Abstract
Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality. To study whether genetic factors may determine UAE, we examined familial aggregation of UAE in 96 large multigenerational pedigrees ascertained for type 2 diabetes. A total of 1,269 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 < 0.001) was found between the median ACR values determined separately in nondiabetic and diabetic members of the same family. To determine whether this familial aggregation of ACR could be explained by the transmission of 1 or more major genes and thus be suitable for gene mapping studies, segregation analyses were performed. In these analyses, ACR was modeled as a continuous trait with the inclusion of age, sex, and duration of diabetes as covariates. Likelihood ratio tests were performed to test competing hypotheses, and Akaike's information criterion was used to determine the most parsimonious models. The Mendelian model with multifactorial inheritance was supported more 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, the evidence for Mendelian inheritance was improved, although a single major locus with additional multifactorial effects was more strongly supported. The 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 measured covariates, such as diabetes.
Highlights
Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality
Urinary albumin excretion (UAE) elevated into the range diagnosed as macroalbuminuria or proteinuria is the hallmark of diabetic nephropathy [1,2]
This study presents, for the first time, a formal analysis of the inheritance characteristics of the major diabetic nephropathy trait, albumin-to-creatinine ratio (ACR), in Caucasian families with type 2 diabetes
Summary
ACR data from all examined members of these families, irrespective of diabetes status, were used in the analyses. At the time of examination, 50% of the diabetic members were treated with insulin, 30% with oral agents, and 20% with diet (not including the 67 individuals with impaired glucose tolerance and 15 with gestational diabetes). In those without diabetes, the distribution of logACR is unimodal (median 6 μg/mg) with a small proportion (5%) having ACR values between 42 and 4,200 μg/mg (Fig. 1 insert).
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