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Shamsad A, Gautam T, Singh R, Banerjee M. Genetic and epigenetic alterations associated with gestational diabetes mellitus and adverse neonatal outcomes. World J Clin Pediatr 2025; 14:99231. [DOI: 10.5409/wjcp.v14.i1.99231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/03/2024] [Accepted: 10/31/2024] [Indexed: 12/20/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disorder, recognised during 24-28 weeks of pregnancy. GDM is linked with adverse newborn outcomes such as macrosomia, premature delivery, metabolic disorder, cardiovascular, and neurological disorders. Recent investigations have focused on the correlation of genetic factors such as β-cell function and insulin secretary genes (transcription factor 7 like 2, potassium voltage-gated channel subfamily q member 1, adiponectin etc.) on maternal metabolism during gestation leading to GDM. Epigenetic alterations like DNA methylation, histone modification, and miRNA expression can influence gene expression and play a dominant role in feto-maternal metabolic pathways. Interactions between genes and environment, resulting in differential gene expression patterns may lead to GDM. Researchers suggested that GDM women are more susceptible to insulin resistance, which alters intrauterine surroundings, resulting hyperglycemia and hyperinsulinemia. Epigenetic modifications in genes affecting neuroendocrine activities, and metabolism, increase the risk of obesity and type 2 diabetes in offspring. There is currently no treatment or effective preventive method for GDM, since the molecular processes of insulin resistance are not well understood. The present review was undertaken to understand the pathophysiology of GDM and its effects on adverse neonatal outcomes. In addition, the study of genetic and epigenetic alterations will provide lead to researchers in the search for predictive molecular biomarkers.
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Affiliation(s)
- Amreen Shamsad
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Tanu Gautam
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Renu Singh
- Department of Obstetrics and Gynecology, King George’s Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Monisha Banerjee
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
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Nikolaev G, Robeva R, Konakchieva R. Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease. Int J Mol Sci 2021; 23:ijms23010471. [PMID: 35008896 PMCID: PMC8745360 DOI: 10.3390/ijms23010471] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
The pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology-for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer.
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Affiliation(s)
- Georgi Nikolaev
- Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1504 Sofia, Bulgaria;
- Correspondence:
| | - Ralitsa Robeva
- Department of Endocrinology, Faculty of Medicine, Medical University, 1431 Sofia, Bulgaria;
| | - Rossitza Konakchieva
- Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1504 Sofia, Bulgaria;
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Popova PV, Klyushina AA, Vasilyeva LB, Tkachuk AS, Vasukova EA, Anopova AD, Pustozerov EA, Gorelova IV, Kravchuk EN, Li O, Pervunina TM, Kostareva AA, Grineva EN. Association of Common Genetic Risk Variants With Gestational Diabetes Mellitus and Their Role in GDM Prediction. Front Endocrinol (Lausanne) 2021; 12:628582. [PMID: 33953693 PMCID: PMC8092356 DOI: 10.3389/fendo.2021.628582] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/23/2021] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE We aimed to explore the associations between common genetic risk variants with gestational diabetes mellitus (GDM) risk in Russian women and to assess their utility in the identification of GDM cases. METHODS We conducted a case-control study including 1,142 pregnant women (688 GDM cases and 454 controls) enrolled at Almazov National Medical Research Centre. The International Association of Diabetes and Pregnancy Study Groups criteria were used to diagnose GDM. A total of 11 single- nucleotide polymorphisms (SNPs), including those in HKDC1 (rs10762264), GCK (rs1799884), MTNR1B (rs10830963 and rs1387153), TCF7L2 (rs7903146 and rs12255372), KCNJ11 (rs5219), IGF2BP2 (rs4402960), IRS1 (rs1801278), FTO (rs9939609), and CDKAL1 (rs7754840) were genotyped using Taqman assays. A logistic regression model was used to calculate odds ratios (ORs) and their confidence intervals (CIs). A simple-count genetic risk score (GRS) was calculated using 6 SNPs. The area under the receiver operating characteristic curve (c-statistic) was calculated for the logistic regression model predicting the risk of GDM using clinical covariates, SNPs that had shown a significant association with GDM in our study, GRS, and their combinations. RESULTS Two variants in MTNR1B (rs1387153 and rs10830963) demonstrated a significant association with an increased risk of GDM. The association remained significant after adjustment for age, pre-gestational BMI, arterial hypertension, GDM in history, impaired glucose tolerance, polycystic ovary syndrome, family history of diabetes, and parity (P = 0.001 and P < 0.001, respectively). After being conditioned by each other, the effect of rs1387153 on GDM predisposition weakened while the effect of rs10830963 remained significant (P = 0.004). The risk of GDM was predicted by clinical variables (c-statistic 0.712, 95 % CI: 0.675 - 0.749), and the accuracy of prediction was modestly improved by adding GRS to the model (0.719, 95 % CI 0.682 - 0.755), and more by adding only rs10830963 (0.729, 95 % CI 0.693 - 0.764). CONCLUSION Among 11 SNPs associated with T2D and/or GDM in other populations, we confirmed significant association with GDM for two variants in MTNR1B in Russian women. However, these variants showed limited value in the identification of GDM cases.
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Affiliation(s)
- Polina V. Popova
- Almazov National Medical Research Centre, Saint Petersburg, Russia
- Department of Internal Diseases and Endocrinology, St. Petersburg Pavlov State Medical University, Saint Petersburg, Russia
- *Correspondence: Polina V. Popova,
| | | | | | | | | | - Anna D. Anopova
- Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Evgenii A. Pustozerov
- Almazov National Medical Research Centre, Saint Petersburg, Russia
- Department of Biomedical Engineering, Saint Petersburg State Electrotechnical University, Saint Petersburg, Russia
| | - Inga V. Gorelova
- Almazov National Medical Research Centre, Saint Petersburg, Russia
| | | | - O. Li
- Almazov National Medical Research Centre, Saint Petersburg, Russia
| | | | | | - Elena N. Grineva
- Almazov National Medical Research Centre, Saint Petersburg, Russia
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Abstract
PURPOSE OF REVIEW In this review, we summarize studies investigating genetics of gestational diabetes mellitus (GDM) and glucose metabolism in pregnancy. We describe these studies in the context of the larger body of literature on type 2 diabetes (T2D) and glycemic trait genomics. RECENT FINDINGS We reviewed 23 genetic association studies for GDM and performed a meta-analysis, which revealed variants at eight T2D loci significantly associated with GDM after the Bonferroni correction. These studies suggest that GDM and T2D share a number of genetic risk loci. Only two unbiased genome-wide association studies (GWASs) have successfully revealed genetic associations for GDM and related glycemic traits in pregnancy. A GWAS for GDM in Korean women identified two loci (near CDKAL1 and MTNR1B) known to be associated with T2D, though the association of the MTNR1B locus with GDM appears to be stronger than that for T2D. A multi-ethnic GWAS for glycemic traits in pregnancy identified two novel loci (near HKDC1 and BACE2) which appear to be associated with post-load glucose and fasting c-peptide specifically in pregnant women. There are ongoing efforts to use this genetic information, in the form of polygenic scores, to predict risk of GDM and postpartum T2D. The body of literature examining genetic associations with GDM is limited, especially when compared to the available literature on T2D and glycemic trait genomics. Additional genetic discovery for glucose metabolism in pregnant women will require larger pregnancy cohorts and international collaborative efforts. Studies on the clinical implications of these findings are also warranted.
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Affiliation(s)
- Camille E Powe
- Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Soo Heon Kwak
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
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Sorlí JV, Barragán R, Coltell O, Portolés O, Pascual EC, Ortega-Azorín C, González JI, Estruch R, Saiz C, Pérez-Fidalgo A, Ordovas JM, Corella D. Chronological Age Interacts with the Circadian Melatonin Receptor 1B Gene Variation, Determining Fasting Glucose Concentrations in Mediterranean Populations. Additional Analyses on Type-2 Diabetes Risk. Nutrients 2020; 12:nu12113323. [PMID: 33138317 PMCID: PMC7692445 DOI: 10.3390/nu12113323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/21/2020] [Accepted: 10/24/2020] [Indexed: 12/25/2022] Open
Abstract
Gene-age interactions have not been systematically investigated on metabolic phenotypes and this modulation will be key for a better understanding of the temporal regulation in nutrigenomics. Taking into account that aging is typically associated with both impairment of the circadian system and a decrease in melatonin secretion, we focused on the melatonin receptor 1B (MTNR1B)-rs10830963 C>G variant that has been associated with fasting glucose concentrations, gestational diabetes, and type-2 diabetes. Therefore, our main aim was to investigate whether the association between the MTNR1B-rs10830963 polymorphism and fasting glucose is age dependent. Our secondary aims were to analyze the polymorphism association with type-2 diabetes and explore the gene-pregnancies interactions on the later type-2 diabetes risk. Three Mediterranean cohorts (n = 2823) were analyzed. First, a cross-sectional study in the discovery cohort consisting of 1378 participants (aged 18 to 80 years; mean age 41 years) from the general population was carried out. To validate and extend the results, two replication cohorts consisting of elderly individuals were studied. In the discovery cohort, we observed a strong gene-age interaction (p = 0.001), determining fasting glucose in such a way that the increasing effect of the risk G-allele was much greater in young (p = 5.9 × 10-10) than in elderly participants (p = 0.805). Consistently, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose concentrations in the two replication cohorts (mean age over 65 years) did not reach statistical significance (p > 0.05 for both). However, in the elderly cohorts, significant associations between the polymorphism and type-2 diabetes at baseline were found. Moreover, in one of the cohorts, we obtained a statistically significant interaction between the MTNR1B polymorphism and the number of pregnancies, retrospectively assessed, on the type-2 diabetes risk. In conclusion, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose is age-dependent, having a greater effect in younger people. However, in elderly subjects, associations of the polymorphism with type-2 diabetes were observed and our exploratory analysis suggested a modulatory effect of the number of past pregnancies on the future type-2 diabetes genetic risk.
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Affiliation(s)
- Jose V. Sorlí
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
| | - Rocío Barragán
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
- Department of Medicine, Sleep Center of Excellence, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Oscar Coltell
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
- Department of Computer Languages and Systems, Universitat Jaume I, 12071 Castellón, Spain
| | - Olga Portolés
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
| | - Eva C. Pascual
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
| | - Carolina Ortega-Azorín
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
| | - José I. González
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
| | - Ramon Estruch
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
- Department of Internal Medicine, Hospital Clinic, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Villarroel, 170, 08036 Barcelona, Spain
| | - Carmen Saiz
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
| | - Alejandro Pérez-Fidalgo
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
- CIBER Cáncer, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Jose M. Ordovas
- Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA;
- Precision Nutrition and Obesity Program, IMDEA Alimentación, 28049 Madrid, Spain
| | - Dolores Corella
- Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain; (J.V.S.); (R.B.); (O.P.); (E.C.P.); (C.O.-A.); (J.I.G.); (C.S.); (A.P.-F.)
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain; (O.C.); (R.E.)
- Correspondence: ; Tel.: +34-96-386-4800
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A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus. Biosci Rep 2020; 39:221430. [PMID: 31808503 PMCID: PMC6923336 DOI: 10.1042/bsr20190744] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 11/16/2019] [Accepted: 12/04/2019] [Indexed: 12/14/2022] Open
Abstract
The melatonin receptor 1B (MTNR1B) polymorphism rs10830963 C>G has been reported to be associated with the risk of gestational diabetes mellitus (GDM) with inconsistent results. To clarify the effect of the polymorphism on the risk of GDM, a meta-analysis therefore was performed. Pooled OR with its corresponding 95%CI was used to estimate the strength of the association. Totally 14 eligible studies with a number of 5033 GDM patients and 5614 controls were included in this meta-analysis. Results indicated that the variant G allele was significantly associated with an increased GDM risk (CG vs. CC: OR = 1.25, 95% CI = 1.11−1.40, P < 0.001; GG vs. CC: OR = 1.78, 95% CI = 1.45−2.19, P < 0.001; G vs. C: OR = 1.33, 95% CI = 1.21−1.47, P < 0.001). In the stratified analysis by ethnicity, similar results were found in Asians (CG vs. CC: OR = 1.15, 95%CI = 1.02−1.28, P = 0.020; GG vs. CC: OR = 1.52, 95% CI = 1.23−1.89, P < 0.001; G vs. C: OR = 1.23, 95% CI = 1.10−1.37, P < 0.001) and in Caucasians (CG vs. CC: OR = 1.40, 95% CI = 1.16−1.70, P < 0.001; GG vs. CC: OR = 2.21, 95% CI = 1.54−3.17, P < 0.001; G vs. C: OR = 1.47, 95% CI = 1.24−1.73, P < 0.001). FPRP and TSA analyses confirmed findings support that the rs10830963 G allele increases the risk of GDM, and further functional experimental studies are warranted to explore and clarify the potential mechanism.
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Jia Y, Shen Y, Shi X, Gu X, Zhang P, Liu Y, Zhu A, Jiang L. MTNR1B gene on susceptibility to gestational diabetes mellitus: a two-stage hospital-based study in Southern China. Mol Genet Genomics 2020; 295:1369-1378. [PMID: 32656703 DOI: 10.1007/s00438-020-01706-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023]
Abstract
Large-scale studies on genetic risk loci for melatonin receptor 1B (MTNR1B) gene and GDM risk have not been well generalized to the Chinese population. In this study, we performed two-stage case-control study: 1.429 pregnant women: 753 GDM/676 controls in the Southern Chinese population by genotyping 5 SNPs (rs10830963, rs1387153, rs2166706, rs1447352, and rs4753426) in MTNR1B. Genotypes were determined using the Sequenom MassARRAY platform and TaqMan allelic discrimination assay. Interactions between genetic variants and age/BMI as predictors of GDM risk were evaluated under the logistic regression model. In the first stage, the SNP rs10830963 was discovered to be potentially related to GDM risk (additive model: OR = 1.27, 95%CI = 1.05-1.55, P = 0.025), which was further confirmed in the second stage with a similar effect (additive model: OR = 1.53, 95%CI = 1.19-1.98, P = 0.005). In the combined stage, the G allele of rs10830963 was potentially associated with GDM risk (additive model: OR = 1.36, 95%CI = 1.17-1.59, P < 0.001; dominant model: OR = 1.45, 95%CI = 1.15-1.83, P = 0.005). The rs10830963 interacted with age and BMI to contribute to GDM risk in the combined participants. And, the similar interactive effects for the other four SNPs also exist. These findings offer the potential to improve our understanding of the etiology of GDM, and particularly of biological mechanisms.
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Affiliation(s)
- Yulong Jia
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Yi Shen
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Xiuying Shi
- Department of Epidemiology and Medical Statistics, School of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Xuefeng Gu
- Shanghai Key Laboratory for Molecular Imaging, University of Medicine and Health Sciences, Shanghai, People's Republic of China
| | - Peng Zhang
- School of Clinical Medicine, University of Medicine and Health Sciences, Shanghai, People's Republic of China
| | - Yuanlin Liu
- Department of Obstetrics and Gynecology, Nantong University Affiliated Hospital, Nantong, Jiangsu, China
| | - Aiyong Zhu
- School of Nursing and Health Management, University of Medicine and Health Sciences, Shanghai, People's Republic of China
| | - Liying Jiang
- Shanghai Key Laboratory for Molecular Imaging, University of Medicine and Health Sciences, Shanghai, People's Republic of China. .,Jiading District Central Hospital, Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China.
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Alharbi KK, Al-Sulaiman AM, Shedaid KMB, Al-Shangiti AM, Marie M, Al-Sheikh YA, Ali Khan I. MTNR1B genetic polymorphisms as risk factors for gestational diabetes mellitus: a case-control study in a single tertiary care center. Ann Saudi Med 2019; 39:309-318. [PMID: 31580701 PMCID: PMC6832319 DOI: 10.5144/0256-4947.2019.309] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a metabolic disease in pregnancy that causes carbohydrate intolerance and hyper-glycemia. Genome-wide association studies and meta-analyses have found that the single nucleotide polymorphisms (SNPs) rs1387153 and rs10830963 of the melatonin receptor 1B ( MTNR1B) gene are associated with GDM. No studies on the MTNR1B gene effect on GDM have been performed in Saudis, other Arabs, or other Middle Eastern populations. OBJECTIVES Investigate the association of genotype or allele frequencies of the two SNPs with GDM and with clinical parameters related to GDM. DESIGN Case-control study. SETTINGS Tertiary care center, Riyadh. PATIENTS AND METHODS We recruited 400 pregnant Saudi women ages 18-45 years (200 were diagnosed with GDM, and 200 were healthy controls). Biochemical assays were performed, and rs1387153 and rs10830963 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis and real-time polymerase chain reaction with TaqMan genotyping. MAIN OUTCOME MEASURES The association of MTNR1B gene (rs1387153 and rs10830963 polymorphisms) with GDM and with biochemical parameters related to GDM. SAMPLE SIZE 200 GDM cases and 200 non-GDM controls. RESULTS Differences in allele frequencies for GDM vs non-GMD were statistically significant or nearly significant for both SNPs after adjustment for age and body mass index. In a logistic regression analysis, genotype TT was positively associated with post-prandial blood glucose (P=.018), but other associations were not statistically significant. CONCLUSION The odds ratios for the associations between the rs1387153 and rs10830963 SNPs and GDM exceeded 1.5-fold, which is higher than typically reported for diseases with complex genetic background. These effect sizes for GDM suggest pregnancy-specific factors related to the MTNR1B risk genotypes. LIMITATIONS Only two SNPs were studied. CONFLICT OF INTEREST None.
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Affiliation(s)
- Khalid Khalaf Alharbi
- From the Department of Clinical Laboratory Sciences, King Saud University, Riyadh, Saudi Arabia
| | | | | | | | - Mohammed Marie
- From the Department of Clinical Laboratory Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Yazeed A Al-Sheikh
- From the Department of Clinical Laboratory Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Imran Ali Khan
- From the Department of Clinical Laboratory Sciences, King Saud University, Riyadh, Saudi Arabia
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Amaral FGD, Andrade-Silva J, Kuwabara WMT, Cipolla-Neto J. New insights into the function of melatonin and its role in metabolic disturbances. Expert Rev Endocrinol Metab 2019; 14:293-300. [PMID: 31192707 DOI: 10.1080/17446651.2019.1631158] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/10/2019] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Melatonin is a pineal hormone that has acquired several unique modes of regulating the physiological effects in mammals due to its characteristic phylogenetic history. While melatonin exhibits immediate nocturnal effects, it also has next-day prospective effects that take place in the absence of this hormone. Besides that, the daily repetition and the annual variation in the duration of its synthesis determine its circadian and seasonal effects that characterize melatonin as a chronobiotic, a molecule that encodes time to the internal environment. Additionally, it presents transgenerational effects that are important for fetal programming, leading to a balanced energy metabolism in the adult life. AREAS COVERED Physiology, pathophysiology and therapeutic value of melatonin in metabolism and metabolic disorders. EXPERT OPINION The typical mechanisms of action of melatonin (immediate, prospective, chronobiotic and transgenerational) should be considered to adequately understand its physiological effects on the regulation of metabolism in humans and, as a result, to understand the metabolic pathophysiological consequences caused by its synthesis and/or signaling disturbances. That points to the importance of a broader understanding of melatonin actions, besides the classical endocrinological point of view, that would allow the clinician/research to proper interpret its role in health maintenance.
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Affiliation(s)
| | - Jéssica Andrade-Silva
- b Department of Physiology and Biophysics , Institute of Biomedical Sciences, University of São Paulo , São Paulo , Brazil
| | - Wilson M T Kuwabara
- b Department of Physiology and Biophysics , Institute of Biomedical Sciences, University of São Paulo , São Paulo , Brazil
| | - José Cipolla-Neto
- b Department of Physiology and Biophysics , Institute of Biomedical Sciences, University of São Paulo , São Paulo , Brazil
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Tan YX, Hu SM, You YP, Yang GL, Wang W. Replication of previous genome-wide association studies of HKDC1, BACE2, SLC16A11 and TMEM163 SNPs in a gestational diabetes mellitus case-control sample from Han Chinese population. Diabetes Metab Syndr Obes 2019; 12:983-989. [PMID: 31417298 PMCID: PMC6602052 DOI: 10.2147/dmso.s207019] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/13/2019] [Indexed: 01/12/2023] Open
Abstract
Background: Four novel glucose metabolism risk loci (HKDC1 rs4746822, BACE2 rs6517656, SLC16A11 rs13342232 and TMEM163 rs998451) were identified in recent genome-wide association studies (GWAS) of Afro-Caribbean, European, Hispanic, Thai, Mexican, Latin American and Indian populations. None of the abovementioned SNPs has been reported in a Han Chinese population. Aim: To replicate the relationships between HKDC1 rs4746822, BACE2 rs6517656, SLC16A11 rs13342232 and TMEM163 rs998451 with gestational diabetes mellitus (GDM) in a Han Chinese population. Methods: This was a case-control study which enrolled 334 pregnant women with GDM and 367 pregnant women with normal glucose tolerance. The linear regression and logistic regression were used to estimate the association between SNPs with the risk of GDM, HOMA-IR and fasting insulin levels. The fasting insulin concentration and HOMA-IR were log10 transformed before analysis. Results: No significant differences in the alleles and genotypes of SLC16A11 rs13342232, HKDC1 rs4746822 and BACE2 rs6517656 were observed between cases and controls. After adjusting the weekly BMI growth, pre-pregnancy BMI and maternal age, under the additive model, SLC16A11 rs13342232 was associated with log10fasting serum insulin (Beta=0.046, p=0.016), log10HOMA-IR level (Beta=0.061, p=0.003) and fasting plasma glucose level (Beta=0.164, p=0.011); HKDC1 rs4746822 was associated with OGTT 2-hr plasma glucose level (Beta=0.239, p=0.016); and BACE2 rs6517656 was associated with log10fasting serum insulin (Beta=-0.053, p=0.044) and log10HOMA-IR level (Beta=-0.060, p=0.048). After correction for multiple testing, the associations of SLC16A11 and HKDC1 with glucose metabolism remained statistically significant. The A allele of TMEM163 rs998451 was not detected in this population. Conclusion: HKDC1 rs4746822, BACE2 rs6517656 and SLC16A11 rs13342232 are associated with glucose metabolism in pregnant women of Han Chinese.
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Affiliation(s)
- Yi-Xiong Tan
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan410013, People’s Republic of China
| | - Shi-Min Hu
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan410078, People’s Republic of China
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing100053, People’s Republic of China
- Beijing Key Laboratory of Neuromodulation
, Beijing100053, People’s Republic of China
- Correspondence: Shi-Min HuDepartment of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, 90 Xiangya Road, Changsha, Hunan410078, People’s Republic of ChinaTel +867 318 885 8435Fax +867 318 480 5454Email
| | - Yi-Ping You
- Department of Obstetrics and Gynecology, Hunan Provincial Hospital of Maternal and Child Health, Changsha, Hunan410008, People’s Republic of China
| | - Gui-Lian Yang
- Nutrition Department, Hunan Provincial Hospital of Maternal and Child Health, Changsha, Hunan410008, People’s Republic of China
| | - Wei Wang
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan410013, People’s Republic of China
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FTO, GCKR, CDKAL1 and CDKN2A/B gene polymorphisms and the risk of gestational diabetes mellitus: a meta-analysis. Arch Gynecol Obstet 2018; 298:705-715. [PMID: 30074065 DOI: 10.1007/s00404-018-4857-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 07/28/2018] [Indexed: 01/11/2023]
Abstract
PURPOSE Studies had examined the associations between genetic polymorphisms and the risk of gestational diabetes mellitus (GDM). However, conclusions of these studies were controversial due to the smaller sample size and limited statistical power. We carried out a meta-analysis with the aim of providing a more comprehensive summary of the currently available research to evaluate the relationship between FTO, GCKR, CDKAL1 and CDKN2A/B gene polymorphisms and GDM risk. METHODS Literature search was carried out in the PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure and Wangfang databases up to November 2017. Data were extracted by two independent reviewers and statistical analyses were performed with STATA software. Pooled odds ratios and 95% confidence intervals were calculated by Z test to assess the association between genetic polymorphisms and GDM risk. Stratified analysis was performed based on ethnicity. Heterogeneity and publication bias between studies were evaluated by Cochran's Q test and Egger regression test, respectively. RESULTS 14 eligible studies were included. CDKAL1 rs7754840 and rs7756992 showed significant correlation with GDM risk under the allele, recessive, dominant, homozygote and heterozygote models. GCKR rs780094 and CDKN2A/B rs10811661 also showed the same association under the allele, recessive and heterozygote models. No associations between FTO rs9939609 and rs8050136, GCKR rs1260326 and GDM risk were found. CONCLUSIONS Our meta-analysis showed that two SNPs in particular(rs7754840 and rs7756992 in CDKAL1) were very strongly associated with GDM risk. GCKR rs780094 and CDKN2A/B rs10811661 polymorphisms were moderately associated with GDM risk.
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12
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Effect of gene-lifestyle interaction on gestational diabetes risk. Oncotarget 2017; 8:112024-112035. [PMID: 29340108 PMCID: PMC5762376 DOI: 10.18632/oncotarget.22999] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 11/27/2017] [Indexed: 11/29/2022] Open
Abstract
We hypothesized that the association of certain lifestyle parameters with gestational diabetes mellitus (GDM) risk would depend on susceptibility loci. In total, 278 Russian women with GDM and 179 controls completed questionnaires about lifestyle habits (food consumption, physical activity and smoking). GDM was diagnosed according to the criteria of the International Association of Diabetes and Pregnancy Study Groups. Maternal blood was sampled for genotyping single-nucleotide polymorphisms (SNPs) in MTNR1B (rs10830963 and rs1387153), GCK (rs1799884), KCNJ11 (rs5219), IGF2BP2 (rs4402960), TCF7L2 (rs7903146 and rs12255372), CDKAL1 (rs7754840), IRS1 (rs1801278) and FTO (rs9939609). Binary logistic regression revealed an interaction effect of sausage intake and the number of risk alleles of two SNPs (rs10830963 in MTNR1B and rs1799884 in GCK) on GDM risk (P < 0.001). Among women without risk alleles of these two SNPs, sausage consumption was positively associated with GDM risk (P trend = 0.045). This difference was not revealed in women carrying 1 or more risk alleles. The risk of GDM increased as the number of risk alles increased in participants with low and moderate sausage consumption (P trend <0.001 and 0.006, respectively), while the risk of GDM in women with high sausage consumption remained relatively high, independent of the number of risk alleles. These findings indicate that the association of sausage consumption with GDM risk can be determined based on the number of risk alleles of rs10830963 in MTNR1B and rs1799884 in GCK.
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Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Pawlik A. MTNR1A and MTNR1B gene polymorphisms in women with gestational diabetes. Gynecol Endocrinol 2017; 33:395-398. [PMID: 28084098 DOI: 10.1080/09513590.2016.1276556] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is glucose intolerance detected during pregnancy. The MTNR1B gene is the genetic locus associated with type 2 diabetes, that may affect insulin secretion and pancreatic glucose sensing. In this study, we examined the association between MTNR1A (rs2119882) and MTNR1B (rs10830963, rs4753426) gene polymorphisms and the risk of GDM. According to the results of their oral glucose tolerance test (OGTT), the women were divided into two groups: 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). There were no statistically significant differences in the distribution of MTNR1A rs2119882 and MTNR1B rs4753426 genotypes and alleles between women with GDM and healthy pregnant women. With regard to the MTNR1B rs10830963 polymorphism, we observed a statistically significant prevalence of GG and CG genotypes and the G allele among pregnant women with GDM (GG + CG vs CC, OR 1.50, 95% CI 1.02-2.22, p = 0.04; G vs C, OR 1.43, 95% CI 1.07-1.90, p = 0.016). In a multivariate logistic regression analysis, a higher number of MTNR1B rs10830963 G alleles was an independent significant predictor of a higher risk of GDM. The results of our study indicate that MTNR1B rs10830963 polymorphism is associated with GDM susceptibility, and women with a higher number of G alleles have an increased risk of GDM development.
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Affiliation(s)
- Maciej Tarnowski
- a Department of Physiology , Pomeranian Medical University , Szczecin , Poland and
| | - Damian Malinowski
- a Department of Physiology , Pomeranian Medical University , Szczecin , Poland and
| | - Krzysztof Safranow
- b Department of Biochemistry and Medical Chemistry , Pomeranian Medical University , Szczecin , Poland
| | - Violetta Dziedziejko
- b Department of Biochemistry and Medical Chemistry , Pomeranian Medical University , Szczecin , Poland
| | - Andrzej Pawlik
- a Department of Physiology , Pomeranian Medical University , Szczecin , Poland and
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Saravani R, Esmaeilzaei E, Noorzehi N, Galavi HR. Melatonin Receptor 1B Gene Polymorphisms, Haplotypes and Susceptibility to Schizophrenia. REV ROMANA MED LAB 2017. [DOI: 10.1515/rrlm-2017-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
Melatonin has an important role in the regulation of human sleep circadian rhythms. Sleep disturbances commonly exist in schizophrenia (SCZ) patients. To begin its performance, melatonin must interact to its receptor. In the present study, Single Nucleotide Polymorphisms (SNPs) of melatonin receptor gene 1 B (MTN1B) with SCZ development in Iranian population were investigated. The current case-control study was performed on 92 SCZ patients and 92 healthy control (HC) subjects. NESTED-PCR and ARMS-PCR modified methods (combination) and ARMSPCR method were used on the genotype. The impact of MTN1B rs3781637 (T/C) and rs10830963(C/G) polymorphism variants on the risk SCZ in the sample of Iranian population was investigated. The findings showed significant association between MTN1B rs10830963(C/G) variant and SCZ (OR=2.78, 95%CI=1.25-6.25, P=0.012, GG vs. CC, OR=1.66, 95%CI=1.09-2.51, P=0.021 G vs. C, OR=3.85 95%CI=.89-8.33, P<0.0001, GG vs. CC+CG). There was no association between MTN1B rs3781637 (T/C) and SCZ risk. In addition, haplotype analysis revealed that TG and CC haplotype of rs3781637 (T/C) and rs10830963 (C/G) polymorphisms were associated with SCZ risk (P=0.039) and protective (P<0.0001) effects, respectively. The findings revealed that MTN1B rs10830963 (C/G) polymorphism was associated with the risk of SCZ; while another SNP rs3781637 (T/C) MTN1B gene did not show any risk/protection association with SCZ. Further studies with larger sample sizes and different ethnicities are required to approve the results.
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Affiliation(s)
- Ramin Saravani
- Cellular and Molecular Research Center and Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences , Zahedan , Iran (Islamic Republic of)
| | - Elahe Esmaeilzaei
- Department of Genetics, School of Medicine, Zahedan University of Medical Sciences , Zahedan , Iran (Islamic Republic of)
| | - Nafiseh Noorzehi
- Department of Biology, Zabol University , Zabol , Iran (Islamic Republic of)
| | - Hamid Reza Galavi
- Cellular and Molecular Research Center and Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences , Zahedan , Iran (Islamic Republic of)
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Anderson G, Vaillancourt C, Maes M, Reiter RJ. Breast Feeding and Melatonin: Implications for Improving Perinatal Health. ACTA ACUST UNITED AC 2016. [DOI: 10.14302/issn.2644-0105.jbfb-16-1121] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The biological underpinnings that drive the plethora of breastfeeding benefits over formula-feeding is an area of intense research, given the cognitive and emotional benefits as well as the offsetting of many childhood- and adult-onset medical conditions that breast-feeding provides. In this article, we review the research on the role of melatonin in driving some of these breastfeeding benefits. Melatonin is a powerful antioxidant, anti-inflammatory and antinociceptive as well as optimizing mitochondrial function. Melatonin is produced by the placenta and, upon parturition, maternal melatonin is passed to the infant upon breastfeeding with higher levels in night-time breast milk. As such, some of the benefits of breastfeeding may be mediated by the higher levels of maternal circulating night-time melatonin, allowing for circadian and antioxidant effects, as well as promoting the immune and mitochondrial regulatory aspects of melatonin; these actions may positively modulate infant development. Herein, it is proposed that some of the benefits of breastfeeding may be mediated by melatonin's regulation of the infant's gut microbiota and immune responses. As such, melatonin is likely to contribute to the early developmental processes that affect the susceptibility to a range of adult onset conditions. Early research on animal models has shown promising results for the regulatory role of melatonin.
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Affiliation(s)
| | - Cathy Vaillancourt
- INRS-Armand-Frappier Institute and Center for Interdisciplinary Research on Well-Being, Health, Society and Environment (CINBIOSE), Laval, QC, Canada
| | - Michael Maes
- Deakin University, Department of Psychiatry, Geelong , Australia
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