The association of genetic variants of type 2 diabetes with kidney function

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Kidney International (Impact Factor: 8.52). 04/2012; 82(2):220-5. DOI: 10.1038/ki.2012.107
Source: PubMed

ABSTRACT Type 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to-creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations.

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Available from: Jean Maccluer, Jul 29, 2015
    • "There are limited studies on the association of the rs12255372 and rs7903146 polymorphisms with DN. The T allele of the rs7903146 TCF7L2 variant has shown association with lower eGFR in American Indians (Franceschini et al., 2012) and with DN in patients with early onset of diabetes in Caucasians of Polish origin (Buraczynska et al., 2011; Buraczynska et al., 2014). A recent study from South India (Hussain et al., 2014) has reported the association of the rs7903146 TCF7L2 gene polymorphism with T2DM and DN. "
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    ABSTRACT: The transcription factor 7-like 2 (TCF7L2) gene plays a significant role in the development of type 2 diabetes and diabetic nephropathy. The aim of this study was to investigate the association of TCF7L2 rs12255372 (G/T)polymorphism with type 2 diabetic nephropathy in the South Indian population. A total of 2102 subjects, 927 normal glucose tolerant (NGT) subjects, 598 type 2 diabetic subjects without nephropathy (DM), and 577 type 2 diabetic subjects with nephropathy (DN) were genotyped by MassARRAY. As compared to the NGT group, the odds ratio (adjusted for age, sex, BMI, HbA1c, and systolic BP) computed for the GT/TT genotype taking the GG genotype as reference was found to be 2.02 (95% CI: 1.16-3.51, p = 0.013) for DN and 1.94 (95% CI: 1.36-2.78, p = 0.0002) for DM. The genotype frequency was not significantly different between the DM and DN groups. In conclusion, the rs12255372 polymorphism in the TCF7L2 gene is associated with type 2 diabetes and DN but its association with DN is mediated through diabetes. © 2015 John Wiley & Sons Ltd/University College London.
    Annals of Human Genetics 07/2015; DOI:10.1111/ahg.12122 · 1.93 Impact Factor
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    ABSTRACT: BACKGROUND: Genetic determinations are important in type 2 diabetes (T2D) pathology. We investigated associations between genetic variants of 17 diabetes-related genes/loci, T2D and diabetic complications in Chinese She subjects. METHODS: A comprehensive gene-based association study was conducted using 17 single nucleotide polymorphisms (SNPs) in Chinese She subjects with normal glucose tolerance (NGT; n=1119), impaired glucose regulation (IGR; n=1767), and T2D (n=443). We applied major abnormal Minnesota Code findings to predict cardiovascular risk and estimated glomerular filtration rate (eGFR) to assess kidney function. RESULTS: Nine variants in FTO rs8050136, WFS1 rs10010131, CDKN2A/B rs10811661, KCNJ11 rs5219, CDC123/CAMK1D rs12779790, JAZF1 rs864745, SLC30A8 rs13266634, CDKAL1 rs10946398 and HHEX/IDE rs5015480 were significantly associated with T2D (p<0.05). SNPs in WFS1 rs10010131, CDKN2A/B rs10811661, CDC123/CAMK1D rs12779790, JAZF1 rs864745, FTO rs8050136 and HHEX/IDE rs5015480 were associated with T2D and IGR. Risk alleles in WFS1 rs10010131, IGF2BP2 rs4402960, CDKAL1 rs10946398, FTO rs8050136, KCNQ1 rs2237897 and ADAMTS9 rs4607103 were significantly associated with decreased HOMA-β (p<0.05). After adjusting for age, gender and BMI, genetic variants JAZF1 rs864745, FTO rs8050136, and HHEX/IDE rs5015480 were significantly related to reduced eGFR (p<0.05). Genetic variants in WFS1 rs10010131, CDKN2A/B rs10811661, CDC123/CAMID rs12779790, JAZF1 rs864745, FTO rs80501360, CDKAL1 rs10946398 and HHEX/IDE rs5015480 correlated with abnormal major Minnesota Code findings (p<0.05). CONCLUSION: Variants in WFS1, CDKN2A/B, KCNJ11, CDC123/CAMK1D, JAZF1, SLC30A8, FTO, CDKAL1 and HHEX/IDE genes are significantly associated with T2D in She Chinese subjects. JAZF1, FTO, CDKAL1 and HHEX/IDE are associated with diabetic nephropathy. WFS1, CDKN2A/B, CDC123/CAMK1D, JAZF1, FTO, CDKAL1 and HHEX/IDE are associated with cardiovascular risk. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.
    Journal of Diabetes 01/2013; 5(2). DOI:10.1111/1753-0407.12025 · 2.35 Impact Factor
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    ABSTRACT: The gene WFS1 encodes a protein with unknown function although its functional deficiency causes different neuropsychiatric and neuroendocrine syndromes. In the present study, we aimed to find the functional networks influenced by the time-dependent silencing of WFS1 in HEK cells. We performed whole genome gene expression profiling (Human Gene 1.0 ST Arrays) in HEK cells 24, 48, 72 and 96 hours after transfection with three different WFS1 siRNAs. In order to verify silencing we performed quantitative RT-PCR and western blot analysis. Analysis was conducted in two ways. First we analyzed the overall effect of the siRNA treatment on the gene expression profile. As a next step we performed time-course analysis separately for different siRNAs and combined for all siRNAs. Quantitative RT-PCR and western blot analysis confirmed clear silencing of the expression of WFS1 after 48 hours. Significant (FDR value less than 10%) changes in the expression of eleven genes was identified with most of these genes being related to the mitochondrial dysfunction and apoptosis. Time-course analysis confirmed significant correlations between WFS1 silencing and changes in the expression profiles of several genes. The pathways that were influenced significantly by WFS1 silencing were related to mitochondrial damage and neurodegenerative diseases. Our findings suggest a role of WSF1 gene in cell survival and its involvement in degenerative diseases.
    Physiological Genomics 01/2013; 45(5). DOI:10.1152/physiolgenomics.00122.2012 · 2.81 Impact Factor
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