant Risk Factors for Gestational Diabetes in the Polish Population. J Pers Med 2022; 12:jpm12020243. [PMID: 35207731 PMCID: PMC8878167 DOI: 10.3390/jpm12020243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/03/2022] [Accepted: 02/03/2022] [Indexed: 11/28/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a common disorder that occurs in pregnant women, leading to many maternal and neonatal complications. The pathogenesis of GDM is complex and includes risk factors, such as: age, obesity, and family history of diabetes. Studies have shown that genetic factors also play a role in the pathogenesis of GDM. The present study investigated whether polymorphisms in the PPARG (rs1801282), TMEM163 (rs6723108 and rs998451), UBE2E2 (rs6780569), and WFS1 (rs4689388) genes are risk factors for the development of GDM and whether they affect selected clinical parameters in women with GDM. This study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). The diagnosis of GDM was based on a 75 g oral glucose tolerance test (OGTT) at 24–28 weeks gestation, according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. There were no statistically significant differences in the distribution of polymorphisms studied between women with GDM and pregnant women with normal carbohydrate tolerance, which suggests that these polymorphisms are not risk factors for GDM. We also examined the associations between studied gene polymorphisms and clinical parameters: fasting glucose, daily insulin requirement, body mass before pregnancy, body mass at birth, body mass increase during pregnancy, BMI before pregnancy, BMI at birth, BMI increase during pregnancy, new-born body mass, and APGAR score in women with GDM. We observed lower BMI values before pregnancy and at birth in women with PPARG rs17036160 TT genotype. The results of this study suggest that the PPARG (rs1801282), TMEM163 (rs6723108 and rs998451), UBE2E2 (rs6780569), and WFS1 (rs4689388) gene polymorphisms are not significant risk factors for GDM development in the Polish population and do not affect the clinical parameters in women with GDM; only rs1801282 of the PPARG gene may influence BMI values in women with GDM.
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Affiliation(s)
- Przemysław Ustianowski
- Department of Obstetrics and Gynecology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Damian Malinowski
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (V.D.); (K.S.)
| | - Violetta Dziedziejko
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-111 Szczecin, Poland; (V.D.); (K.S.)
| | - Maciej Tarnowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland;
- Correspondence:
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5
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Abstract
Diabetes mellitus is a major risk factor for coronary heart disease (CHD). The major form of diabetes mellitus is type 2 diabetes mellitus (T2D), which is thus largely responsible for the CHD association in the general population. Recent years have seen major advances in the genetics of T2D, principally through ever-increasing large-scale genome-wide association studies. This article addresses the question of whether this expanding knowledge of the genomics of T2D provides insight into the etiologic relationship between T2D and CHD. We will investigate this relationship by reviewing the evidence for shared genetic loci between T2D and CHD; by examining the formal testing of this interaction (Mendelian randomization studies assessing whether T2D is causal for CHD); and then turn to the implications of this genetic relationship for therapies for CHD, for therapies for T2D, and for therapies that affect both. In conclusion, the growing knowledge of the genetic relationship between T2D and CHD is beginning to provide the promise for improved prevention and treatment of both disorders.
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Affiliation(s)
- Mark O. Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jerome I. Rotter
- Institute for Translational Genomics and Population Sciences and Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
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6
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Khatami F, Mohajeri-Tehrani MR, Tavangar SM. The Importance of Precision Medicine in Type 2 Diabetes Mellitus (T2DM): From Pharmacogenetic and Pharmacoepigenetic Aspects. Endocr Metab Immune Disord Drug Targets 2020; 19:719-731. [PMID: 31122183 DOI: 10.2174/1871530319666190228102212] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/18/2018] [Accepted: 11/21/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Type 2 Diabetes Mellitus (T2DM) is a worldwide disorder as the most important challenges of health-care systems. Controlling the normal glycaemia greatly profit long-term prognosis and gives explanation for early, effective, constant, and safe intervention. MATERIAL AND METHODS Finding the main genetic and epigenetic profile of T2DM and the exact molecular targets of T2DM medications can shed light on its personalized management. The comprehensive information of T2DM was earned through the genome-wide association study (GWAS) studies. In the current review, we represent the most important candidate genes of T2DM like CAPN10, TCF7L2, PPAR-γ, IRSs, KCNJ11, WFS1, and HNF homeoboxes. Different genetic variations of a candidate gene can predict the efficacy of T2DM personalized strategy medication. RESULTS SLCs and AMPK variations are considered for metformin, CYP2C9, KATP channel, CDKAL1, CDKN2A/2B and KCNQ1 for sulphonylureas, OATP1B, and KCNQ1 for repaglinide and the last but not the least ADIPOQ, PPAR-γ, SLC, CYP2C8, and SLCO1B1 for thiazolidinediones response prediction. CONCLUSION Taken everything into consideration, there is an extreme need to determine the genetic status of T2DM patients in some known genetic region before planning the medication strategies.
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Affiliation(s)
- Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad R Mohajeri-Tehrani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed M Tavangar
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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7
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Yahaya TO, Salisu TF. A Review of Type 2 Diabetes Mellitus Predisposing Genes. Curr Diabetes Rev 2019; 16:52-61. [PMID: 30514191 DOI: 10.2174/1573399815666181204145806] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 11/22/2018] [Accepted: 11/28/2018] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Scientists are considering the possibility of treating diabetes mellitus (DM) using a personalized approach in which various forms of the diseases will be treated based on the causal gene and its pathogenesis. To this end, scientists have identified mutations in certain genes as probable causes of Type 2 diabetes mellitus (T2DM) with diverse mechanisms. AIM This review was aimed at articulating already identified T2DM genes with their mechanisms of action and phenotypic presentations for the awareness of all stakeholders. METHOD The Google search engine was used to retrieve relevant information on the subject from reliable academic databases such as PubMed, Medline, and Google Scholar, among others. RESULTS At least seventy (70) genes are currently being suspected in the biogenesis of T2DM. However, mutations in, or variants of KCNJ11, PPARG, HNF1B and WFS1 genes, are the most suspected and reported in the pathogenesis of the disease. Mutations in these genes can cause disruption of insulin biosynthesis through the destruction of pancreatic beta cells, change of beta cell morphology, destruction of insulin receptors, among others. These cellular events may lead to insulin resistance and hyperglycemia and, along with environmental triggers such as obesity and overweight, culminate in T2DM. It was observed that each identified gene has its distinct mechanism by which it interacts with other genes and environmental factors to cause T2DM. CONCLUSION Healthcare providers are advised to formulate T2DM drugs or treatment by targeting the causal genes along with their mechanisms.
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Affiliation(s)
- Tajudeen O Yahaya
- Department of Biology, Federal University Birnin Kebbi, Kebbi State, Nigeria
| | - Titilola F Salisu
- Department of Cell Biology and Genetics, University of Lagos, Lagos, Nigeria
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8
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Danilova T, Lindahl M. Emerging Roles for Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) in Pancreatic Beta Cells and Diabetes. Front Physiol 2018; 9:1457. [PMID: 30386256 PMCID: PMC6198132 DOI: 10.3389/fphys.2018.01457] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 09/26/2018] [Indexed: 12/31/2022] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) was originally identified as a secreted trophic factor for dopamine neurons in vitro. It protects and restores damaged cells in rodent models of Parkinson's disease, brain and heart ischemia, spinocerebellar ataxia and retina in vivo. However, its exact mechanism of action is not known. MANF is widely expressed in most human and mouse organs with high levels in secretory tissues. Intracellularly, MANF localizes to the endoplasmic reticulum (ER) and ER stress increases it's expression in cells and tissues. Furthermore, increased MANF levels has been detected in the sera of young children with newly diagnosed Type 1 (T1D) diabetes and Type 2 (T2D) diabetic patients. ER stress is caused by the accumulation of misfolded and aggregated proteins in the ER. It activates a cellular defense mechanism, the unfolded protein response (UPR), a signaling cascade trying to restore ER homeostasis. However, if prolonged, unresolved ER stress leads to apoptosis. Unresolved ER stress contributes to the progressive death of pancreatic insulin-producing beta cells in both T1D and T2D. Diabetes mellitus is characterized by hyperglycemia, caused by the inability of the beta cells to maintain sufficient levels of circulating insulin. The current medications, insulin and antidiabetic drugs, alleviate diabetic symptoms but cannot reconstitute physiological insulin secretion which increases the risk of devastating vascular complications of the disease. Thus, one of the main strategies in improving current diabetes therapy is to define and validate novel approaches to protect beta cells from stress as well as activate their regeneration. Embryonic deletion of the Manf gene in mice led to gradual postnatal development of insulin-deficient diabetes caused by reduced beta cell proliferation and increased beta cell death due to increased and sustained ER stress. In vitro, recombinant MANF partly protected mouse and human beta cells from ER stress-induced beta cell death and potentiated mouse and human beta cell proliferation. Importantly, in vivo overexpression of MANF in the pancreas of T1D mice led to increased beta cell proliferation and decreased beta cell death, suggesting that MANF could be a new therapeutic candidate for beta cell protection and regeneration in diabetes.
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Affiliation(s)
- Tatiana Danilova
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Maria Lindahl
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
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Muscarinic Agonist Ameliorates Insulin Secretion in Wfs1-Deficient Mice. Can J Diabetes 2018; 43:115-120. [PMID: 30266217 DOI: 10.1016/j.jcjd.2018.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 05/15/2018] [Accepted: 06/18/2018] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Similar to patients with Wolfram syndrome and to heterozygous Wolframin1 (Wfs1) mutation carriers, Wfs1-deficient mice exhibit impaired glucose tolerance and lower plasma insulin levels. Muscarinic receptor 3 agonists have previously been shown to potentiate glucose-stimulated insulin secretion. Therefore, the aim of this study was to investigate insulin-secretion dynamics in Wfs1-deficient mice and evaluate carbachol, muscarinic agonist and the ability to ameliorate the insulin secretion deficits caused by the Wfs1 mutation. METHODS Wild-type Wfs1 heterozygous and Wfs1 mutant mice were used. Blood glucose was measured after glucose and carbachol administration. Insulin secretion was measured from serum using ELISA. RESULTS Glucose administration causes hyperglycemia in Wfs1-deficient mice due to decreased insulin secretion. This deficit is abolished by administration of the muscarinic agonist carbachol. CONCLUSIONS Activation of the muscarinic pathway to potentiate insulin secretion may present a target to manage diabetes resulting from Wfs1 deficiency.
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Varga TV, Kurbasic A, Aine M, Eriksson P, Ali A, Hindy G, Gustafsson S, Luan J, Shungin D, Chen Y, Schulz CA, Nilsson PM, Hallmans G, Barroso I, Deloukas P, Langenberg C, Scott RA, Wareham NJ, Lind L, Ingelsson E, Melander O, Orho-Melander M, Renström F, Franks PW. Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults. Int J Epidemiol 2018; 46:1211-1222. [PMID: 27864399 DOI: 10.1093/ije/dyw245] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2016] [Indexed: 11/14/2022] Open
Abstract
Background Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids. Methods Participants from the GLACIER Study (Nmax = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms; replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (ΔTC) and triglycerides (ΔTG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; Nmax = 8263 participants) were used for replication. We conducted an in silico look-up for association with coronary artery disease (CAD) in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) Consortium (N ∼ 190 000) and functional annotation for the top ranking variants. Results In total, 956 variants were associated (P < 0.01) with either ΔTC or ΔTG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with ΔTG and multiple SNPs in the APOA1/A4/C3/A5 region at genome-wide significance (P < 5 × 10-8), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P < 1.7 × 10-6). The rs7412 variant at APOE was associated with ΔTC in GLACIER (P < 1.7 × 10-6). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with ΔTC and for ΔTG, respectively (P < 10-3). Of these, a variant at CAPN3 (P = 1.2 × 10-4), multiple variants at HPR (Pmin = 1.5 × 10-6) and a variant at SIX5 (P = 1.9 × 10-4) showed evidence for association with CAD. Conclusions We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.
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Affiliation(s)
- Tibor V Varga
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Azra Kurbasic
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Mattias Aine
- Division of Oncology and Pathology, Skåne University Hospital, Lund University, Lund, Sweden
| | - Pontus Eriksson
- Division of Oncology and Pathology, Skåne University Hospital, Lund University, Lund, Sweden
| | - Ashfaq Ali
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - George Hindy
- Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden
| | - Stefan Gustafsson
- Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Jian'an Luan
- Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Dmitry Shungin
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.,Department of Odontology.,Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden
| | - Yan Chen
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | | | - Peter M Nilsson
- Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Göran Hallmans
- Department of Biobank Research, Umeå University, Umeå, Sweden
| | - Inês Barroso
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.,Metabolic Research Laboratories.,NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Panos Deloukas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK.,Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Claudia Langenberg
- Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Robert A Scott
- Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Nicholas J Wareham
- Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Erik Ingelsson
- Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.,Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Olle Melander
- Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, Skåne University Hospital, Malmö, Sweden
| | - Marju Orho-Melander
- Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden
| | - Frida Renström
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.,Department of Biobank Research, Umeå University, Umeå, Sweden
| | - Paul W Franks
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.,Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.,Department of Nutrition, Harvard T.H Chan School of Public Health, Boston, MA, USA
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11
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Torkamandi S, Bastami M, Ghaedi H, Tarighi S, Shokri F, Javadi A, Mirfakhraie R, Omrani MD. Association of CpG-SNP and 3'UTR-SNP of WFS1 with the Risk of Type 2 Diabetes Mellitus in an Iranian Population. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2017; 6:197-203. [PMID: 29988211 PMCID: PMC6004294 DOI: 10.22088/bums.6.4.197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 11/17/2017] [Indexed: 01/04/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most common multifactorial disorders in Iran. Recent genome wide association studies (GWASs) and functional studies have suggested that WFS1 may predispose individuals to T2DM. However, to date, the possible association of such variants with T2DM in Iranians remained unknown. Here, we investigated the association of the two polymorphisms of WFS1 (rs1801214 a CpG-SNP, and rs1046320 a 3’UTR-SNP) with T2DM in an Iranian population. The study population comprised 432 unrelated Iranian individuals including 220 patients with T2DM, and 211 unrelated healthy control subjects. Genotyping was performed using PCR-RFLP, and confirmed with sequencing. In a logistic regression analysis, the rs1801214-T allele was associated with a significantly lower risk of T2DM assuming the log-additive model (OR: 0.68, 95% CI: 0.52-0.91, P= 0.007539). Moreover, the G allele of rs1046320 was associated with a lower risk of T2DM assuming the log-additive model (OR: 0.68, 95% CI: 0.50- 0.91, P= 0.008313). Haplotype analysis revealed that haplotypes that carry at least one protective allele are associated with a lower risk of T2DM. This is a first evidence for the association of WFS1 rs1801214, and rs1046320 with T2DM in an Iranian population.
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Affiliation(s)
- Shahram Torkamandi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Medical Genetics and Immunology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Milad Bastami
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Ghaedi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahriar Tarighi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fazlollah Shokri
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolreza Javadi
- Department of Pathology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Mirfakhraie
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mir Davood Omrani
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Wang XF, Lin X, Li DY, Zhou R, Greenbaum J, Chen YC, Zeng CP, Peng LP, Wu KH, Ao ZX, Lu JM, Guo YF, Shen J, Deng HW. Linking Alzheimer's disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach. J Neurol Sci 2017; 380:262-272. [PMID: 28870582 DOI: 10.1016/j.jns.2017.07.044] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 06/29/2017] [Accepted: 07/28/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Both type 2 diabetes (T2D) and Alzheimer's disease (AD) occur commonly in the aging populations and T2D has been considered as an important risk factor for AD. The heritability of both diseases is estimated to be over 50%. However, common pleiotropic single-nucleotide polymorphisms (SNPs)/loci have not been well-defined. The aim of this study is to analyze two large public accessible GWAS datasets to identify novel common genetic loci for T2D and/or AD. METHODS AND MATERIALS The recently developed novel conditional false discovery rate (cFDR) approach was used to analyze the summary GWAS datasets from International Genomics of Alzheimer's Project (IGAP) and Diabetes Genetics Replication And Meta-analysis (DIAGRAM) to identify novel susceptibility genes for AD and T2D. RESULTS We identified 78 SNPs (including 58 novel SNPs) that were associated with AD in Europeans conditional on T2D (cFDR<0.05). 66 T2D SNPs (including 40 novel SNPs) were identified by conditioning on SNPs association with AD (cFDR<0.05). A conjunction-cFDR (ccFDR) analysis detected 8 pleiotropic SNPs with a significance threshold of ccFDR<0.05 for both AD and T2D, of which 5 SNPs (rs6982393, rs4734295, rs7812465, rs10510109, rs2421016) were novel findings. Furthermore, among the 8 SNPs annotated at 6 different genes, 3 corresponding genes TP53INP1, TOMM40 and C8orf38 were related to mitochondrial dysfunction, critically involved in oxidative stress, which potentially contribute to the etiology of both AD and T2D. CONCLUSION Our study provided evidence for shared genetic loci between T2D and AD in European subjects by using cFDR and ccFDR analyses. These results may provide novel insight into the etiology and potential therapeutic targets of T2D and/or AD.
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Affiliation(s)
- Xia-Fang Wang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Xu Lin
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Ding-You Li
- Department of Gastroenterology, Children's Mercy Kansas City, University of Missouri Kansas City School of Medicine, Kansas City MO 64108, USA
| | - Rou Zhou
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Jonathan Greenbaum
- Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Yuan-Cheng Chen
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Chun-Ping Zeng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Lin-Ping Peng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Ke-Hao Wu
- Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Zeng-Xin Ao
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Jun-Min Lu
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Yan-Fang Guo
- Institute of Bioinformatics, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Jie Shen
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China
| | - Hong-Wen Deng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, PR China; Center for Bioinformatics and Genomics, Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA.
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13
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Ivask M, Hugill A, Kõks S. RNA-sequencing of WFS1-deficient pancreatic islets. Physiol Rep 2016; 4:4/7/e12750. [PMID: 27053292 PMCID: PMC4831324 DOI: 10.14814/phy2.12750] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Accepted: 03/03/2016] [Indexed: 11/24/2022] Open
Abstract
Wolfram syndrome, an autosomal recessive disorder characterized by juvenile‐onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. WFS1 encodes an endoplasmic reticulum resident transmembrane protein. The Wfs1‐null mice exhibit progressive insulin deficiency and diabetes. The aim of this study was to describe the insulin secretion and transcriptome of pancreatic islets in WFS1‐deficient mice. WFS1‐deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild‐type (WT) mice. Wfs1KO pancreatic islets secreted less insulin after incubation in 2 and 10 mmol/L glucose and with tolbutamide solution compared to WT and Wfs1HZ islets, but not after stimulation with 20 mmol/L glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KO had an increased level of proinsulin. After incubation in 2 mmol/L glucose solution the proinsulin/insulin ratio in Wfs1KO was significantly higher than that of WT and Wfs1HZ. RNA‐seq from pancreatic islets found melastatin‐related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated in WFS1‐deficient mice. Functional annotation of RNA sequencing results showed that WFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network.
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Affiliation(s)
- Marilin Ivask
- Department of Pathophysiology, Institute of Biomedicine and Translational Medicine University of Tartu, Tartu, Estonia
| | - Alison Hugill
- Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire, United Kingdom
| | - Sulev Kõks
- Department of Pathophysiology, Institute of Biomedicine and Translational Medicine University of Tartu, Tartu, Estonia
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14
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Elek Z, Dénes R, Prokop S, Somogyi A, Yowanto H, Luo J, Souquet M, Guttman A, Rónai Z. Multicapillary gel electrophoresis based analysis of genetic variants in the WFS1 gene. Electrophoresis 2016; 37:2313-21. [DOI: 10.1002/elps.201600251] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 11/10/2022]
Affiliation(s)
- Zsuzsanna Elek
- Department of Medical Chemistry; Molecular Biology and Pathobiochemistry, Semmelweis University; Budapest Hungary
| | - Réka Dénes
- Department of Medical Chemistry; Molecular Biology and Pathobiochemistry, Semmelweis University; Budapest Hungary
| | - Susanne Prokop
- Department of Medical Chemistry; Molecular Biology and Pathobiochemistry, Semmelweis University; Budapest Hungary
| | - Anikó Somogyi
- The 2nd Department of Internal Medicine; Semmelweis University; Budapest Hungary
| | | | | | | | - András Guttman
- SCIEX Separations; Brea CA USA
- MTA-PE Translational Glycomics Group; University of Pannonia; Veszprém Hungary
- Horváth Laboratory of Bioseparation Sciences; University of Debrecen; Debrecen Hungary
| | - Zsolt Rónai
- Department of Medical Chemistry; Molecular Biology and Pathobiochemistry, Semmelweis University; Budapest Hungary
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15
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Ali A, Varga TV, Stojkovic IA, Schulz CA, Hallmans G, Barroso I, Poveda A, Renström F, Orho-Melander M, Franks PW. Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia? ACTA ACUST UNITED AC 2016; 9:162-71. [PMID: 26865658 DOI: 10.1161/circgenetics.115.001218] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 01/27/2016] [Indexed: 12/11/2022]
Abstract
Background—
Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability.
Methods and Results—
We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene–Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmö Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRS
TG
) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRS
TG
were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m
2
) associated with 2.8% (
P
=8.4×10
–84
) higher triglyceride concentration and each additional WGRS
TG
unit with 2% (
P
=7.6×10
–48
) higher triglyceride concentration. Each unit of the WGRS
TG
was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (
P
interaction
=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRS
TG
×BMI interaction effect (
P
interaction
=6.0×10
–4
), which was strengthened by including data from the Danish cohorts (
P
interaction
=6.5×10
–7
). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRS
TG
×BMI×sex) was observed (
P
interaction
=0.03), where the WGRS
TG
×BMI interaction was only statistically significant in females. Using protein–protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci.
Conclusions—
Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.
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Affiliation(s)
- Ashfaq Ali
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Tibor V. Varga
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Ivana A. Stojkovic
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Christina-Alexandra Schulz
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Göran Hallmans
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Inês Barroso
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Alaitz Poveda
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Frida Renström
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Marju Orho-Melander
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
| | - Paul W. Franks
- From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human
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16
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Poveda A, Koivula RW, Ahmad S, Barroso I, Hallmans G, Johansson I, Renström F, Franks PW. Innate biology versus lifestyle behaviour in the aetiology of obesity and type 2 diabetes: the GLACIER Study. Diabetologia 2016; 59:462-71. [PMID: 26625858 PMCID: PMC4742501 DOI: 10.1007/s00125-015-3818-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 10/29/2015] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS We compared the ability of genetic (established type 2 diabetes, fasting glucose, 2 h glucose and obesity variants) and modifiable lifestyle (diet, physical activity, smoking, alcohol and education) risk factors to predict incident type 2 diabetes and obesity in a population-based prospective cohort of 3,444 Swedish adults studied sequentially at baseline and 10 years later. METHODS Multivariable logistic regression analyses were used to assess the predictive ability of genetic and lifestyle risk factors on incident obesity and type 2 diabetes by calculating the AUC. RESULTS The predictive accuracy of lifestyle risk factors was similar to that yielded by genetic information for incident type 2 diabetes (AUC 75% and 74%, respectively) and obesity (AUC 68% and 73%, respectively) in models adjusted for age, age(2) and sex. The addition of genetic information to the lifestyle model significantly improved the prediction of type 2 diabetes (AUC 80%; p = 0.0003) and obesity (AUC 79%; p < 0.0001) and resulted in a net reclassification improvement of 58% for type 2 diabetes and 64% for obesity. CONCLUSIONS/INTERPRETATION These findings illustrate that lifestyle and genetic information separately provide a similarly high degree of long-range predictive accuracy for obesity and type 2 diabetes.
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Affiliation(s)
- Alaitz Poveda
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Clinical Research Center Building 91, Level 10, Jan Waldenströms gata 35, SE-20502, Malmö, Sweden
- Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain
| | - Robert W Koivula
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Clinical Research Center Building 91, Level 10, Jan Waldenströms gata 35, SE-20502, Malmö, Sweden
| | - Shafqat Ahmad
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Clinical Research Center Building 91, Level 10, Jan Waldenströms gata 35, SE-20502, Malmö, Sweden
| | - Inês Barroso
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
- NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
- Metabolic Research Laboratories Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - Göran Hallmans
- Department of Biobank Research, Umeå University, Umeå, Sweden
| | | | - Frida Renström
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Clinical Research Center Building 91, Level 10, Jan Waldenströms gata 35, SE-20502, Malmö, Sweden
- Department of Biobank Research, Umeå University, Umeå, Sweden
| | - Paul W Franks
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Clinical Research Center Building 91, Level 10, Jan Waldenströms gata 35, SE-20502, Malmö, Sweden.
- Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University, Umeå, Sweden.
- Department of Nutrition, Harvard Chan School of Public Health, Boston, MA, USA.
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17
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Ryu J, Lee C. Differential promoter activity by nucleotide substitution at a type 2 diabetes genome-wide association study signal upstream of the wolframin gene. J Diabetes 2016; 8:253-9. [PMID: 25800097 DOI: 10.1111/1753-0407.12289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 02/09/2015] [Accepted: 02/22/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Functional knowledge of most genetic variants identified from genome-wide association studies (GWAS) for type 2 diabetes (T2D) is limited. A recent T2D GWAS revealed an association signal (rs4689388) upstream of the gene encoding Wolfram syndrome 1 (WFS1) whose intrinsic nucleotide variants had been previously associated with T2D in several candidate gene analyses. The aim of the present study was to identify functional variants of the GWAS signal. METHODS Promoter activity of luciferase reporter constructs was compared with haplotypes including variants composing a linkage disequilibrium block in the vicinity of rs4689388 in HEK293 and HepG2 cells. RESULTS Promoter activity was highest with the most frequent haplotype (H1; ATCGT) and lowest with second most frequent haplotype (H2; GATCG), whose nucleotide alleles were all complementary to those of H1. Further analysis with artificial haplotypes revealed differential transcriptional activity by nucleotide substitution of rs4320200, rs13107806, or rs13127445 (P < 0.05). This concurred with changes in predicted transcription factor binding site by their allele substitutions. CONCLUSIONS The previously reported GWAS signal for T2D may be identified by the differential promoter activity of rs4320200, rs13107806, and rs13127445 in the promoter of WFS1 by nucleotide substitution.
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Affiliation(s)
- Jihye Ryu
- School of Systems Biomedical Science, Soongsil University, Seoul, Korea
| | - Chaeyoung Lee
- School of Systems Biomedical Science, Soongsil University, Seoul, Korea
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18
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Wang X, Strizich G, Hu Y, Wang T, Kaplan RC, Qi Q. Genetic markers of type 2 diabetes: Progress in genome-wide association studies and clinical application for risk prediction. J Diabetes 2016; 8:24-35. [PMID: 26119161 DOI: 10.1111/1753-0407.12323] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 05/22/2015] [Accepted: 06/16/2015] [Indexed: 12/18/2022] Open
Abstract
Type 2 diabetes (T2D) has become a leading public health challenge worldwide. To date, a total of 83 susceptibility loci for T2D have been identified by genome-wide association studies (GWAS). Application of meta-analysis and modern genotype imputation approaches to GWAS data from diverse ethnic populations has been key in the effort to discover T2D loci. Genetic information is expected to play a vital role in the prediction of T2D, and many efforts have been made to develop T2D risk models that include both conventional and genetic risk factors. Yet, because most T2D genetic variants identified have small effect size individually (10%-20% increased risk of T2D per risk allele), their clinical utility remains unclear. Most studies report that a genetic risk score combining multiple T2D genetic variants does not substantially improve T2D risk prediction beyond conventional risk factors. In this article, we summarize the recent progress of T2D GWAS and further review the incremental predictive performance of genetic markers for T2D.
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Affiliation(s)
- Xueyin Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Garrett Strizich
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Yonghua Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Tao Wang
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Qibin Qi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA
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19
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Hanson RL, Rong R, Kobes S, Muller YL, Weil EJ, Curtis JM, Nelson RG, Baier LJ. Role of Established Type 2 Diabetes-Susceptibility Genetic Variants in a High Prevalence American Indian Population. Diabetes 2015; 64:2646-57. [PMID: 25667308 PMCID: PMC4477349 DOI: 10.2337/db14-1715] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 02/03/2015] [Indexed: 01/08/2023]
Abstract
Several single nucleotide polymorphisms (SNPs) associated with type 2 diabetes mellitus (T2DM) have been identified, but there is little information on their role in populations at high risk for T2DM. We genotyped SNPs at 63 T2DM loci in 3,421 individuals from a high-risk American Indian population. Nominally significant (P < 0.05) associations were observed at nine SNPs in a direction consistent with the established association. A genetic risk score derived from all loci was strongly associated with T2DM (odds ratio 1.05 per risk allele, P = 6.2 × 10(-6)) and, in 292 nondiabetic individuals, with lower insulin secretion (by 4% per copy, P = 4.1 × 10(-6)). Genetic distances between American Indians and HapMap populations at T2DM markers did not differ significantly from genomic expectations. Analysis of U.S. national survey data suggested that 66% of the difference in T2DM prevalence between African Americans and European Americans, but none of the difference between American Indians and European Americans, was attributable to allele frequency differences at these loci. These analyses suggest that, in general, established T2DM loci influence T2DM in American Indians and that risk is mediated in part through an effect on insulin secretion. However, differences in allele frequencies do not account for the high population prevalence of T2DM.
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Affiliation(s)
- Robert L Hanson
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ
| | - Rong Rong
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ
| | - Sayuko Kobes
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ
| | - Yunhua Li Muller
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ
| | - E Jennifer Weil
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ
| | - Jeffrey M Curtis
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ
| | - Robert G Nelson
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ
| | - Leslie J Baier
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ
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Cho YM. Incretin physiology and pathophysiology from an Asian perspective. J Diabetes Investig 2014; 6:495-507. [PMID: 26417406 PMCID: PMC4578486 DOI: 10.1111/jdi.12305] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 10/21/2014] [Indexed: 12/25/2022] Open
Abstract
Incretin hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted on oral nutrient ingestion and regulate postprandial glucose homeostasis by conveying the signal of intestinal glucose flux. In East Asians, the secretion of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 is not reduced in type 2 diabetes relative to normal glucose tolerance. Although the incretin effect is blunted in European patients with type 2 diabetes, a few East Asian studies showed no difference in the incretin effect between type 2 diabetes and normal glucose tolerance. Interestingly, the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 receptor agonists was reported to be greater in Asians than in non-Asians. The difference in the treatment responses could be ascribed to a different pathophysiology of type 2 diabetes (lower insulin secretory function and less insulin resistance), lower body mass index, different genetic makeups, preserved incretin effect and different food compositions in East Asians compared with other ethnic groups. Based on the currently available data, incretin-based therapies appear to be safe and well tolerated in East Asians. Nevertheless, continuous pharmacovigilance is required. The characteristics of incretin biology and treatment responses to incretin-based therapies should be considered in developing ethnicity-specific treatment guidelines and making patient-centered decisions for patients with type 2 diabetes.
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Affiliation(s)
- Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine Seoul, Korea
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21
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McLaughlin HM, Ceyhan-Birsoy O, Christensen KD, Kohane IS, Krier J, Lane WJ, Lautenbach D, Lebo MS, Machini K, MacRae CA, Azzariti DR, Murray MF, Seidman CE, Vassy JL, Green RC, Rehm HL. A systematic approach to the reporting of medically relevant findings from whole genome sequencing. BMC MEDICAL GENETICS 2014; 15:134. [PMID: 25714468 PMCID: PMC4342199 DOI: 10.1186/s12881-014-0134-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 12/03/2014] [Indexed: 01/22/2023]
Abstract
Background The MedSeq Project is a randomized clinical trial developing approaches to assess the impact of integrating genome sequencing into clinical medicine. To facilitate the return of results of potential medical relevance to physicians and patients participating in the MedSeq Project, we sought to develop a reporting approach for the effective communication of such findings. Methods Genome sequencing was performed on the Illumina HiSeq platform. Variants were filtered, interpreted, and validated according to methods developed by the Laboratory for Molecular Medicine and consistent with current professional guidelines. The GeneInsight software suite, which is integrated with the Partners HealthCare electronic health record, was used for variant curation, report drafting, and delivery. Results We developed a concise 5–6 page Genome Report (GR) featuring a single-page summary of results of potential medical relevance with additional pages containing structured variant, gene, and disease information along with supporting evidence for reported variants and brief descriptions of associated diseases and clinical implications. The GR is formatted to provide a succinct summary of genomic findings, enabling physicians to take appropriate steps for disease diagnosis, prevention, and management in their patients. Conclusions Our experience highlights important considerations for the reporting of results of potential medical relevance and provides a framework for interpretation and reporting practices in clinical genome sequencing. Electronic supplementary material The online version of this article (doi:10.1186/s12881-014-0134-1) contains supplementary material, which is available to authorized users.
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Gene-Lifestyle Interactions in Complex Diseases: Design and Description of the GLACIER and VIKING Studies. Curr Nutr Rep 2014; 3:400-411. [PMID: 25396097 DOI: 10.1007/s13668-014-0100-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Most complex diseases have well-established genetic and non-genetic risk factors. In some instances, these risk factors are likely to interact, whereby their joint effects convey a level of risk that is either significantly more or less than the sum of these risks. Characterizing these gene-environment interactions may help elucidate the biology of complex diseases, as well as to guide strategies for their targeted prevention. In most cases, the detection of gene-environment interactions will require sample sizes in excess of those needed to detect the marginal effects of the genetic and environmental risk factors. Although many consortia have been formed, comprising multiple diverse cohorts to detect gene-environment interactions, few robust examples of such interactions have been discovered. This may be because combining data across studies, usually through meta-analysis of summary data from the contributing cohorts, is often a statistically inefficient approach for the detection of gene-environment interactions. Ideally, single, very large and well-genotyped prospective cohorts, with validated measures of environmental risk factor and disease outcomes should be used to study interactions. The presence of strong founder effects within those cohorts might further strengthen the capacity to detect novel genetic effects and gene-environment interactions. Access to accurate genealogical data would also aid in studying the diploid nature of the human genome, such as genomic imprinting (parent-of-origin effects). Here we describe two studies from northern Sweden (the GLACIER and VIKING studies) that fulfill these characteristics.
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Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features. PLoS One 2014; 9:e106906. [PMID: 25211237 PMCID: PMC4161373 DOI: 10.1371/journal.pone.0106906] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 08/11/2014] [Indexed: 11/20/2022] Open
Abstract
Background Wolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS. Methodology The minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing. Principal Findings Sixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations. Conclusion/Significance This study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.
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Varga TV, Sonestedt E, Shungin D, Koivula RW, Hallmans G, Escher SA, Barroso I, Nilsson P, Melander O, Orho-Melander M, Renström F, Franks PW. Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study. PLoS Genet 2014; 10:e1004388. [PMID: 24922540 PMCID: PMC4055682 DOI: 10.1371/journal.pgen.1004388] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 04/01/2014] [Indexed: 01/04/2023] Open
Abstract
Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0×10−11 for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0×10−5 for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0×10−5), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1×10−4) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4×10−8), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P≤0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels. Although large cross-sectional studies have proven highly successful in identifying gene variants related to lipid levels and other cardiometabolic traits, very few examples of well-designed longitudinal studies exist where associations between genotypes and long-term changes in lipids have been assessed. Here we undertook analyses in the GLACIER Study to determine whether the 157 previously identified lipid-associated genes variants associate with changes in blood lipid levels over 10-yr follow-up. We identified a variant in APOE that is robustly associated with total cholesterol change and two variants in TRIB1 and APOA1 respectively that are robustly associated with triglyceride change. We replicated these findings in a second Swedish cohort (the MDC Study). The identified genes had previously been associated with cardiovascular traits such as myocardial infarction or coronary heart disease; hence, these novel lipid associations provide additional insight into the pathogenesis of atherosclerotic heart and large vessel disease. By incorporating all 157 established variants into gene scores, we also observed strong associations with 10-yr lipid changes, illustrating the polygenic nature of blood lipid deterioration.
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Affiliation(s)
- Tibor V Varga
- Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - Emily Sonestedt
- Department of Clinical Sciences, Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden
| | - Dmitry Shungin
- Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Odontology, Umeå University, Umeå, Sweden; Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden
| | - Robert W Koivula
- Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - Göran Hallmans
- Department of Biobank Research, Umeå University, Umeå, Sweden
| | - Stefan A Escher
- Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - Inês Barroso
- NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
| | - Peter Nilsson
- Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Olle Melander
- Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, Skåne University Hospital, Malmö, Sweden
| | - Marju Orho-Melander
- Department of Clinical Sciences, Diabetes and Cardiovascular Disease - Genetic Epidemiology, Skåne University Hospital, Malmö, Sweden
| | - Frida Renström
- Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Biobank Research, Umeå University, Umeå, Sweden
| | - Paul W Franks
- Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America
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Bonnycastle LL, Chines PS, Hara T, Huyghe JR, Swift AJ, Heikinheimo P, Mahadevan J, Peltonen S, Huopio H, Nuutila P, Narisu N, Goldfeder RL, Stitzel ML, Lu S, Boehnke M, Urano F, Collins FS, Laakso M. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes 2013; 62:3943-50. [PMID: 23903355 PMCID: PMC3806620 DOI: 10.2337/db13-0571] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
We used an unbiased genome-wide approach to identify exonic variants segregating with diabetes in a multigenerational Finnish family. At least eight members of this family presented with diabetes with age of diagnosis ranging from 18 to 51 years and a pattern suggesting autosomal dominant inheritance. We sequenced the exomes of four affected members of this family and performed follow-up genotyping of additional affected and unaffected family members. We uncovered a novel nonsynonymous variant (p.Trp314Arg) in the Wolfram syndrome 1 (WFS1) gene that segregates completely with the diabetic phenotype. Multipoint parametric linkage analysis with 13 members of this family identified a single linkage signal with maximum logarithm of odds score 3.01 at 4p16.2-p16.1, corresponding to a region harboring the WFS1 locus. Functional studies demonstrate a role for this variant in endoplasmic reticulum stress, which is consistent with the β-cell failure phenotype seen in mutation carriers. This represents the first compelling report of a mutation in WFS1 associated with dominantly inherited nonsyndromic adult-onset diabetes.
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Affiliation(s)
| | - Peter S. Chines
- National Human Genome Research Institute, Bethesda, Maryland
| | - Takashi Hara
- Department of Medicine and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Jeroen R. Huyghe
- Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, Michigan
| | - Amy J. Swift
- National Human Genome Research Institute, Bethesda, Maryland
| | - Pirkko Heikinheimo
- Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland
| | - Jana Mahadevan
- Department of Medicine and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Sirkku Peltonen
- Department of Dermatology, University of Turku, Turku, Finland
| | - Hanna Huopio
- Department of Paediatrics, Kuopio University Hospital, Kuopio, Finland
| | - Pirjo Nuutila
- Department of Medicine and Turku PET Centre, University of Turku, Turku, Finland
- Department of Medicine and Turku PET Centre, Turku University Hospital, Turku, Finland
| | - Narisu Narisu
- National Human Genome Research Institute, Bethesda, Maryland
| | | | | | - Simin Lu
- Department of Medicine and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, Michigan
| | - Fumihiko Urano
- Department of Medicine and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Francis S. Collins
- National Human Genome Research Institute, Bethesda, Maryland
- Corresponding author: Francis S. Collins,
| | - Markku Laakso
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
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Abstract
Type 2 diabetes (T2D) is the result of interaction between environmental factors and a strong hereditary component. We review the heritability of T2D as well as the history of genetic and genomic research in this area. Very few T2D risk genes were identified using candidate gene and linkage-based studies, but the advent of genome-wide association studies has led to the identification of multiple genes, including several that were not previously known to play any role in T2D. Highly replicated genes, for example TCF7L2, KCNQ1 and KCNJ11, are discussed in greater detail. Taken together, the genetic loci discovered to date explain only a small proportion of the observed heritability. We discuss possible explanations for this “missing heritability”, including the role of rare variants, gene-environment interactions and epigenetics. The clinical utility of current findings and avenues of future research are also discussed.
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Varga TV, Hallmans G, Hu FB, Renström F, Franks PW. Smoking status, snus use, and variation at the CHRNA5-CHRNA3-CHRNB4 locus in relation to obesity: the GLACIER study. Am J Epidemiol 2013; 178:31-7. [PMID: 23729684 DOI: 10.1093/aje/kws413] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
A genetic variant within the CHRNA5-CHRNA3-CHRNB4 region (rs1051730), previously associated with smoking quantity, was recently shown to interact with smoking on obesity predisposition. We attempted to replicate this finding in the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk (GLACIER) Study, a prospective cohort study of adults from northern Sweden (n = 16,426). We also investigated whether a similar interaction is apparent between rs1051730 and snus, a type of moist oral tobacco, to determine whether this interaction is driven by factors that cigarettes and snus have in common, such as nicotine. Main effects of smoking, snus, and the rs1051730 variant and pairwise interaction terms (smoking × rs1051730 and snus × rs1051730) were tested in relation to body mass index (BMI; calculated as weight (kg)/height (m)²) through the use of multivariate linear models adjusted for age and sex. Smoking status and BMI were inversely related (β = -0.46 kg/m², standard error (SE) = 0.08; P < 0.0001). Snus use and BMI were positively related (β = 0.35 kg/m², SE = 0.12; P = 0.003). The rs1051730 variant was not significantly associated with smoking status or snus use (P > 0.05); the T allele was associated with lower BMI in the overall cohort (β = -0.10 kg/m², SE = 0.05; P = 0.03) and with smoking quantity in those in whom this was measured (n = 5,304) (β = 0.08, SE = 0.01; P < 0.0001). Neither smoking status (Pinteraction = 0.29) nor snus use (Pinteraction = 0.89) modified the association between the rs1051730 variant and BMI.
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Affiliation(s)
- Tibor V Varga
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital Malmö, Sweden
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Marshall BA, Permutt MA, Paciorkowski AR, Hoekel J, Karzon R, Wasson J, Viehover A, White NH, Shimony JS, Manwaring L, Austin P, Hullar TE, Hershey T. Phenotypic characteristics of early Wolfram syndrome. Orphanet J Rare Dis 2013; 8:64. [PMID: 23981289 PMCID: PMC3651298 DOI: 10.1186/1750-1172-8-64] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 04/16/2013] [Indexed: 01/22/2023] Open
Abstract
Background Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. Methods Eighteen subjects (ages 5.9–25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. Results Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. Conclusions WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression.
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WFS1 variants in Finnish patients with diabetes mellitus, sensorineural hearing impairment or optic atrophy, and in suicide victims. J Hum Genet 2013; 58:495-500. [PMID: 23595122 DOI: 10.1038/jhg.2013.29] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Revised: 01/02/2013] [Accepted: 03/26/2013] [Indexed: 11/09/2022]
Abstract
Mutations in the wolframin gene, WFS1, cause Wolfram syndrome, a rare recessive neurodegenerative disorder. The clinical features include early-onset bilateral optic atrophy (OA), diabetes mellitus (DM), diabetes insipidus, hearing impairment, urinary tract abnormalities and psychiatric illness, and, furthermore, WFS1 variants appear to be associated with non-syndromic DM and hearing impairment. Variation of WFS1 was investigated in Finnish subjects consisting 182 patients with DM, 117 patients with sensorineural hearing impairment (SNHI) and 44 patients with OA, and in 95 suicide victims. Twenty-two variants were found in the coding region of WFS1, including three novel nonsynonymous variants. The frequency of the p.[His456] allele was significantly higher in the patients with SNHI (11.5%; corrected P=0.00008), DM (6.6%; corrected P=0.036) or OA (9.1%; corrected P=0.043) than that in the 285 controls (3.3%). The frequency of the p.[His611] allele was 55.8% in the patients with DM being higher than that in the controls (47%; corrected P=0.039). The frequencies of p.[His456] and p.[His611] were similarly increased in an independent group of patients with DM (N=299). The results support previous findings that genetic variation of WFS1 contributes to the risk of DM and SNHI.
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Kerékgyártó M, Németh N, Kerekes T, Rónai Z, Guttman A. Ultrafast haplotyping of putative microRNA-binding sites in the WFS1 gene by multiplex polymerase chain reaction and capillary gel electrophoresis. J Chromatogr A 2013; 1286:229-34. [DOI: 10.1016/j.chroma.2013.02.062] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 02/19/2013] [Accepted: 02/19/2013] [Indexed: 10/27/2022]
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The role of the unfolded protein response in diabetes mellitus. Semin Immunopathol 2013; 35:333-50. [PMID: 23529219 DOI: 10.1007/s00281-013-0369-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 03/13/2013] [Indexed: 12/13/2022]
Abstract
The endoplasmic reticulum (ER) plays a key role in the synthesis and modification of secretory and membrane proteins in all eukaryotic cells. Under normal conditions, these proteins are correctly folded and assembled in the ER. However, when cells are exposed to environmental factors such as overproduction of ER proteins, viral infections, or glucose deprivation, the secretory and membrane proteins can accumulate in unfolded or misfolded forms in the lumen of the ER, and consequently, cause stress in the ER. To maintain cellular homeostasis, cells induce several responses to ER stress. In mammalian cells, ER stress responses are induced by a diversity of signal pathways. There are three ER-located transmembrane proteins that play important roles in mammalian ER stress responses: activating transcription factor 6, inositol-requiring protein 1, and protein kinase RNA-like endoplasmic reticulum kinase. ER stress is linked to various diseases, including diabetes. This review highlights the particular importance of ER stress-responsive molecules in insulin biosynthesis, glyconeogenesis, insulin resistance, glucose intolerance, and pancreatic β-cell apoptosis. An understanding of the pathogenic mechanism of diabetes from the aspect of ER stress is crucial in formulating therapeutic strategies.
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Abstract
Type 2 diabetes (T2D) has become a leading health problem throughout the world. It is caused by environmental and genetic factors, as well as interactions between the two. However, until very recently, the T2D susceptibility genes have been poorly understood. During the past 5 years, with the advent of genome-wide association studies (GWAS), a total of 58 T2D susceptibility loci have been associated with T2D risk at a genome-wide significance level (P < 5 × 10(-8) ), with evidence showing that most of these genetic variants influence pancreatic β-cell function. Most novel T2D susceptibility loci were identified through GWAS in European populations and later confirmed in other ethnic groups. Although the recent discovery of novel T2D susceptibility loci has contributed substantially to our understanding of the pathophysiology of the disease, the clinical utility of these loci in disease prediction and prognosis is limited. More studies using multi-ethnic meta-analysis, gene-environment interaction analysis, sequencing analysis, epigenetic analysis, and functional experiments are needed to identify new susceptibility T2D loci and causal variants, and to establish biological mechanisms.
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Affiliation(s)
- Qibin Qi
- Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA
| | - Frank B. Hu
- Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA
- Department of Epidemiology, Harvard School of Public Health, Boston
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston
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Abstract
Polygenic type 2 diabetes mellitus (T2DM) is a multi-factorial disease due to the interplay between genes and the environment. Over the years, several genes/loci have been associated with this type of diabetes, with the majority of them being related to β cell dysfunction. In this review, the available information on how polymorphisms in T2DM-associated genes/loci do directly affect the properties of human islet cells are presented and discussed, including some clinical implications and the role of epigenetic mechanisms.
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Affiliation(s)
- Piero Marchetti
- Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
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Abstract
A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.
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Affiliation(s)
- Shiyu Wang
- Degenerative Disease Research Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
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35
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Vaxillaire M, Bonnefond A, Froguel P. The lessons of early-onset monogenic diabetes for the understanding of diabetes pathogenesis. Best Pract Res Clin Endocrinol Metab 2012; 26:171-87. [PMID: 22498247 DOI: 10.1016/j.beem.2011.12.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Monogenic diabetes consists of different subtypes of single gene disorders comprising a large spectrum of phenotypes, namely neonatal diabetes mellitus or monogenic diabetes of infancy, dominantly inherited familial forms of early-onset diabetes (called Maturity-Onset Diabetes of the Young) and rarer diabetes-associated syndromic diseases. All these forms diagnosed at a very-young age are unrelated to auto-immunity. Their genetic dissection has revealed major genes in developmental and/or functional processes of the pancreatic β-cell physiology, and various molecular mechanisms underlying the primary pancreatic defects. Most of these discoveries have had remarkable consequences on the patients care and patient's long-term condition with outstanding examples of successful genomic medicine, which are highlighted in this chapter. Increasing evidence also shows that frequent polymorphisms in or near monogenic diabetes genes may contribute to adult polygenic type 2 diabetes. In this regard, unelucidated forms of monogenic diabetes represent invaluable models for identifying new targets of β-cell dysfunction.
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Affiliation(s)
- Martine Vaxillaire
- Centre National de la Recherche Scientifique UMR, Genomics and Metabolic Diseases, Lille Pasteur Institute, Lille Nord de France University, France.
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Lilja M, Rolandsson O, Norberg M, Söderberg S. The impact of leptin and adiponectin on incident type 2 diabetes is modified by sex and insulin resistance. Metab Syndr Relat Disord 2012; 10:143-51. [PMID: 22283633 DOI: 10.1089/met.2011.0123] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Adiponectin and leptin and their ratio have been associated with incident type 2 diabetes (T2DM), although the data presented are conflicting and the populations studied have been small. In this large, prospective, nested, case referent study, we hypothesized that these associations are sex specific and may be modified by insulin resistance. METHODS Men and women aged 30-60 years with incident T2DM (n=640) and a prior health survey within the Västerbotten Intervention Programme (VIP) and matched referents (n=1564) were identified. Using conditional logistic regression analyses, we tested whether baseline plasma adiponectin and leptin levels and their ratio independently predicted incident T2DM, stratified for gender and insulin resistance. RESULTS Adjusted for traditional risk factors, fourth-quartile levels of adiponectin were associated with a reduced risk of T2DM in men [odds ratio (OR) 0.55 (0.36-0.86)] and women [OR 0.47 (0.27-0.83)]. Quartile four of the leptin/adiponectin ratio predicted T2DM in both men [OR 3.08 (1.68-5.67)] and women [OR 3.31 (1.56-7.03)], whereas quartile-four levels of leptin predicted T2DM only in men [OR 2.30 (1.32-4.02)]. When stratified for insulin sensitivity and adjusted for body mass index (BMI), log(e)-transformed leptin predicted T2DM in insulin-sensitive men [OR 1.56 (1.13-2.17)] but not in insulin-resistant men [OR 1.03 (0.76-1.39)]. The effect of adiponectin and the leptin/adiponectin ratio was not influenced by the insulin sensitivity status. CONCLUSIONS Leptin in men and adiponectin in both sexes were independent predictors of T2DM. The association was modified by the degree of insulin sensitivity. The leptin/adiponectin ratio may add predictive information beyond the separate hormones.
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Affiliation(s)
- Mikael Lilja
- The Research and Development Unit, Jämtland County Council, Östersund, Sweden.
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37
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Schäfer SA, Machicao F, Fritsche A, Häring HU, Kantartzis K. New type 2 diabetes risk genes provide new insights in insulin secretion mechanisms. Diabetes Res Clin Pract 2011; 93 Suppl 1:S9-24. [PMID: 21864758 DOI: 10.1016/s0168-8227(11)70008-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes results from the inability of beta cells to increase insulin secretion sufficiently to compensate for insulin resistance. Insulin resistance is thought to result mainly from environmental factors, such as obesity. However, there is compelling evidence that the decline of both insulin sensitivity and insulin secretion have also a genetic component. Recent genome-wide association studies identified several novel risk genes for type 2 diabetes. The vast majority of these genes affect beta cell function by molecular mechanisms that remain unknown in detail. Nevertheless, we and others could show that a group of genes affect glucose-stimulated insulin secretion, a group incretin-stimulated insulin secretion (incretin sensitivity or secretion) and a group proinsulin-to-insulin conversion. The most important so far type 2 diabetes risk gene, TCF7L2, interferes with all three mechanisms. In addition to advancing knowledge in the pathophysiology of type 2 diabetes, the discovery of novel genetic determinants of diabetes susceptibility may help understanding of gene-environment, gene-therapy and gene-gene interactions. It was also hoped that it could make determination of the individual risk for type 2 diabetes feasible. However, the allelic relative risks of most genetic variants discovered so far are relatively low. Thus, at present, clinical criteria assess the risk for type 2 diabetes with greater sensitivity and specificity than the combination of all known genetic variants.
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Affiliation(s)
- Silke A Schäfer
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University of Tübingen, Germany
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Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic β-cell death. Trends Endocrinol Metab 2011; 22:266-74. [PMID: 21458293 PMCID: PMC3130122 DOI: 10.1016/j.tem.2011.02.008] [Citation(s) in RCA: 194] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2010] [Revised: 01/31/2011] [Accepted: 02/23/2011] [Indexed: 12/12/2022]
Abstract
In pancreatic β-cells, the endoplasmic reticulum (ER) is an important cellular compartment for insulin biosynthesis, which accounts for half of the total protein production in these cells. Protein flux through the ER must be carefully monitored to prevent dysregulation of ER homeostasis and stress. ER stress elicits a signaling cascade known as the unfolded protein response (UPR), which influences both life and death decisions in cells. β-cell loss is a pathological component of both type 1 and type 2 diabetes, and recent findings suggest that ER stress is involved. In this review, we address the transition from the physiological ER stress response to the pathological response, and explore the mechanisms of ER stress-mediated β-cell loss during the progression of diabetes.
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Affiliation(s)
- Sonya G. Fonseca
- Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Jesper Gromada
- Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Fumihiko Urano
- Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, U.S.A
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Rees SD, Hydrie MZI, Shera AS, Kumar S, O'Hare JP, Barnett AH, Basit A, Kelly MA. Replication of 13 genome-wide association (GWA)-validated risk variants for type 2 diabetes in Pakistani populations. Diabetologia 2011; 54:1368-74. [PMID: 21350842 DOI: 10.1007/s00125-011-2063-2] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2010] [Accepted: 01/05/2011] [Indexed: 12/29/2022]
Abstract
AIMS/HYPOTHESIS Recent genome-wide association (GWA) studies and subsequent replication studies have greatly increased the number of validated type 2 diabetes susceptibility variants, but most of these have been conducted in European populations. Despite the high prevalence of the disease in South Asians, studies investigating GWA-validated type 2 diabetes risk variants in this ethnic group are limited. We investigated 30 single nucleotide polymorphisms (SNPs), predominantly derived from recent GWA studies, to determine if and to what extent these variants affect type 2 diabetes risk in two Punjabi populations, originating predominantly from the District of Mirpur, Pakistan. METHODS Thirty SNPs were genotyped in 1,678 participants with type 2 diabetes and 1,584 normoglycaemic control participants from two populations; one resident in the UK and one indigenous to the District of Mirpur. RESULTS SNPs in or near PPARG, TCF7L2, FTO, CDKN2A/2B, HHEX/IDE, IGF2BP2, SLC30A8, KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 displayed significant (p < 0.05) associations with type 2 diabetes, with similar effect sizes to those seen in European populations. A constructed genetic risk score was associated with type 2 diabetes (p = 5.46 × 10(-12)), BMI (p = 2.25 × 10(-4)) and age at onset of diabetes (p = 0.002). CONCLUSIONS/INTERPRETATION We have demonstrated that 13 variants confer an increased risk of type 2 diabetes in our Pakistani populations; to our knowledge this is the first time that SNPs in or near KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 have been significantly associated with the disease in South Asians. Large-scale studies and meta-analyses of South Asian populations are needed to further confirm the effect of these variants in this ethnic group.
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Affiliation(s)
- S D Rees
- Diabetes Research Laboratory, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The Medical School, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK.
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40
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Sim X, Ong RTH, Suo C, Tay WT, Liu J, Ng DPK, Boehnke M, Chia KS, Wong TY, Seielstad M, Teo YY, Tai ES. Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia. PLoS Genet 2011; 7:e1001363. [PMID: 21490949 PMCID: PMC3072366 DOI: 10.1371/journal.pgen.1001363] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Accepted: 03/04/2011] [Indexed: 12/24/2022] Open
Abstract
Recent large genome-wide association studies (GWAS) have identified multiple loci
which harbor genetic variants associated with type 2 diabetes mellitus (T2D),
many of which encode proteins not previously suspected to be involved in the
pathogenesis of T2D. Most GWAS for T2D have focused on populations of European
descent, and GWAS conducted in other populations with different ancestry offer a
unique opportunity to study the genetic architecture of T2D. We performed
genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945
controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians
(977 cases, 1,169 controls). In addition to the search for novel variants
implicated in T2D, these multi-ethnic cohorts serve to assess the
transferability and relevance of the previous findings from European descent
populations in the three major ethnic populations of Asia, comprising half of
the world's population. Of the SNPs associated with T2D in previous GWAS,
only variants at CDKAL1 and
HHEX/IDE/KIF11 showed the strongest
association with T2D in the meta-analysis including all three ethnic groups.
However, consistent direction of effect was observed for many of the other SNPs
in our study and in those carried out in European populations. Close examination
of the associations at both the CDKAL1 and
HHEX/IDE/KIF11 loci provided some evidence of locus and
allelic heterogeneity in relation to the associations with T2D. We also detected
variation in linkage disequilibrium between populations for most of these loci
that have been previously identified. These factors, combined with limited
statistical power, may contribute to the failure to detect associations across
populations of diverse ethnicity. These findings highlight the value of
surveying across diverse racial/ethnic groups towards the fine-mapping efforts
for the casual variants and also of the search for variants, which may be
population-specific. Type 2 diabetes mellitus (T2D) is a chronic disease which can lead to
complications such as heart disease, stroke, hypertension, blindness due to
diabetic retinopathy, amputations from peripheral vascular diseases, and kidney
disease from diabetic nephropathy. The increasing prevalence and complications
of T2D are likely to increase the health and economic burden of individuals,
families, health systems, and countries. Our study carried out in three major
Asian ethnic groups (Chinese, Malays, and Indians) in Singapore suggests that
the findings of studies carried out in populations of European ancestry (which
represents most studies to date) may be relevant to populations in Asia.
However, our study also raises the possibility that different genes, and within
the genes different variants, may confer susceptibility to T2D in these
populations. These findings are particularly relevant in Asia, where the
greatest growth of T2D is expected in the coming years, and emphasize the
importance of studying diverse populations when trying to localize the regions
of the genome associated with T2D. In addition, we may need to consider novel
methods for combining data across populations.
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Affiliation(s)
- Xueling Sim
- Centre for Molecular Epidemiology, National University of Singapore,
Singapore, Singapore
| | - Rick Twee-Hee Ong
- Centre for Molecular Epidemiology, National University of Singapore,
Singapore, Singapore
- NUS Graduate School for Integrative Science and Engineering, National
University of Singapore, Singapore, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and
Research, Singapore, Singapore
| | - Chen Suo
- Centre for Molecular Epidemiology, National University of Singapore,
Singapore, Singapore
| | - Wan-Ting Tay
- Singapore Eye Research Institute, Singapore National Eye Centre,
Singapore, Singapore
| | - Jianjun Liu
- Genome Institute of Singapore, Agency for Science, Technology and
Research, Singapore, Singapore
| | - Daniel Peng-Keat Ng
- Department of Epidemiology and Public Health, National University of
Singapore, Singapore, Singapore
| | - Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, School
of Public Health, University of Michigan, Ann Arbor, Michigan, United States of
America
| | - Kee-Seng Chia
- Centre for Molecular Epidemiology, National University of Singapore,
Singapore, Singapore
- Department of Epidemiology and Public Health, National University of
Singapore, Singapore, Singapore
| | - Tien-Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Centre,
Singapore, Singapore
- Department of Epidemiology and Public Health, National University of
Singapore, Singapore, Singapore
- Department of Ophthalmology, National University of Singapore, Singapore,
Singapore
- Centre for Eye Research Australia, University of Melbourne, Melbourne,
Australia
| | - Mark Seielstad
- Genome Institute of Singapore, Agency for Science, Technology and
Research, Singapore, Singapore
| | - Yik-Ying Teo
- Centre for Molecular Epidemiology, National University of Singapore,
Singapore, Singapore
- NUS Graduate School for Integrative Science and Engineering, National
University of Singapore, Singapore, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and
Research, Singapore, Singapore
- Department of Epidemiology and Public Health, National University of
Singapore, Singapore, Singapore
- Department of Statistics and Applied Probability, National University of
Singapore, Singapore, Singapore
- * E-mail: (E-ST); (Y-YT)
| | - E-Shyong Tai
- Department of Epidemiology and Public Health, National University of
Singapore, Singapore, Singapore
- Department of Medicine, National University of Singapore, Singapore,
Singapore
- Duke-National University of Singapore Graduate Medical School, Singapore,
Singapore
- * E-mail: (E-ST); (Y-YT)
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Cheurfa N, Brenner GM, Reis AF, Dubois-Laforgue D, Roussel R, Tichet J, Lantieri O, Balkau B, Fumeron F, Timsit J, Marre M, Velho G. Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study. Diabetologia 2011; 54:554-62. [PMID: 21127832 DOI: 10.1007/s00125-010-1989-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Accepted: 10/22/2010] [Indexed: 12/01/2022]
Abstract
AIMS/HYPOTHESIS We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. METHODS We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. RESULTS We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. CONCLUSIONS/INTERPRETATION The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.
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Affiliation(s)
- N Cheurfa
- INSERM, Research Unit 695, 16 rue Henri Huchard, 75018, Paris, France
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Chistiakov DA, Khodyrev DS, Smetanina SA, Bel'chikova LN, Suplotova LA, Nosikov VV. A WFS1 haplotype consisting of the minor alleles of rs752854, rs10010131, and rs734312 shows a protective role against type 2 diabetes in Russian patients. Rev Diabet Stud 2011; 7:285-92. [PMID: 21713316 DOI: 10.1900/rds.2010.7.285] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Rare variants of the WFS1 gene encoding wolframin cause Wolfram syndrome, a monogenic disease associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. In contrast, common variants of WFS1 showed association with type 2 diabetes (T2D) in numerous Caucasian populations. AIM In this study, we tested whether the markers rs752854, rs10010131, and rs734312, located in the WFS1 gene, are related to the development of T2D in a Russian population. METHODS The polymorphic markers were genotyped in Russian diabetic (n = 1,112) and non-diabetic (n = 1,097) patients using a Taqman allele discrimination assay. The correlation between the carriage of disease-associated WFS1 variants and the patients' clinical and metabolic characteristics was studied using ANOVA and ANCOVA. Adjustment for confounding variables such as gender, age, body mass index, obesity, HbA1c, and hypertension was made. RESULTS Haplotype GAG, consisting of the minor alleles of rs752854, rs10010131, and rs734312, respectively, showed association with decreased risk of T2D (OR = 0.44, 95% CI = 0.32-0.61, p = 4.3 x 10(-7)). Compared to other WFS1 variants, non-diabetic individuals homozygous for GAG/CAG had significantly increased fasting insulin (p(adjusted) = 0.047) and homeostasis model assessment of β-cell function (HOMA-β) index (p(adjusted) = 0.006). Diabetic patients homozygous for GAG/GAG showed significantly elevated levels of 2-h insulin (p(adjusted) = 0.029) and HOMA-β = 0.011. CONCLUSIONS Disease-associated variants of WFS1 contribute to the pathogenesis of T2D through impaired insulin response to glucose stimulation and altered β-cell function.
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Abstract
BACKGROUND
Type 2 diabetes (T2D) is a complex disorder that is affected by multiple genetic and environmental factors. Extensive efforts have been made to identify the disease-affecting genes to better understand the disease pathogenesis, find new targets for clinical therapy, and allow prediction of disease.
CONTENT
Our knowledge about the genes involved in disease pathogenesis has increased substantially in recent years, thanks to genomewide association studies and international collaborations joining efforts to collect the huge numbers of individuals needed to study complex diseases on a population level. We have summarized what we have learned so far about the genes that affect T2D risk and their functions. Although more than 40 loci associated with T2D or glycemic traits have been reported and reproduced, only a minor part of the genetic component of the disease has been explained, and the causative variants and affected genes are unknown for many of the loci.
SUMMARY
Great advances have recently occurred in our understanding of the genetics of T2D, but much remains to be learned about the disease etiology. The genetics of T2D has so far been driven by technology, and we now hope that next-generation sequencing will provide important information on rare variants with stronger effects. Even when variants are known, however, great effort will be required to discover how they affect disease risk.
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Affiliation(s)
- Emma Ahlqvist
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Tarunveer Singh Ahluwalia
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Leif Groop
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, Skåne University Hospital, Malmö, Sweden
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45
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Renström F, Shungin D, Johansson I, Florez JC, Hallmans G, Hu FB, Franks PW. Genetic predisposition to long-term nondiabetic deteriorations in glucose homeostasis: Ten-year follow-up of the GLACIER study. Diabetes 2011; 60:345-54. [PMID: 20870969 PMCID: PMC3012192 DOI: 10.2337/db10-0933] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVE To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits. RESEARCH DESIGN AND METHODS Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER) Study, a population-based prospective cohort study from northern Sweden. Genotypes were tested for association with baseline fasting and 2-h postchallenge glycemia (N = 16,330), and for changes in these glycemic traits during a 10-year follow-up period (N = 4,059). RESULTS Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12 of 16 variants; 10 variants were also associated with impaired fasting glucose (IFG) and 7 were independently associated with 2-h postchallenge glucose concentrations. In prospective analyses, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, and G6PC2 rs560887) were nominally associated with worsening fasting glucose concentrations during 10-years of follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on postchallenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-h glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80th vs. 20th centiles) was associated with a 0.16 mmol/l (P = 2.4 × 10⁻⁶) greater elevation in fasting glucose and a 64% (95% CI: 33-201%) higher risk of developing IFG during 10 years of follow-up. CONCLUSIONS Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant.
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Affiliation(s)
- Frida Renström
- Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
- Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
| | - Dmitry Shungin
- Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
- Department of Odontology, Umeå University Hospital, Umeå, Sweden
| | | | - the MAGIC Investigators
- Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, U.K
| | - Jose C. Florez
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Göran Hallmans
- Department of Public Health and Clinical Medicine, Section for Nutritional Research, Umeå University Hospital, Umeå, Sweden
| | - Frank B. Hu
- Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
| | - Paul W. Franks
- Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
- Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
- Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden
- Corresponding author: Paul W. Franks,
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Oslowski CM, Urano F. The binary switch that controls the life and death decisions of ER stressed β cells. Curr Opin Cell Biol 2010; 23:207-15. [PMID: 21168319 DOI: 10.1016/j.ceb.2010.11.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Revised: 11/15/2010] [Accepted: 11/20/2010] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus is a group of common metabolic disorders defined by hyperglycemia. One of the most important factors contributing to hyperglycemia is dysfunction and death of β cells. Increasing experimental, clinical, and genetic evidence indicates that endoplasmic reticulum (ER) stress plays an important role in β cell dysfunction and death during the progression of type 1 and type 2 diabetes as well as genetic forms of diabetes such as Wolfram syndrome. The mechanisms of ER stress-mediated β cell dysfunction and death are complex and not homogenous. Here we review the recent key findings on the role of ER stress and the unfolded protein response (UPR) in β cells and the mechanisms of ER stress-mediated β cell dysfunction and death. Complete understanding of these mechanisms will lead to novel therapeutic modalities for diabetes.
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Affiliation(s)
- Christine M Oslowski
- Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA
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47
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Affiliation(s)
- Mark I McCarthy
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford OX3 7LJ, United Kingdom
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Alimadadi A, Ebrahim-Habibi A, Abbasi F, Amoli MM, Sayahpour FA, Larijani B. Novel mutations of wolframin: a report with a look at the protein structure. Clin Genet 2010; 79:96-9. [DOI: 10.1111/j.1399-0004.2010.01511.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Fontaine-Bisson B, Renström F, Rolandsson O, Payne F, Hallmans G, Barroso I, Franks PW. Evaluating the discriminative power of multi-trait genetic risk scores for type 2 diabetes in a northern Swedish population. Diabetologia 2010; 53:2155-62. [PMID: 20571754 PMCID: PMC2931645 DOI: 10.1007/s00125-010-1792-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Accepted: 04/13/2010] [Indexed: 01/26/2023]
Abstract
AIMS/HYPOTHESIS We determined whether single nucleotide polymorphisms (SNPs) previously associated with diabetogenic traits improve the discriminative power of a type 2 diabetes genetic risk score. METHODS Participants (n = 2,751) were genotyped for 73 SNPs previously associated with type 2 diabetes, fasting glucose/insulin concentrations, obesity or lipid levels, from which five genetic risk scores (one for each of the four traits and one combining all SNPs) were computed. Type 2 diabetes patients and non-diabetic controls (n = 1,327/1,424) were identified using medical records in addition to an independent oral glucose tolerance test. RESULTS Model 1, including only SNPs associated with type 2 diabetes, had a discriminative power of 0.591 (p < 1.00 x 10(-20) vs null model) as estimated by the area under the receiver operator characteristic curve (ROC AUC). Model 2, including only fasting glucose/insulin SNPs, had a significantly higher discriminative power than the null model (ROC AUC 0.543; p = 9.38 x 10(-6) vs null model), but lower discriminative power than model 1 (p = 5.92 x 10(-5)). Model 3, with only lipid-associated SNPs, had significantly higher discriminative power than the null model (ROC AUC 0.565; p = 1.44 x 10(-9)) and was not statistically different from model 1 (p = 0.083). The ROC AUC of model 4, which included only obesity SNPs, was 0.557 (p = 2.30 x 10(-7) vs null model) and smaller than model 1 (p = 0.025). Finally, the model including all SNPs yielded a significant improvement in discriminative power compared with the null model (p < 1.0 x 10(-20)) and model 1 (p = 1.32 x 10(-5)); its ROC AUC was 0.626. CONCLUSIONS/INTERPRETATION Adding SNPs previously associated with fasting glucose, insulin, lipids or obesity to a genetic risk score for type 2 diabetes significantly increases the power to discriminate between people with and without clinically manifest type 2 diabetes compared with a model including only conventional type 2 diabetes loci.
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Affiliation(s)
- B. Fontaine-Bisson
- Department of Nutrition Sciences, University of Ottawa, Ottawa, ON Canada
| | - F. Renström
- Genetic Epidemiology & Clinical Research Group, Department of Public Health & Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
| | - O. Rolandsson
- Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University Hospital, Umeå, Sweden
| | - The MAGIC investigators
- Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
| | - F. Payne
- Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
| | - G. Hallmans
- Department of Public Health & Clinical Medicine, Section for Nutritional Research, Umeå University Hospital, Umeå, Sweden
| | - I. Barroso
- Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK
- University of Cambridge Metabolic Research Labs, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
| | - P. W. Franks
- Genetic Epidemiology & Clinical Research Group, Department of Public Health & Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
- Department of Clinical Sciences, Lund University, Malmö, Sweden
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Morgan AR, Thompson JMD, Murphy R, Black PN, Lam WJ, Ferguson LR, Mitchell EA. Obesity and diabetes genes are associated with being born small for gestational age: results from the Auckland Birthweight Collaborative study. BMC MEDICAL GENETICS 2010; 11:125. [PMID: 20712903 PMCID: PMC2928774 DOI: 10.1186/1471-2350-11-125] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Accepted: 08/16/2010] [Indexed: 01/01/2023]
Abstract
Background Individuals born small for gestational age (SGA) are at increased risk of rapid postnatal weight gain, later obesity and diseases in adulthood such as type 2 diabetes, hypertension and cardiovascular diseases. Environmental risk factors for SGA are well established and include smoking, low pregnancy weight, maternal short stature, maternal diet, ethnic origin of mother and hypertension. However, in a large proportion of SGA, no underlying cause is evident, and these individuals may have a larger genetic contribution. Methods In this study we tested the association between SGA and polymorphisms in genes that have previously been associated with obesity and/or diabetes. We undertook analysis of 54 single nucleotide polymorphisms (SNPs) in 546 samples from the Auckland Birthweight Collaborative (ABC) study. 227 children were born small for gestational age (SGA) and 319 were appropriate for gestational age (AGA). Results and Conclusion The results demonstrated that genetic variation in KCNJ11, BDNF, PFKP, PTER and SEC16B were associated with SGA and support the concept that genetic factors associated with obesity and/or type 2 diabetes are more prevalent in those born SGA compared to those born AGA. We have previously determined that environmental factors are associated with differences in birthweight in the ABC study and now we have demonstrated a significant genetic contribution, suggesting that the interaction between genetics and the environment are important.
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Affiliation(s)
- Angharad R Morgan
- Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
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