Abstract

Objective: The purpose of this study was to examine whether known genetic risk factors for type 1 diabetes (HLA DRB1, DQA1, and DQB1, and insulin locus) play a role in the etiology of diabetic nephropathy.

Research Design and Methods: Genetic analysis of HLA DRB1, DQA1, DQB1 and the insulin gene (INS) was performed in the GoKinD collection of DNA (European ancestry subset), which includes case patients with type 1 diabetes and nephropathy (N=829) and control patients with type 1 diabetes but not nephropathy (N=904). The availability of phenotypic and genotypic data on GoKinD participants allowed a detailed analysis of the association of these genes with diabetic nephropathy.

Results: Diabetic probands who were homozygous for HLA DRB1 04 were 50% less likely to have nephropathy than probands without any DRB1 04 alleles. In heterozygous carriers, a protective effect of this allele was not as clearly evident so the mode of inheritance remains unclear. This association was seen in probands, both with short duration (<28 years, p=0.02) and long duration (≥28 years, p=0.0001) of diabetes. HbA1c, a marker of sustained hyperglycemia, was increased in control probands with normoalbuminuira despite long-duration diabetes from 7.2 to 7.3 to 7.7% with 0, 1 and 2 copies of the DRB1 04 allele, respectively. This result is consistent with a protective effect of DRB1 04 that may allow individuals to tolerate higher levels of hyperglycemia as measure by HbA1c without developing nephropathy.

Conclusions: These data suggest that carriers of DRB1 04 are protected from some of the injurious hyperglycemic effects related to nephropathy. Interestingly, DRB1 04 appears to be both a risk allele for type 1 diabetes and a protective allele for nephropathy.