The Peroxisome Poliferator–Activated Receptor-γ2 Pro12Ala Variant
Association With Type 2 Diabetes and Trait Differences
- Julie A. Douglas1,
- Michael R. Erdos2,
- Richard M. Watanabe3,
- Andi Braun4,
- Cristy L. Johnston4,
- Paul Oeth4,
- Karen L. Mohlke2,
- Timo T. Valle5,
- Christian Ehnholm5,
- Thomas A. Buchanan6,
- Richard N. Bergman7,
- Francis S. Collins2,
- Michael Boehnke1 and
- Jaakko Tuomilehto58
- 1Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
- 2Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, Maryland
- 3Division of Biostatistics, Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles
- 4Sequenom Inc., San Diego, California
- 5Department of Epidemiology and Health Promotion, Diabetes and Genetic Epidemiology Unit, and the Department of Biochemistry, National Public Health Institute, Helsinki, Finland
- 6Department of Medicine and the
- 7Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
- 8Department of Public Health, University of Helsinki, Helsinki, Finland
Abstract
Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator–activated receptor-γ2 (PPAR-γ2), 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-γ2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.
- AIRG, 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
- SI, insulin sensitivity
Footnotes
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Address correspondence and reprint requests to Michael Boehnke, University of Michigan, Department of Biostatistics, 1420 Washington Heights, Ann Arbor, Michigan 48109-2029. E-mail: boehnke{at}umich.edu.
Received for publication 12 June 2000 and accepted in revised form 29 December 2000.
J.A.D. and M.R.E. contributed equally to this work.
Additional information can be found in an online appendix at www.diabetes.org/diabetes/appendix.asp.
