Genetic Studies of Late Diabetic Complications

Abstract

Genes play a role in many processes underlying late diabetic complications, but efforts to identify genetic variants have produced disappointing and contradictory results. Here, we evaluate whether the study designs and analytic methods commonly being used are optimal for finding susceptibility genes for diabetic complications. We do so by generating plausible genetic models and assessing the performance of case-control and family-based trio study designs. What emerges as a key determinant of success is duration of diabetes. This perspective focuses on duration of diabetes before complication onset and its influence on the ability to detect major and minor gene effects. It does not delve into the distinct effect of duration after complication onset, which can enrich case subjects with genotypes conferring survival advantage. We use clinically diagnosed nephropathy in type 1 diabetes to show how ignoring duration can result in considerable power loss in both case-control and family-based trio designs. We further show how, under certain circumstances, disregard for duration information can paradoxically lead to implicating nonrisk alleles as causative. Our results indicate that problems can be minimized by selecting case subjects with short diabetes duration and, to a lesser extent, control subjects with long duration or, perhaps, by adjusting for duration during analysis. Diabetes 51: [1655][1656][1657][1658][1659][1660][1661][1662] 2002

Identification of a Common Risk Haplotype for Diabetic Nephropathy at the Protein Kinase C-β1 (PRKCB1) Gene Locus

“…Specifically, the Ͻ24-yr duration group exhibited excess transmission of the T-G haplotype, whereas the Ն24-yr duration group exhibited deficient transmission of the same haplotype. This is precisely the pattern we would expect for a broad class of genetic models of diabetic nephropathy in which the duration of diabetes mellitus is important (19).…”

“…The cutoff value of 24 yr was determined a priori, on the basis of previously recorded information on the median diabetes mellitus duration (20), as described in Materials and Methods. The rationale for this stratification was to identify patients with shorter diabetes mellitus duration at the onset of proteinuria, because we previously demonstrated that this group was ideal for the identification of nephropathy genes (19). Lacking a direct estimate of the duration of diabetes mellitus at the onset of proteinuria, we chose to use the diabetes mellitus duration at the time of enrollment for patients with proteinuria and the duration at the initiation of dialysis for those with ESRD.…”

“…As we recently demonstrated, the duration of diabetes mellitus is an important factor to be controlled in genetic studies of diabetic nephropathy (19). A susceptibility allele would be more strongly associated with affected individuals with a short duration, rather than a long duration, of diabetes mellitus.…”

“…The duration of diabetes mellitus is an important effect modifier of genetic susceptibility to diabetic nephropathy (19). Simulation studies performed by our group demonstrated that focusing on individuals who developed diabetic nephropathy early in the course of diabetes mellitus could significantly improve the power of case-control and TDT studies to detect alleles contributing to susceptibility to diabetic nephropathy (19).…”

“…Simulation studies performed by our group demonstrated that focusing on individuals who developed diabetic nephropathy early in the course of diabetes mellitus could significantly improve the power of case-control and TDT studies to detect alleles contributing to susceptibility to diabetic nephropathy (19). Therefore, for this study we stratified the study group into two groups according to the median diabetes mellitus duration among case patients (24 yr), one group with a mean diabetes mellitus duration of 19 yr and the other with a mean duration of 31 yr.…”