Abstract
A genome-wide association scan of type 1 diabetic patients from the GoKinD collections previously identified four novel diabetic nephropathy susceptibility loci that have subsequently been shown to be associated with diabetic nephropathy in unrelated patients with type 2 diabetes. To expand these findings, we examined whether single nucleotide polymorphisms (SNPs) at these susceptibility loci were associated with diabetic nephropathy in patients from the Joslin Study of Genetics of Nephropathy in Type 2 Diabetes Family Collection. Six SNPs across the four loci identified in the GoKinD collections and 7 haplotype tagging SNPs, were genotyped in 66 extended families of European ancestry. Pedigrees from this collection contained an average of 18.5 members, including 2 to 14 members with type 2 diabetes. Among diabetic family members, the 9q21.32 locus approached statistical significance with advanced diabetic nephropathy (P = 0.037 [adjusted P = 0.222]). When we expanded our definition of diabetic nephropathy to include individuals with high microalbuminuria, the strength of this association improved significantly (P = 1.42×10−3 [adjusted P = 0.009]). This same locus also trended toward statistical significance with variation in urinary albumin excretion in family members with type 2 diabetes (P = 0.032 [adjusted P = 0.192]) and in analyses expanded to include all relatives (P = 0.019 [adjusted P = 0.114]). These data increase support that SNPs identified in the GoKinD collections on chromosome 9q21.32 are true diabetic nephropathy susceptibility loci.
Highlights
IntroductionIn both the microalbuminuric and proteinuric ranges, is a hallmark of diabetic nephropathy (DN) [1,2]
Increased urinary albumin excretion, in both the microalbuminuric and proteinuric ranges, is a hallmark of diabetic nephropathy (DN) [1,2]
Our genome-wide association (GWA) scan of the Genetics of Kidneys in Diabetes (GoKinD) collections identified strong association at four distinct chromosomal regions, including loci on chromosomes 9q21.32, 11p15.4, and 13q33.3 that have since been confirmed in multiple collections comprised of unrelated type 1 diabetic (T1D) or type 2 diabetic (T2D) subjects [18,20,21,22]
Summary
In both the microalbuminuric and proteinuric ranges, is a hallmark of diabetic nephropathy (DN) [1,2]. We identified strong associations at several common single nucleotide polymorphisms (SNPs, minor allele frequencies .5%) located across four distinct chromosomal regions Three of these loci, located on chromosome 9q21.32 near the FRMD3 gene, chromosome 11p15.4 at the CARS gene, and chromosome 13q33.3 at the MYO16/IRS2 locus, have since been confirmed in multiple diverse collections of unrelated T1D or type 2 diabetic (T2D) patients [18,20,22]. A more recent meta-analysis of T1D nephropathy, defined as end-stage renal disease (ESRD), in European-derived populations, failed to confirm these, as well as several other, previously reported genetic associations; reinforcing the need for further investigation of these and other loci to truly understand their role in the genetic basis of DN [23]
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