Genetic variants in ELMO1
have recently been shown to be associated with diabetic nephropathy in two independent and ethnically distinct collections of patients with type 2 diabetes (10
). In this report, we examined whether variants in this same gene are associated with the risk of diabetic nephropathy in patients with type 1 diabetes. Through our comprehensive analysis of this locus, we extend these previous findings by demonstrating that variants in ELMO1
are also associated with the risk of diabetic nephropathy in Caucasian type 1 diabetic patients.
We investigated the role of 118 SNPs in ELMO1
, including 12 SNPs previously reported to be associated with diabetic nephropathy in type 2 diabetes. Our analysis identified associations at several intronic SNPs (rs7785934, rs2041801, rs11769038, and rs1882080; P
= 1.7 × 10−3
to 5.6 × 10−3
). Although none of these SNPs met stringent criteria for significance following adjustment for multiple testing (P
< 0.05/118 = 4.3 × 10−4
), this threshold was exceeded by one SNP (rs7785934) when our analysis was limited to case subjects with ESRD. Moreover, the modest effect size of this variant (OR 1.33) is consistent with those previously reported in two independent African American ESRD populations (14
), suggesting a comparable effect in the two populations. Additionally, the two-SNP haplotypes formed by rs7785934 and either rs11769038 or rs1882080 were more strongly associated with ESRD than these individual SNPs, suggesting that the LD block containing these SNPs forms a larger haplotype that either contains or is in tight LD with the causal variant at this locus. Together, these data also suggest that ELMO1
may have a role in the advanced stages of diabetic nephropathy, perhaps contributing to renal function decline, rather than its initiation. We acknowledge, however, that the GoKinD collection is heavily weighted with case subjects with ESRD. The small number of case subjects with proteinuria may have limited our ability to detect ELMO1
variants that are primarily associated with the risk of proteinuria. Despite this limitation, functional studies have demonstrated that ELMO1 contributes to the progression of chronic glomerular injury through its dysregulation of extracellular matrix (ECM) metabolism, resulting in renal ECM accumulation (11
). This accumulation contributes to both glomerular and tubular basement membrane thickening, two well-established hallmarks of advanced diabetic nephropathy (23
Our investigation marks the third report of genetic associations in ELMO1
with diabetic nephropathy, further establishing its role in conferring increased susceptibility to this disease. Previous reports (10
) identified their strongest associations at variants located more than 280 kb apart in introns 17 and 13. Although our strongest associations are located near the associated SNP reported by Shimazaki et al. (10
), our most associated SNPs are independent of those reported in this study. Furthermore, no evidence of association for the variants reported in either type 2 diabetic population was identified in our collection. The associations at ELMO1
across each study are consistent with allelic heterogeneity, likely contributed by the diverse ancestral genetic backgrounds of the different ethnic groups. Examination of the associated SNPs from each study in the available HapMap populations (www.hapmap.org
) confirms the variable allele frequencies of these variants among different ethnic and racial groups (data not shown). We hypothesize that rare polymorphisms in ELMO1
, either the same variants or those in strong or complete LD, may be common to each ethnic group and merely tagged by the common variants identified in each study. Further investigation of rare SNPs at the ELMO1
locus is necessary to fully understand the commonality of these associations and to elucidate the mechanism(s) underlying their role in diabetic nephropathy.
In summary, our study provides the first comprehensive analysis of genetic variants at the ELMO1 locus in a Caucasian population with diabetic nephropathy and type 1 diabetes. Our analysis identified several associations that are independent of those previously identified in other ethnic groups with diabetic nephropathy and type 2 diabetes; however, our examination of this locus in the GoKinD collection further supports its potential role in this disease. Confirmation of the associations identified in our study in additional collections, including ethnically diverse populations with either type 1 or type 2 diabetes, is necessary to better understand the role of these variants, and, perhaps, rare variants yet to be examined may underlie the genetic susceptibility of diabetic nephropathy attributed to this locus.