The Pro12→Ala Substitution in PPAR-γ Is Associated With Resistance to Development of Diabetes in the General Population

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Abstract
The allele frequencies for a Pro12→Ala substitution in peroxisome proliferator–activated receptor-γ differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of this polymorphism and its effects on clinical characteristics have now been evaluated with a large number of Japanese individuals with type 2 diabetes (n = 2,201) and normal control subjects (n = 1,212) recruited by 10 institutions located in seven different cities in Japan. The allele frequency for the Ala12 variant was significantly lower in the type 2 diabetic group than in the control group (2.39 vs. 4.13%, P = 0.000054). However, compared with subjects without the Ala12 variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total cholesterol (P = 0.001), manifested a reduced capacity for insulin secretion as evaluated by homeostasis model assessment (P = 0.007), and tended to possess a higher level of HbA1c. These data suggest that the Ala12 variant is associated with a reduced risk for the development of diabetes in the general population, but that it may be also a risk factor for insulin deficiency and disease severity in individuals with type 2 diabetes.

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