Effect of the peroxisome proliferator-activated receptor-gamma 2 Pro(12)Ala variant on obesity, glucose homeostasis, and blood pressure in members offamilial type 2 diabetic kindreds

The Pro(12)Ala (P12A) variant of exon B of the peroxisome proliferator-acti vated receptor gamma (2) (PPAR gamma) been variably associated with obesity , insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis th at this variant is associated with the insulin resistance syndrome by genot yping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model deter mination of insulin sensitivity. We estimated the frequency of the A12 alle le as 0.12, within the range observed in random Caucasian samples. We were unable to demonstrate any effect on direct measures of insulin sensitivity, and no trait was linked to markers near PPAR gamma on chromosome 3q. Howev er, body mass index, serum total cholesterol levels, triglyceride levels, s ystolic and diastolic blood pressures, and glucose concentration showed at least a trend to association (P < 0.1) when tested separately for a family- based association. When these 6 traits were included in a multivariate anal ysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with t he P12A variant (P < 0.05), whereas the effect of P12A on liability for dia betes was not significant. The predicted means for each trait and each geno type suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1-2% o f the population. We confirm an association of the P12A variant in traits c ommonly ascribed to the insulin resistance syndrome, but not with direct me asures of insulin sensitivity. The tendency for this variant to act in a re cessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.