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The Peroxisome Poliferator–Activated Receptor-2 Pro12Ala Variant

Association With Type 2 Diabetes and Trait Differences

¹ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
² Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, Maryland
³ Division of Biostatistics, Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles
⁴ Sequenom Inc., San Diego, California
⁵ Department of Epidemiology and Health Promotion, Diabetes and Genetic Epidemiology Unit, and the Department of Biochemistry, National Public Health Institute, Helsinki, Finland
⁶ Department of Medicine and the
⁷ Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
⁸ Department of Public Health, University of Helsinki, Helsinki, Finland

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator–activated receptor-2 (PPAR-2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m²) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.

Abbreviations: AIR_G, acute insulin response to glucose; dBP, diastolic blood pressure; DI, disposition index; FUSION, Finland–United States Investigation of Non–Insulin-Dependent Diabetes Mellitus Genetics; MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; OGTT, oral glucose tolerance test; PPAR, peroxisome proliferator–activated receptor; PROBE, primer oligo base extension reaction; sBP, systolic blood pressure; S_I, insulin sensitivity

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