Hidden population substructures in an apparently homogeneous population bias association studies.

Linkage- and association-based approaches have been applied to attempt to unravel the genetic predisposition for complex diseases. However, studies often report contradictory results even when similar population backgrounds are investigated. Unrecognized population substructures could possibly explain these inconsistencies. In an apparently homogeneous German sample of 612 patients with type 2 diabetic and end-stage diabetic nephropathy and 214 healthy controls, we tested for hidden population substructures and their possible effects on association. Using a genetic vector space analysis of genotypes of 20 microsatellite markers, we identified four distinct subsets of cases and controls. The significance of these substructures was demonstrated by subsequent association analyses, using three genetic markers (UCSNP-43,-19,-63; intron 3 of the calpain-10 gene). In the undivided sample, we found no association between individual SNPs or any haplogenotypes (ie the genotype combination of two multilocus haplotypes) and type 2 diabetes. In contrast, when analyzing the four groups separately, we found that there was evidence for association of the common C allele of UCSNP-63 with the trait in the largest group (n=547 cases/101 controls; P=0.002). In this subset haplotype 112 was more frequent in controls than in cases (P=0.006; haplogenotype 112/121: odds ratio (OR)=0.27, 95% confidence intervals (CI)=0.13-0.57), indicating a protective effect against the development of type 2 diabetes. Our study demonstrates that unconsidered population substructures (ethnicity-dependent factors) can severely bias association studies.

Genetic aspects of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy from type 2 diabetes mellitus is the most common cause of end-stage renal disease (ESRD) in the United States and in Western Europe. Although patients with overt nephropathy generally experience greater cumulative glycemic exposure, the difference in glycemic control between patients developing nephropathy compared to those who did not, could not be demonstrated. This observation is consistent with the notion that perhaps other factors, in addition to glycemic control, have a bearing on the development of nephropathy. Genetic factors, which specifically increase the susceptibility to nephropathy in patients with diabetes, have been proposed. METHODS: A range of linkage and association studies has been performed for revealing the genetic background of diabetic nephropathy. RESULTS: Until now, no mutation has been identified which could explain the development of diabetic nephropathy in the majority of diabetic patients. CONCLUSIONS: Because of relatively small case numbers of all studies being performed so far, conclusions from those studies are limited. With the development of better technologies for an affordable genome-wide association study using thousands of markers, it might become possible to unravel the genetic causes of diabetic nephropathy.

Diabetic nephropathy: an inherited disease or just a diabetic complication?

Type 2 diabetic nephropathy is the most common cause of end-stage renal disease in western Europe and the United States. Although patients with overt nephropathy generally experience greater cumulative glycemic exposure, the difference in glycemic control between patients developing nephropathy and to those who did not could not be demonstrated. This observation is consistent with the finding that factors other than glycemic control are involved in the development of nephropathy. Genetic factors which specifically increase the susceptibility to nephropathy in patients with diabetes have been proposed. A range of linkage, association, and gene expression studies have been performed for revealing the genetic background of diabetic nephropathy but were not yet successful in identifying mutations which could explain the development of diabetic nephropathy in the majority of diabetic patients. Because of relatively small case numbers of all studies being performed so far, conclusions from those studies are limited. With the development of better technologies for an affordable genomewide association study using thousands of markers, it might become possible to unravel the genetic susceptibility factors for diabetic nephropathy. Comparing the expression levels of thousands of genes in patients and controls may identify key players in the pathogenesis of diabetic nephropathy and targets for pharmacologic intervention in the future.