Segregation analysis of urinary albumin excretion in families with type 2 diabetes

Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality. To study whether genetic facto rs may determine UAE, we examined familial aggregation of UAE in 96 large m ultigenerational pedigrees ascertained for type 2 diabetes. A total of 1,26 9 subjects had UAE measured as the urinary albumin-to-creatinine ratio (ACR ). This included 630 subjects with type 2 diabetes and 639 subjects without diabetes. A significant correlation (Spearman's correlation 0.34, P < 0.00 1) was found between the median ACR values determined separately in nondiab etic and diabetic members of the same family To determine whether this fami lial aggregation of ACR could be explained by the transmission of 1 or more major genes and thus be suitable for gene mapping studies, segregation ana lyses were performed. In these analyses, ACR was modeled as a continuous tr ait with the inclusion of age, sex, and duration of diabetes as covariates. Likelihood ratio tests were performed to test competing hypotheses, and Ak aike's information criterion was used to determine the most parsimonious mo dels. The Mendelian model with multifactorial inheritance was supported mor e strongly than Mendelian inheritance alone. These analyses suggested that the best model for ACR levels was multifactorial with evidence for a common major gene. When the analyses were repeated for diabetic subjects only, th e evidence for Mendelian inheritance was improved, although a single major locus with additional multifactorial effects was more strongly supported. T he results from the current study suggest that levels of UAE are determined by a mixture of genes with large and small effects as well as other measur ed covariates, such as diabetes.