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Moretto L, Brondani LDA, Girardi E, Vieira ACM, Lemos NE, Fiegenbaum M, Canani LH, Crispim D, Dieter C. The C allele of the rs741301 polymorphism in the ELMO1 gene is associated with increased risk of diabetic retinopathy in patients with type 2 diabetes mellitus. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2025; 68:e240283. [PMID: 40215453 PMCID: PMC11967185 DOI: 10.20945/2359-4292-2024-0283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/17/2024] [Indexed: 04/15/2025]
Abstract
OBJECTIVE To investigate the association of the rs741301 polymorphism in the ELMO1 gene with diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS This study analyzed 350 patients withT2DM and DR (cases) and 234 patients withT2DM without this complication but with more than 10 years of diabetes mellitus (DM) (controls). DR was diagnosed by indirect fundoscopy. Genotyping was performed by allelic discrimination real-time PCR. RESULTS The frequency of the C/C genotype of the rs741301 polymorphism in the ELMO1 gene was 26.9% in cases and 17.9% in controls (P = 0.011). After adjustment for covariables, the C/C genotype was associated with an increased risk of DR [odds ratio (OR) = 1.805, 95%CI 1.101-2.961; P = 0.019]. This association remained significant in dominant and additive inheritance models after adjustment for the same variables [OR = 1.597, 95%CI 1.089-2.343; P = 0.017; and OR = 1.818, 95%CI 1.099-3.007; P = 0.020]. CONCLUSION This study demonstrated an association between the presence of the C allele of the ELMO1 rs741301 polymorphism and an increased risk of DR in patients with T2DM from Southern Brazil.
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Affiliation(s)
- Luciane Moretto
- Serviço de Endocrinologia do Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brasil
- Programa de Pós-graduação em Ciências
Médicas: Endocrinologia, Faculdade de Medicina, Departamento de Clínica
Médica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Letícia de Almeida Brondani
- Unidade de Pesquisa Laboratorial, Centro de Pesquisa Experimental, Hospital
de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| | - Eliandra Girardi
- Serviço de Endocrinologia do Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brasil
| | | | - Natália Emerim Lemos
- Departamento de Bioquímica, Instituto de Química,
Universidade de São Paulo, São Paulo, SP, Brasil
| | - Marilu Fiegenbaum
- Programa de Pós-graduação em Biociências,
Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS,
Brasil
| | - Luís Henrique Canani
- Serviço de Endocrinologia do Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brasil
- Programa de Pós-graduação em Ciências
Médicas: Endocrinologia, Faculdade de Medicina, Departamento de Clínica
Médica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Daisy Crispim
- Serviço de Endocrinologia do Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brasil
- Programa de Pós-graduação em Ciências
Médicas: Endocrinologia, Faculdade de Medicina, Departamento de Clínica
Médica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Cristine Dieter
- Serviço de Endocrinologia do Hospital de Clínicas de Porto
Alegre, Porto Alegre, RS, Brasil
- Programa de Pós-graduação em Ciências
Médicas: Endocrinologia, Faculdade de Medicina, Departamento de Clínica
Médica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
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Hassan EA, Elsaid AM, Abou-Elzahab MM, El-Refaey AM, Elmougy R, Youssef MM. The Potential Impact of MYH9 (rs3752462) and ELMO1 (rs741301) Genetic Variants on the Risk of Nephrotic Syndrome Incidence. Biochem Genet 2024; 62:1304-1324. [PMID: 37594641 DOI: 10.1007/s10528-023-10481-y] [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: 06/04/2023] [Accepted: 08/02/2023] [Indexed: 08/19/2023]
Abstract
The kidney lost a lot of protein in the urine when you have nephrotic syndrome (NS). Clinical manifestations mostly common in NS include massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Idiopathic nephrotic syndrome is currently classified into steroid-dependent (SDNS) and steroid-resistant (SRNS) based on the initial response to corticosteroid therapy at presentation. Several reports examined the association of the MYH9 gene (rs3752462, C > T) variant and ELMO1 gene (rs741301 G > A) variant as risk factors for Nephrotic Syndrome. This study aimed to determine the potential effect of the MYH9 gene (rs3752462, C > T) and ELMO1 gene (rs741301) variant on the risk of (NS) among Egyptian Children. This study included two hundred participants involving 100 nephrotic syndrome (NS) cases and 100 healthy controls free from nephrotic syndrome (NS). The MYH9 gene (rs3752462, C > T) variant and ELMO1 gene (rs G > A741301) variant were analyzed by ARMS-PCR technique. Nephrotic syndrome cases include 74% SRNS and 26% SDNS. Higher frequencies of the heterozygous carrier (CT) and homozygous variant (TT) genotypes of the MYH9 (rs3752462, C > T) variant were observed in NS patients compared to the controls with p-value < 0.001. The frequencies of the MYH9 (rs3752462, C > T variant indicated a statistically significant elevated risk of NS under various genetic models, including allelic model (OR 2.85, p < 0.001), dominant (OR 3.97, p < 0.001) models, and the recessive model OR 5.94, p < 0.001). Higher frequencies of the heterozygous carrier (GA) and homozygous variant (AA) genotypes of ELMO1gene (rs G > A741301) variant were observed in NS patients compared to the controls with p-value < 0.001. The frequencies of the ELMO1 (rs G > A741301) variant indicated a statistically significant elevated risk of NS under various genetic models, including allelic model (OR 2.15, p < 0.001), dominant models (OR 2.8, p < 0.001), and the recessive model (OR 4.17, p = 0.001). Both MYH9 and ELMO1 gene variants are significantly different in NS in comparison with the control group (p < 0.001). The MYH9 gene (rs3752462, C > T) and ELMO1gene (rs G > A741301) variants were considered independent risk factors for NS among Egyptian Children.
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Affiliation(s)
- Eglal A Hassan
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt.
| | - Afaf M Elsaid
- Genetic Unit, Children Hospital, Mansoura University, Mansoura, Egypt
| | - M M Abou-Elzahab
- Organic Chemistry Division, Chemistry Department, Faculty Of Science, Mansoura University, Mansoura, Egypt
| | - Ahmed M El-Refaey
- Department of Pediatrics, Mansoura University Childrens Hospital, Mansoura University, Mansoura, Egypt
| | - Rehab Elmougy
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Magdy M Youssef
- Biochemistry Division, Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
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Sarray S, Lamine LB, Dallel M, Ezzidi I, Sellami N, Turki A, Moustafa AEEA, Mtiraoui N. Association of matrix metalloproteinase-2 gene variants with diabetic nephropathy risk. J Gene Med 2023; 25:e3553. [PMID: 37312425 DOI: 10.1002/jgm.3553] [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: 02/16/2023] [Revised: 05/11/2023] [Accepted: 05/30/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Diabetic nephropathy is a highly destructive microvascular complication of diabetes. Genetic predisposition is involved in the pathogenesis of diabetic nephropathy, with multiple allelic polymorphisms associated with the development and progression of the disease, thereby increasing the overall risk. To date, no study is available that shows the association of matrix metalloproteinase-2 (MMP-2) gene polymorphisms with diabetic nephropathy risk. Thus, we investigated the potential genetic influence of MMP-2 promoter variants in the development of diabetic nephropathy in type 2 diabetic patients. METHODS In total, 726 type 2 diabetic patients and 310 healthy controls were included in the study and genotyped for MMP-2, -1306C/T, -790T/G, -1575G/T and -735C/T by real-time PCR. The analysis of the outcomes was performed assuming three genetic models. The threshold for statistical significance was set at 0.05. RESULTS The results showed that the minor allele frequency of the -790T/G variant was significantly higher in patients with and without nephropathy compared to controls. Furthermore, the distribution analysis revealed a significant association of the -790T/G variant, in all genetic models, with increased risk of diabetic nephropathy that persisted after adjusting for key covariates. No significant associations between MMP-2, -1306C/T, -1575G/T, -735C/T and the risk of diabetic nephropathy were detected. Haplotype analysis identified two risk haplotypes GCGC and GTAC associated with diabetic nephropathy. CONCLUSIONS The present study is the first to demonstrate the allelic and genotypic association of the MMP-2-790T/G variant and two haplotypes with an increased risk of diabetic nephropathy in a Tunisian population with type 2 diabetes.
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Affiliation(s)
- Sameh Sarray
- Arabian Gulf University, Manama, Bahrain
- Faculty of Sciences, University Tunis EL Manar, Tunis, Tunisia
| | - Laila Ben Lamine
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Meriem Dallel
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Intissar Ezzidi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia
| | - Nejla Sellami
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | - Amira Turki
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
| | | | - Nabil Mtiraoui
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia
- Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia
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Boger M, Bennewitz K, Wohlfart DP, Hausser I, Sticht C, Poschet G, Kroll J. Comparative Morphological, Metabolic and Transcriptome Analyses in elmo1−/−, elmo2−/−, and elmo3−/− Zebrafish Mutants Identified a Functional Non-Redundancy of the Elmo Proteins. Front Cell Dev Biol 2022; 10:918529. [PMID: 35874819 PMCID: PMC9304559 DOI: 10.3389/fcell.2022.918529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
The ELMO protein family consists of the homologues ELMO1, ELMO2 and ELMO3. Several studies have shown that the individual ELMO proteins are involved in a variety of cellular and developmental processes. However, it has poorly been understood whether the Elmo proteins show similar functions and act redundantly. To address this question, elmo1−/−, elmo2−/− and elmo3−/− zebrafish were generated and a comprehensive comparison of the phenotypic changes in organ morphology, transcriptome and metabolome was performed in these mutants. The results showed decreased fasting and increased postprandial blood glucose levels in adult elmo1−/−, as well as a decreased vascular formation in the adult retina in elmo1−/−, but an increased vascular formation in the adult elmo3−/− retina. The phenotypical comparison provided few similarities, as increased Bowman space areas in adult elmo1−/− and elmo2−/− kidneys, an increased hyaloid vessel diameter in elmo1−/− and elmo3−/− and a transcriptional downregulation of the vascular development in elmo1−/−, elmo2−/−, and elmo3−/− zebrafish larvae. Besides this, elmo1−/−, elmo2−/−, and elmo3−/− zebrafish exhibited several distinct changes in the vascular and glomerular structure and in the metabolome and the transcriptome. Especially, elmo3−/− zebrafish showed extensive differences in the larval transcriptome and an impaired survivability. Together, the data demonstrated that the three zebrafish Elmo proteins regulate not only similar but also divergent biological processes and mechanisms and show a low functional redundancy.
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Affiliation(s)
- Mike Boger
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Katrin Bennewitz
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - David Philipp Wohlfart
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ingrid Hausser
- Institute of Pathology IPH, EM Lab, Heidelberg University Hospital, Heidelberg, Germany
| | - Carsten Sticht
- NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Gernot Poschet
- Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany
| | - Jens Kroll
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- *Correspondence: Jens Kroll,
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Omar TA, Zewain SK, Ghonaim MM, Refaat KA, Abou-Elela DH. Role of engulfment and cell motility 1 (ELMO1) gene polymorphism in development of diabetic kidney disease. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-021-00167-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Diabetic kidney disease (DKD) is a progressive kidney disease that affects diabetic patients irrespective of glycemic state or hypertension. Therefore, early detection of DKD is of critical importance. Many genome-wide association studies have identified the engulfment and cell motility 1 (ELMO1) gene as a genetic marker linked to DKD. This study aimed to investigate the association between ELMO1 rs741301 gene polymorphism and the development of DKD among Egyptian patients with type 2 diabetes mellitus (T2DM). Allele and genotype frequencies were investigated in 304 subjects by real-time PCR allelic discrimination assay: 100 DKD patients, 102 diabetic patients without DKD, and 102 healthy controls.
Results
GG genotype of ELMO1 (rs741301) SNP and its allele frequencies were significantly high in all diabetic patients. GG genotype had an odds ratio (OR) of 6.095 and 95% confidence interval (CI) of 2.456–15.125, p < 0.001, while the frequent allele G had an OR of 2.366 and 95% CI of 1.450–3.859, p = 0.001. No significant difference was observed between T2DM without DKD and DKD.
Conclusion
Our results could not establish an association between the ELMO1 rs741301 variant and the progression of DKD.
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Smyth LJ, Kilner J, Nair V, Liu H, Brennan E, Kerr K, Sandholm N, Cole J, Dahlström E, Syreeni A, Salem RM, Nelson RG, Looker HC, Wooster C, Anderson K, McKay GJ, Kee F, Young I, Andrews D, Forsblom C, Hirschhorn JN, Godson C, Groop PH, Maxwell AP, Susztak K, Kretzler M, Florez JC, McKnight AJ. Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study. Clin Epigenetics 2021; 13:99. [PMID: 33933144 PMCID: PMC8088646 DOI: 10.1186/s13148-021-01081-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/15/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10-8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. RESULTS Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. CONCLUSIONS Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.
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Affiliation(s)
- L J Smyth
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK.
| | - J Kilner
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - V Nair
- Internal Medicine, Department of Nephrology, University of Michigan, Ann Arbor, MI, USA
| | - H Liu
- Department of Department of Medicine/ Nephrology, Department of Genetics, Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - E Brennan
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - K Kerr
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - N Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - J Cole
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA
- Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - E Dahlström
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - A Syreeni
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - R M Salem
- Department of Family Medicine and Public Health, UC San Diego, San Diego, CA, USA
| | - R G Nelson
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | - H C Looker
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | - C Wooster
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - K Anderson
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - G J McKay
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - F Kee
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - I Young
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
| | - D Andrews
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - C Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - J N Hirschhorn
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - C Godson
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - P H Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - A P Maxwell
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
- Regional Nephrology Unit, Belfast City Hospital, Belfast, Northern Ireland, UK
| | - K Susztak
- Department of Department of Medicine/ Nephrology, Department of Genetics, Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - M Kretzler
- Internal Medicine, Department of Nephrology, University of Michigan, Ann Arbor, MI, USA
| | - J C Florez
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - A J McKnight
- Molecular Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK
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Yang J, Xiong X, Xiao Y, Wei L, Li L, Yang M, Han Y, Zhao H, Li C, Jiang N, Xiong S, Zeng L, Zhou Z, Liu S, Wang N, Fan Y, Sun L. The single nucleotide polymorphism rs11643718 in SLC12A3 is associated with the development of diabetic kidney disease in Chinese people with type 2 diabetes. Diabet Med 2020; 37:1879-1889. [PMID: 32634861 PMCID: PMC7589246 DOI: 10.1111/dme.14364] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 06/13/2020] [Accepted: 07/01/2020] [Indexed: 01/05/2023]
Abstract
AIMS To examine the association between 24 literature-based single nucleotide polymorphisms and diabetic kidney disease in Chinese people with type 2 diabetes. METHODS AND RESULTS Twenty-four candidate diabetic kidney disease-susceptible single nucleotide polymorphisms were genotyped in 208 participants with type 2 diabetes and diabetic kidney disease and 200 participants with type 2 diabetes without diabetic kidney disease (case and control groups, respectively), together with 206 healthy participants using MassARRAY. Rs11643718 in the SLC12A3 gene was associated with diabetic kidney disease in the recessive model after adjusting for confounding factors, such as age and gender (adjusted odds ratio 2.056, 95% CI 1.120-3.776; P = 0.020). Meta-analyses further confirmed the association (P = 0.002). In addition, participants with the GG genotype had worse renal function and more albuminuria than those with the AA+AG genotype (P < 0.05). Renal section immunohistochemistry was conducted in participants with type 2 diabetes, diabetic kidney disease and AA+AG or GG genotypes and in participants with glomerular minor lesions. Together with data from the Nephroseq database, it was shown that the abundance of SLC12A3 was reduced in patients with the GG genotype, while elevated expression of SLC12A3 was associated with better renal function. In addition, rs10951509 and rs1345365 in ELMO1, which were determined to be in high linkage disequilibrium by SHEsis software, were also associated with diabetic kidney disease (adjusted P = 0.010 and 0.015, respectively). CONCLUSIONS The G allele and GG genotype of SLC12A3 rs11643718 are associated with the development of diabetic kidney disease in a Chinese population with type 2 diabetes.
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Affiliation(s)
- J.‐F. Yang
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - X.‐F. Xiong
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - Y. Xiao
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - L. Wei
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - L. Li
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - M. Yang
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - Y.‐C. Han
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - H. Zhao
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - C.‐R. Li
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - N. Jiang
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - S. Xiong
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - L.‐F. Zeng
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
| | - Z.‐G. Zhou
- National Clinical Research Centre for Metabolic Diseases Diabetes CentreDepartment of EndocrinologySecond Xiangya Hospital at Central South UniversityChangshaChina
| | - S.‐P. Liu
- National Clinical Research Centre for Metabolic Diseases Diabetes CentreDepartment of EndocrinologySecond Xiangya Hospital at Central South UniversityChangshaChina
| | - N.‐S. Wang
- Department of NephrologyShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Y. Fan
- Department of NephrologyShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - L. Sun
- Department of NephrologyHunan Key Laboratory of Kidney Disease and Blood PurificationSecond Xiangya Hospital at Central South UniversityChangshaChina
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Kakoki M, Bahnson EM, Hagaman JR, Siletzky RM, Grant R, Kayashima Y, Li F, Lee EY, Sun MT, Taylor JM, Rice JC, Almeida MF, Bahr BA, Jennette JC, Smithies O, Maeda-Smithies N. Engulfment and cell motility protein 1 potentiates diabetic cardiomyopathy via Rac-dependent and Rac-independent ROS production. JCI Insight 2019; 4:127660. [PMID: 31217360 DOI: 10.1172/jci.insight.127660] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/08/2019] [Indexed: 01/31/2023] Open
Abstract
Engulfment and cell motility protein 1 (ELMO1) is part of a guanine nucleotide exchange factor for Ras-related C3 botulinum toxin substrate (Rac), and ELMO1 polymorphisms were identified to be associated with diabetic nephropathy in genome-wide association studies. We generated a set of Akita Ins2C96Y diabetic mice having 5 graded cardiac mRNA levels of ELMO1 from 30% to 200% of normal and found that severe dilated cardiomyopathy develops in ELMO1-hypermorphic mice independent of renal function at age 16 weeks, whereas ELMO1-hypomorphic mice were completely protected. As ELMO1 expression increased, reactive oxygen species indicators, dissociation of the intercalated disc, mitochondrial fragmentation/dysfunction, cleaved caspase-3 levels, and actin polymerization increased in hearts from Akita mice. Cardiomyocyte-specific overexpression in otherwise ELMO1-hypomorphic Akita mice was sufficient to promote cardiomyopathy. Cardiac Rac1 activity was positively correlated with the ELMO1 levels, and oral administration of a pan-Rac inhibitor, EHT1864, partially mitigated cardiomyopathy of the ELMO1 hypermorphs. Disrupting Nox4, a Rac-independent NADPH oxidase, also partially mitigated it. In contrast, a pan-NADPH oxidase inhibitor, VAS3947, markedly prevented cardiomyopathy. Our data demonstrate that in diabetes mellitus ELMO1 is the "rate-limiting" factor of reactive oxygen species production via both Rac-dependent and Rac-independent NADPH oxidases, which in turn trigger cellular signaling cascades toward cardiomyopathy.
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Affiliation(s)
- Masao Kakoki
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Edward M Bahnson
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Surgery, Division of Vascular Surgery, and Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - John R Hagaman
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Robin M Siletzky
- Department of Surgery, Division of Vascular Surgery, and Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ruriko Grant
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yukako Kayashima
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Feng Li
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Esther Y Lee
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Michelle T Sun
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Joan M Taylor
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jessica C Rice
- Biotechnology Research and Training Center, University of North Carolina at Pembroke, Pembroke, North Carolina, USA
| | - Michael F Almeida
- Biotechnology Research and Training Center, University of North Carolina at Pembroke, Pembroke, North Carolina, USA
| | - Ben A Bahr
- Biotechnology Research and Training Center, University of North Carolina at Pembroke, Pembroke, North Carolina, USA
| | - J Charles Jennette
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Oliver Smithies
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Nobuyo Maeda-Smithies
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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9
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Gu HF. Genetic and Epigenetic Studies in Diabetic Kidney Disease. Front Genet 2019; 10:507. [PMID: 31231424 PMCID: PMC6566106 DOI: 10.3389/fgene.2019.00507] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 05/08/2019] [Indexed: 01/19/2023] Open
Abstract
Chronic kidney disease is a worldwide health crisis, while diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease (ESRD). DKD is a microvascular complication and occurs in 30–40% of diabetes patients. Epidemiological investigations and clinical observations on the familial clustering and heritability in DKD have highlighted an underlying genetic susceptibility. Furthermore, DKD is a progressive and long-term diabetic complication, in which epigenetic effects and environmental factors interact with an individual’s genetic background. In recent years, researchers have undertaken genetic and epigenetic studies of DKD in order to better understand its molecular mechanisms. In this review, clinical material, research approaches and experimental designs that have been used for genetic and epigenetic studies of DKD are described. Current information from genetic and epigenetic studies of DKD and ESRD in patients with diabetes, including the approaches of genome-wide association study (GWAS) or epigenome-wide association study (EWAS) and candidate gene association analyses, are summarized. Further investigation of molecular defects in DKD with new approaches such as next generation sequencing analysis and phenome-wide association study (PheWAS) is also discussed.
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Affiliation(s)
- Harvest F Gu
- Center for Pathophysiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
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10
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Yahya MJ, Ismail PB, Nordin NB, Akim ABM, Yusuf WSBM, Adam NLB, Yusoff MJ. Association of CCL2, CCR5, ELMO1, and IL8 Polymorphism with Diabetic Nephropathy in Malaysian Type 2 Diabetic Patients. Int J Chronic Dis 2019; 2019:2053015. [PMID: 30713847 PMCID: PMC6333004 DOI: 10.1155/2019/2053015] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/02/2018] [Accepted: 12/13/2018] [Indexed: 12/26/2022] Open
Abstract
The unique variants or biomarkers of individuals help to understand the pathogenesis as well as the potential risk of individuals or patients to diabetic nephropathy (DN). The aim of this study was to investigate the association of a genetic polymorphism of monocyte chemoattractant protein-1 (CCL2-rs3917887), chemokine receptor 5 (CCR5-rs1799987), engulfment and cell mortality (ELMO1-rs74130), and interleukin-8 (IL8-rs4073) with the development of DN among Malaysian type 2 diabetes mellitus (T2DM) patients. More than one thousand diabetic patients were examined and a total of 652 T2DM patients were tested comprising 227 Malays (nonnephrotic=96 and nephrotic=131), 203 Chinese (nonnephrotic=95 and nephrotic=108), and 222 Indians (nonnephrotic=136 and nephrotic=86). DNA Sequenom mass ARRAY was employed to identify polymorphisms in CCL2, CCR5, ELMO1, and IL8 genes. DNA was extracted from the secondary blood samples taken from the T2DM patients. The alleles and genotypes were tested using four genetic models and the best mode of inheritance was chosen. CCR5 rs1799987 (G>A) showed strong association with the development of diabetic nephropathy only among the Chinese with OR=6.71 (2.55-17.68) 95% CI while IL8 rs4073 (T>A) showed association with nephropathy only among the Indians with OR=1.57 (0.66-3.71) 95% CI. The additive model was the best model for the mode of inheritance of all the genes. The contribution of genetic variants differs across ethnic groups or background. Further studies which involve environmental risk factors should be taken into consideration.
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Affiliation(s)
- Mohd Jokha Yahya
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia
| | - Patimah binti Ismail
- Department of Human Development and Growth, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia
| | - Norshariza binti Nordin
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia
| | - Abdah binti Md Akim
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia
| | | | - Noor Lita binti Adam
- Department of Medicine (Endocrinology & Nephrology), Hospital Tuanku Ja'afar, Malaysia
| | - Maryam Jamielah Yusoff
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia
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11
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Hou Y, Gao Y, Zhang Y, Lin ST, Yu Y, Yang L. Interaction between ELMO1 gene polymorphisms and environment factors on susceptibility to diabetic nephropathy in Chinese Han population. Diabetol Metab Syndr 2019; 11:97. [PMID: 31798690 PMCID: PMC6882154 DOI: 10.1186/s13098-019-0492-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 11/09/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The association of diabetic nephropathy (DN) risk with single nucleotide polymorphisms (SNPs) within Engulfment and Cell Motility 1 (ELMO1) gene and gene-environment synergistic effect have not been extensively examined in, therefore, the purpose of this study is to explore the association between multiple SNPs in ELMO1 gene, and the relationship between gene-environment synergy effect and the risk of DN. METHODS Genotyping for 4 SNPs was performed with polymerase chain reaction (PCR) and following restriction fragment length polymorphism (RFLP) methods. Hardy-Weinberg balance of the control group was tested by SNPstats (online software: http://bioinfo.iconologia.net/snpstats). The best combination of four SNPs of ELMO1 gene and environmental factors was screened by GMDR model. Logistic regression was used to calculating the OR values between different genotypes of ELMO1 gene and DN. RESULTS The rs741301-G allele and the rs10255208-GG genotype were associated with an increased risk of DN risk, adjusted ORs (95% CI) were 1.75 (1.19-2.28) and 1.41 (1.06-1.92), respectively, both p-values were < 0.001. We also found that the others SNPs-rs1345365 and rs7782979 were not significantly associated with susceptibility to DN. GMDR model found a significant gene-alcohol drinking interaction combination (p = 0.0107), but no significant gene-hypertension interaction combinations. Alcohol drinkers with rs741301-AG/GG genotype also have the highest DN risk, compared to never drinkers with rs741301-AA genotype, OR (95% CI) 3.52 (1.93-4.98). CONCLUSIONS The rs741301-G allele and the rs10255208-GG genotype, gene-environment interaction between rs741301 and alcohol drinking were all associated with increased DN risk.
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Affiliation(s)
- Yi Hou
- Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin People’s Republic of China
| | - Yong Gao
- Department of Critical Care, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin People’s Republic of China
| | - Yan Zhang
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin People’s Republic of China
| | - Si-Tong Lin
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin People’s Republic of China
| | - Yue Yu
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin People’s Republic of China
| | - Liu Yang
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun, 130033 Jilin People’s Republic of China
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12
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Li M, Pezzolesi MG. Advances in understanding the genetic basis of diabetic kidney disease. Acta Diabetol 2018; 55:1093-1104. [PMID: 30083980 DOI: 10.1007/s00592-018-1193-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/16/2018] [Indexed: 02/08/2023]
Abstract
Diabetic kidney disease (DKD) is a devastating complication of Type 1 and Type 2 diabetes and leads to increased morbidity and mortality. Earlier work in families has provided strong evidence that heredity is a major determinant of DKD. Previous linkage analyses and candidate gene studies have identified potential DKD genes; however, such approaches have largely been unsuccessful. Genome-wide association studies (GWAS) have made significant contribution in identifying SNPs associated with common complex diseases. Thanks to advanced technology, new analytical approaches, and international research collaborations, many DKD GWASs have reported unique genes, highlighted novel biological pathways and suggested new disease mechanisms. This review summarizes the current state of GWAS technology; findings from GWASs of DKD and its related traits conducted over the past 15 years and discuss the future of this field.
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Affiliation(s)
- Man Li
- Division of Nephrology and Hypertension, Department of Internal Medicine,, University of Utah School of Medicine, Salt Lake City, UT, 84105, USA
- VA Boston Healthcare System, VA Cooperative Studies Program, Boston, MA, USA
| | - Marcus G Pezzolesi
- Division of Nephrology and Hypertension, Department of Internal Medicine,, University of Utah School of Medicine, Salt Lake City, UT, 84105, USA.
- Diabetes and Metabolism Center, University of Utah School of Medicine, Salt Lake City, UT, USA.
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA.
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13
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Wei L, Xiao Y, Li L, Xiong X, Han Y, Zhu X, Sun L. The Susceptibility Genes in Diabetic Nephropathy. KIDNEY DISEASES 2018; 4:226-237. [PMID: 30574499 DOI: 10.1159/000492633] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 08/03/2018] [Indexed: 12/22/2022]
Abstract
Background Diabetes mellitus (DM) poses a severe threat to global public health. Diabetic nephropathy (DN) is one of the most common complications of diabetes and the leading cause of end-stage renal disease (ESRD). Approximately 30-40% of DM patients in the world progress to ESRD, which emphasizes the effect of genetic factors on DN. Family clustering also supports the important role of hereditary factors in DN and ESRD. Therefore, a large number of genetic studies have been carried out to identify susceptibility genes in different diabetic cohorts. Extensive susceptibility genes of DN and ESRD have not been identified until recently. Summary and Key Messages Some of these associated genes function as pivotal regulators in the pathogenesis of DN, such as those related to glycometabolism and lipid metabolism. However, the functions of most of these genes remain unclear. In this article, we review several susceptibility genes according to their genetic functions to make it easier to determine their exact effect on DN and to provide a better understanding of the advancements from genetic studies. However, several challenges associated with investigating the genetic factors of DN still exist. For instance, it is difficult to determine whether these variants affect the expression of the protein they encode or other cytokines. More efforts should be made to determine how these genes influence the progression of DN. In addition, many results could not be replicated among races, suggesting that the association between genetic polymorphisms and DN is race-specific. Therefore, large, well-designed studies involving more relevant variables and ethnic groups and more relevant functional studies are urgently needed. These studies may be beneficial and retard the progression of DN by early intervention, especially for patients who carry certain risk alleles or genotypes.
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Affiliation(s)
- Ling Wei
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Ying Xiao
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Li Li
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaofen Xiong
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yachun Han
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Xuejing Zhu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Lin Sun
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
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Zebrafish as a Model for the Study of Microvascular Complications of Diabetes and Their Mechanisms. Int J Mol Sci 2017; 18:ijms18092002. [PMID: 28925940 PMCID: PMC5618651 DOI: 10.3390/ijms18092002] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 08/31/2017] [Accepted: 09/14/2017] [Indexed: 12/21/2022] Open
Abstract
Diabetes mellitus (DM) is a crucial metabolic disease that leads to severe disorders. These include macrovascular complications such as myocardial infarction, stroke, and peripheral artery disease and microvascular complications including diabetic nephropathy, neuropathy, and retinopathy. Diabetes mellitus, along with its associated organ pathologies, is one of the key problems in today's medicine. Zebrafish is an upcoming disease model organism in diabetes research. Its glucose metabolism and the pathways of reactive metabolite formation are very similar to those of humans. Moreover, several physiological and pathophysiological pathways that also exist in humans and other mammals have been identified in this species or are currently under intense investigation. Zebrafish offer sophisticated imaging techniques and allow simple and fast genetic and pharmacological approaches with a high throughput. In this review, we highlight achievements and mechanisms concerning microvascular complications discovered in zebrafish, and we discuss the advantages and disadvantages of zebrafish as a model for studying diabetic complications.
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15
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Mehrabzadeh M, Pasalar P, Karimi M, Abdollahi M, Daneshpour M, Asadolahpour E, Razi F. Association between ELMO1 gene polymorphisms and diabetic nephropathy in an Iranian population. J Diabetes Metab Disord 2016; 15:43. [PMID: 27761430 PMCID: PMC5055690 DOI: 10.1186/s40200-016-0265-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 09/29/2016] [Indexed: 01/01/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is one of the leading causes of death in patients with type 2 diabetes mellitus (T2DM). Several genome-wide association studies have introduced Engulfment and Cell Motility 1 (ELMO1) as a candidate gene which is associated with DN. This study assessed the association of ELMO1 gene polymorphisms with DN in order to investigate the effects of ELMO1 gene on susceptibility to DN in an Iranian population. METHODS In the present study, 100 patients with T2DM, 100 patients with DN and 100 healthy subjects who were matched for sex were selected. Allele and genotype frequencies were determined by Tetra-ARMS PCR technique. In all groups, levels of FBS, creatinine, urea, HbA1C, urine levels of albumin creatinine ratio and glomerular filtration rate were measured. RESULTS A statistically significant association was shown between G allele of rs741301 (odds ratio (OR) = 1.7 [95 % CI 1.17-2.63]; p value = 0.005), and GG genotypes of rs741301 (OR = 2.5 [95 % CI 1.2-5.4]; p value = 0.01) and DN. A significant association was not detected between allelic and genotypic frequencies of rs1345365 and DN. Linkage Disequilibrium (LD) between two variants was weak (D' = 0.11, r2 = 0.008). rs1345365A/rs741301A haplotypes were more frequent in patients with T2DM as compared to DN (OR = 0.5 [95 % CI 0.3-0.7]; p value = 0.0006). Also, genotypes of variant rs741301 in all subjects had significant difference with respect to the mean of ACR (p Value < 0.05). CONCLUSION This study first investigated the association of ELMO1 gene polymorphisms (rs741301) with DN in an Iranian population, supporting its key role as a candidate gene in the susceptibility to DN.
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Affiliation(s)
- Mohsen Mehrabzadeh
- Department of Medical Biochemistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Parvin Pasalar
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Science Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mostafa Karimi
- Department of Medical Biochemistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Abdollahi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, 1411413137 Iran
| | - Maryam Daneshpour
- Endocrinology and Metabolism Clinical Sciences Institute, Shahid beheshti University of Medical Sciences, Tehran, Iran
| | - Effat Asadolahpour
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, 1411413137 Iran
| | - Farideh Razi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, 1411413137 Iran
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Lin CH, Chang YC, Chuang LM. Early detection of diabetic kidney disease: Present limitations and future perspectives. World J Diabetes 2016; 7:290-301. [PMID: 27525056 PMCID: PMC4958689 DOI: 10.4239/wjd.v7.i14.290] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/29/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common diabetic complications, as well as the leading cause of chronic kidney disease and end-stage renal disease around the world. To prevent the dreadful consequence, development of new assays for diagnostic of DKD has always been the priority in the research field of diabetic complications. At present, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) are the standard methods for assessing glomerular damage and renal function changes in clinical practice. However, due to diverse tissue involvement in different individuals, the so-called “non-albuminuric renal impairment” is not uncommon, especially in patients with type 2 diabetes. On the other hand, the precision of creatinine-based GFR estimates is limited in hyperfiltration status. These facts make albuminuria and eGFR less reliable indicators for early-stage DKD. In recent years, considerable progress has been made in the understanding of the pathogenesis of DKD, along with the elucidation of its genetic profiles and phenotypic expression of different molecules. With the help of ever-evolving technologies, it has gradually become plausible to apply the thriving information in clinical practice. The strength and weakness of several novel biomarkers, genomic, proteomic and metabolomic signatures in assisting the early diagnosis of DKD will be discussed in this article.
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17
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High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy. Proc Natl Acad Sci U S A 2016; 113:2218-22. [PMID: 26858454 DOI: 10.1073/pnas.1600511113] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2(Akita) gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.
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18
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Tomino Y, Gohda T. The Prevalence and Management of Diabetic Nephropathy in Asia. KIDNEY DISEASES 2015; 1:52-60. [PMID: 27536665 DOI: 10.1159/000381757] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 03/16/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN), especially type 2 diabetes, is now increasing rapidly worldwide, also in Asian countries, and is one of the major long-term vascular complications. The pathogenesis of DN involves both genetic and environmental factors. Around 30-40% of type 2 diabetic patients develop DN despite strict blood glucose and/or blood pressure control. Although it is considered that the genetic background may influence the initiation and progression of DN, the candidate genes are still obscure. SUMMARY To search for genes that are involved in the susceptibility of DN, a candidate gene approach was taken in the beginning before the development of genome-wide association studies. Although a candidate gene approach can detect rare genetic variants, in advance we need known or presumed pathophysiological knowledge of the specific gene. Investigations using spontaneous animal models are important to determine the pathogenesis and treatment of DN patients. There are many spontaneous animal models, such as the NOD and Akita mice for type 1 diabetes and the Ob/Ob, db/db, Tsumura Suzuki Obese Diabetics, and KK-A (y) mice for type 2 diabetes. Furthermore, the toxicity of persistent hyperglycemia, the activation of reactive oxygen species, systemic and/or glomerular hypertension, microinflammation, dyslipidemia, and other factors are considered to play important roles. Diabetic patients with normoalbuminuria and normal renal function showed typical histological patterns of DN. The discovery of a specific and reliable diagnostic and prognostic biomarker other than albuminuria is urgently needed and indispensable. Since large clinical trials of oral hypoglycemic drugs in renal failure are lacking, these recommendations will need to be regularly updated after results of larger randomized trials with longer follow-up durations are available. KEY MESSAGE It is necessary to summarize the basic and clinical features of DN patients in Asia and to use these for the treatment of such patients. FACTS FROM EAST AND WEST The prevalence of DN is increasing in Asia and Western countries alike. The deletion (D) allele of the angiotensin-converting enzyme gene is associated with progression to end-stage renal disease in Asian patients with DN, but this association is uncertain in Europeans. An association between DN and polymorphism of the gene coding for acetyl coenzyme A carboxylase β has been reported in Asian and Western populations. Both in Japan and the US, criteria for diagnosis are a 5-year history of diabetes and persistent albuminuria. Renal biopsy should be done in patients with severe hematuria, cellular casts and - in the US - hepatitis and HIV to rule out other pathologies. Diabetic retinopathy is considered a key criterion in Japan, but the absence of it does not rule out DN in the US. Enlargement of the kidney is observed as a diagnostic criterion in Japan. The differential use of renal biopsy as diagnostic tool might account for a different prevalence between Asian countries. Some Japanese diabetic patients showed typical histological alterations for DN with a normal ACR and GFR. The clinical classification is similar between Japan and the US including five stages based on ACR and GFR. The Japanese guidelines do not include blood pressure values for the classification of DN. Guidelines for DN treatment are evolving quickly both in Asia and Western countries based on the numerous clinical trials performed worldwide. Targeting the angiotensin system for its hemodynamic and nonhemodynamic effects is a common approach. DPP-4 inhibitors are widely used in Japan and might have a higher glucose-lowering effect in Asian patients due to their specific diet. A randomized, double-blind placebo-controlled study has been launched to assess the efficacy of the Chinese herbal tea extract Shenyan Kangfu in DN.
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Affiliation(s)
- Yasuhiko Tomino
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Tomohito Gohda
- Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
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19
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Liao LN, Chen CC, Wu FY, Lin CC, Hsiao JH, Chang CT, Kardia SLR, Li TC, Tsai FJ. Identified single-nucleotide polymorphisms and haplotypes at 16q22.1 increase diabetic nephropathy risk in Han Chinese population. BMC Genet 2014; 15:113. [PMID: 25359423 PMCID: PMC4222374 DOI: 10.1186/s12863-014-0113-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 10/13/2014] [Indexed: 12/20/2022] Open
Abstract
Background Diabetic nephropathy (DN) has become one of the most common causes of end-stage renal disease (ESRD) in many countries, such as 44.5% in Taiwan. Previous studies have shown that there is a genetic component to ESRD. Studies attempting to determine which genetic variants are related to DN in Han Chinese are limited. A case–control study was conducted to identify DN susceptibility variants in Han Chinese patients with type 2 diabetes. Results We included 574 unrelated type 2 diabetes patients (217 DN cases and 357 controls), who were genotyped using Illumina HumanHap550-Duo BeadChip. In single-SNP association tests, the SNPs rs11647932, rs11645214, and rs6499323 located at 16q22.1 under the additive-effect disease model were significantly associated with an approximately 2-fold increased risk of DN. In haplotype association tests, identified haplotypes located in the chromosome 16q22.1 region (containing ST3GAL2, COG4, SF3B3, and IL34 genes) raised DN risk. The strongest association was found with haplotype rs2288491-rs4985534-rs11645214 (C-C-G) (adjusted odds ratio [AOR] 1.93, 95% confidence interval [CI] 1.83-2.03, p = 6.25 × 10−7), followed by haplotype rs8052125-rs2288491-rs4985534-rs11645214 (G-C-C-G) (AOR 1.92, 95% CI 1.82-2.02, p = 6.56 × 10−7), and haplotype rs2303792-rs8052125-rs2288491-rs4985534-rs11645214 (A-G-C-C-G) (AOR 1.91, 95% CI 1.81-2.01, p = 1.15 × 10−6). Conclusions Our results demonstrate that the novel SNPs and haplotypes located at the 16q22.1 region may involve in the biological pathways of DN in Han Chinese patients with type 2 diabetes. This study can provide new insights into the etiology of DN. Electronic supplementary material The online version of this article (doi:10.1186/s12863-014-0113-8) contains supplementary material, which is available to authorized users.
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