Segregation analysis of diabetic nephropathy in Pima Indians

Familial aggregation of diabetic nephropathy suggests the existence of gene s determining susceptibility to nephropathy in addition to those leading to diabetes. In the present study, complex segregation analysis was performed in diabetic members of Pima Indian families to determine whether familial aggregation of nephropathy in this population could reflect the action of a single major gene. Nephropathy, defined by a urinary protein-to-creatinine ratio (PCR) greater than or equal to 500 mg/g, was analyzed as a discrete trait in a class C regressive logistic model. Individuals with PCR <500 mg/ g were considered unaffected. Segregation analysis was performed both for n ephropathy at the last examination (prevalent cases) and for duration of di abetes at the onset of nephropathy (incident cases). The REGD program was u sed for the analysis of the prevalent cases and the REGTL program for the i ncident cases, both from the Statistical Analysis for Genetic Epidemiology package (Case Western University, Cleveland, OH). The analysis of prevalent cases included 2,107 Pima Indians from 715 nuclear families. A subset of 5 04 of these families containing 1,403 individuals was used in the analysis of incident cases. Analysis of prevalent cases supported the existence of a gene with a major role, in that hypotheses of no major effect and of no tr ansmission of a major effect were rejected (P = 0.00001; P = 0.003), wherea s Mendelian transmission was not rejected (P = 0.85). A dominant model prov ided the best fit, but a recessive model could not be rejected, The analysi s of incident cases, however, did not support a major gene effect on durati on of diabetes at the onset of nephropathy: and analyses of lifetime occurr ence of nephropathy were inconclusive. The analysis of prevalent cases supp orts the hypothesis of a major genetic effect on susceptibility to diabetic nephropathy in Pima Indians, but the analysis of incident cases does not s upport a genetic effect on duration of diabetes at the onset of nephropathy . The discrepancy may reflect the difficulty in precisely dating onset of n ephropathy. The parameters of the model derived from segregation analysis o f prevalent cases may be useful in linkage studies to detect nephropathy su sceptibility loci.