Abstract
To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10−4) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10−10. We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10−10). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.
Highlights
Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD), and its prevalence is progressively increasing according to the increase of number of patients with diabetes mellitus [1,2]
We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10−10)
After combining all association data (Stage-1 set-1, set-2 and Stage-2) using the inverse-variance fixed-effects metaanalysis, we found that one SNP locus, rs56094641 in FTO at chromosome (Chr) 16, 16q12.2, showed a genome-wide significant association with diabetic nephropathy (P = 7.74 × 10−10, odds ratio (OR) = 1.23, 95% confidence interval (CI) 1.15−1.31, Table 2 and S2 Table)
Summary
Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD), and its prevalence is progressively increasing according to the increase of number of patients with diabetes mellitus [1,2]. Worldwide efforts to identify susceptibility loci for diabetic nephropathy, have not yet met with success so much. Several susceptibility loci to diabetic nephropathy or its related traits which showed their lowest p-values close to or with a genome-wide significance level have been unveiled; rs2268388 in ACACB [7], rs7583877 in AFF3 locus, rs17709344 in RGMA-MCTP2 locus [8], rs4972593 in Sp3-CDCA7 locus [9], rs1801239 in CUBN locus [10], rs161740 in EPO locus [11]. The results have not been conclusive, and most susceptibility loci for diabetic nephropathy remain to be un-identified, suggesting heterogeneity of the disease or contribution of non-genetic factors, which have not been taken into account, may produce inconsistent results among the studies
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