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Effect of the Peroxisome Proliferator-Activated Receptor-2 Pro¹²Ala Variant on Obesity, Glucose Homeostasis, and Blood Pressure in Members of Familial Type 2 Diabetic Kindreds¹

Department of Human Genetics, University of Utah (S.J.H.), Salt Lake City, Utah 84112-5330; and Division of Endocrinology, Department of Medicine, Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences (Q.-F.R., K.T., S.C.E.), Little Rock, Arkansas 72205

Address all correspondence and requests for reprints to: Steven C. Elbein, M.D., Endocrinology 111J/LR, 4300 West 7th Street, Little Rock, Arkansas 72205. E-mail: elbeinstevenc{at}exchange.uams.edu

The Pro¹²Ala (P12A) variant of exon B of the peroxisome proliferator-activated receptor ₂ (PPAR) been variably associated with obesity, insulin sensitivity, diabetes, and dyslipidemia, but its role in insulin resistance-associated traits remains uncertain. We tested the hypothesis that this variant is associated with the insulin resistance syndrome by genotyping 619 members of 52 familial type 2 diabetes kindreds. A subset of 124 family members underwent iv glucose tolerance tests and minimal model determination of insulin sensitivity. We estimated the frequency of the A12 allele 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 on chromosome 3q. However, body mass index, serum total cholesterol levels, triglyceride levels, systolic 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 analysis, body mass index, systolic and diastolic blood pressures, triglyceride levels, and glucose concentration remained significantly associated with the P12A variant (P < 0.05), whereas the effect of P12A on liability for diabetes was not significant. The predicted means for each trait and each genotype suggested that the P12A variant acted most like a recessive mutation, with the major effect among homozygous individuals who comprise only 1–2% of the population. We confirm an association of the P12A variant in traits commonly ascribed to the insulin resistance syndrome, but not with direct measures of insulin sensitivity. The tendency for this variant to act in a recessive manner with effects on multiple traits may explain the inconsistent associations noted in previous studies.

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