Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy

Abstract

Objective: To examine the association between single nucleotide polymorphisms (SNPs) in the engulfment and cell motility 1 (ELMO1) gene, a locus previously shown to be associated with diabetic nephropathy in two ethnically distinct type 2 diabetic populations, and the risk of nephropathy in type 1 diabetes.

Research design and methods: Genotypic data from a genome-wide association scan (GWAS) of the Genetics of Kidneys in Diabetes (GoKinD) study collection were analyzed for associations across the ELMO1 locus. In total, genetic associations were assessed using 118 SNPs and 1,705 individuals of European ancestry with type 1 diabetes (885 normoalbuminuric control subjects and 820 advanced diabetic nephropathy case subjects).

Results: The strongest associations in ELMO1 occurred at rs11769038 (odds ratio [OR] 1.24; P = 1.7 x 10(-3)) and rs1882080 (OR 1.23; P = 3.2 x 10(-3)) located in intron 16. Two additional SNPs, located in introns 18 and 20, respectively, were also associated with diabetic nephropathy. No evidence of association for variants previously reported in type 2 diabetes was observed in our collection.

Conclusions: Using GWAS data from the GoKinD collection, we comprehensively examined evidence of association across the ELMO1 locus. Our investigation marks the third report of associations in ELMO1 with diabetic nephropathy, further establishing its role in the susceptibility of this disease. There is evidence of allelic heterogeneity, contributed by the diverse genetic backgrounds of the different ethnic groups examined. Further investigation of SNPs at this locus is necessary to fully understand the commonality of these associations and the mechanism(s) underlying their role in diabetic nephropathy.

FIG. 1.

Summary of association results for SNPs in the ELMO1 locus in the GoKinD collection. GWAS and imputed data for 118 SNPs across the ELMO1 locus on chromosome 7p are presented. Shaded circles represent SNPs genotyped on the Affymetrix array (n = 106), and unshaded circles represent imputed SNPs from previous reports by Shimazaki et al. and Leak et al. (10,14) (n = 12). The strongest associations in GoKinD occurred at rs7785934, rs2041801, rs11769038, and rs1882080 and localize to three LD blocks (BL1, BL2, and BL3; shown in gray) that span introns 16–21 of the ELMO1 gene.