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Studies of the Pro12Ala Polymorphism of the PPAR- Gene in the Danish MONICA Cohort: Homozygosity of the Ala Allele Confers a Decreased Risk of the Insulin Resistance Syndrome

Department of Endocrinology (L.F., K.B., S.M., S.A.U.) and Clinical Biochemistry (M.F.), Hvidovre University Hospital, Hvidovre DK-2650, Denmark; Center of Preventive Medicine (T.J.), Glostrup University Hospital, Glostrup DK-2600, Denmark; and Steno Diabetes Center (K.B.-J.), Copenhagen DK-2820, Denmark

Address all correspondence and requests for reprints to: Søren A. Urhammer, M.D., D.M.Sci, Department of Endocrinology, Hvidovre University Hospital, Kettegård Alle 30, DK-2650 Hvidovre, Copenhagen, Denmark. E-mail: . sau{at}dadlnet.dk

Abstract

The Pro12Ala polymorphism of PPAR-2 has been shown to influence insulin sensitivity and the risk of type 2 diabetes in various ethnic populations. We examined whether the polymorphism was related to the insulin resistance syndrome (IRS) among nondiabetic Danish subjects. The Pro12Ala variant was examined using PCR-restriction fragment length polymorphism in a phenotypically well characterized population-based sample of 2245 nondiabetic subjects. The study participants were characterized by a number of anthropometric and biochemical measurements and the European Group for the Study of Insulin Resistance criteria enabling a classification of the study population in an IRS group and a non-IRS group. The allelic frequency of the Pro12Ala polymorphism in the total study sample was 14% (95% confidence interval, 13–15%). Two hundred ninety-four subjects fulfilled the European Group for the Study of Insulin Resistance criteria defining the IRS. The frequency of the Ala allele was 12.6% in the IRS group and 14.2% among subjects classified as not having the IRS (P = 0.15). However, the frequency of the variant in the homozygous form was significantly lower in the IRS group [0.7% (0–1.6%)] compared with the frequency in the non-IRS group [2.8% (2.1–3.5%); P = 0.02; odds ratio, 0.24 (0.06–0.99)]. Moreover, in the total study population, homozygous carriers of the variant had lower levels of fasting serum triglyceride [1.1 ± 0.4 mmol/liter (means ± SD) vs. 1.4 ± 0.9 mmol/liter; P = 0.04] and a lower diastolic blood pressure (79 ± 8 mm Hg vs. 82 ± 11 mm Hg; P = 0.01) compared with wild-type carriers. The same tendency was observed with regard to the homeostasis model assessment estimate of insulin resistance (P = 0.16). There were no differences between genotype groups with respect to measures of body composition (BMI and waist circumference). In conclusion, homozygosity of the codon 12 variant of PPAR-2 confers a reduced risk of the IRS among Danish Caucasian subjects.

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