Luan J, Browne P O, Harding A H, Halsall D J, O'Rahilly S, Chatterjee V K, Wareham N J
Department of Public Health and Primary Care, University of Cambridge, UK.
Diabetes. 2001 Mar;50(3):686-9. doi: 10.2337/diabetes.50.3.686.
The importance of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) in regulating insulin resistance and blood pressure has been demonstrated in families with loss of function mutations. Gain of function mutations has been associated with severe obesity. However, previous population studies of the common variant Pro12Ala have produced conflicting results. As it is likely that the natural ligands for this receptor may include fatty acids, we hypothesized that the effect of this common variant may be altered by the character of the diet, particularly the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio). We studied 592 nondiabetic participants in an ongoing population-based cohort study who were genotyped for the Pro12Ala polymorphism in the PPAR gamma2 isoform. As the Ala homozygotes were uncommon (2.0%), all analyses were conducted comparing Pro homozygotes (79.1%) to Ala allele carriers. There was no difference in fasting insulin concentration or BMI between Ala allele carriers and Pro homozygotes. The fasting insulin concentration was negatively associated with the P:S ratio (P = 0.0119) after adjustment for age and sex, and a strong interaction was evident between the P:S ratio and the Pro12Ala polymorphism for both BMI (P = 0.0038) and fasting insulin (P = 0.0097). The data suggest that when the dietary P:S ratio is low, the BMI in Ala carriers is greater than that in Pro homozygotes, but when the dietary ratio is high, the opposite is seen. This gene-nutrient interaction emphasizes the difficulty of examining the effect of common polymorphisms in the absence of data on nongenetic exposures, and may explain the heterogeneity of findings in previous studies.
核受体过氧化物酶体增殖物激活受体γ（PPARγ）在调节胰岛素抵抗和血压方面的重要性已在功能丧失性突变的家族中得到证实。功能获得性突变与严重肥胖有关。然而，先前关于常见变体Pro12Ala的人群研究产生了相互矛盾的结果。由于该受体的天然配体可能包括脂肪酸，我们推测这种常见变体的作用可能会因饮食特征而改变，特别是膳食多不饱和脂肪与饱和脂肪的比例（P:S比例）。我们在一项正在进行的基于人群的队列研究中，对592名非糖尿病参与者进行了PPARγ2亚型Pro12Ala多态性的基因分型。由于丙氨酸纯合子不常见（2.0%），所有分析都是将脯氨酸纯合子（79.1%）与丙氨酸等位基因携带者进行比较。丙氨酸等位基因携带者和脯氨酸纯合子之间的空腹胰岛素浓度或体重指数没有差异。在调整年龄和性别后，空腹胰岛素浓度与P:S比例呈负相关（P = 0.0119），并且P:S比例与Pro12Ala多态性在体重指数（P = 0.0038）和空腹胰岛素（P = 0.0097）方面都存在明显的强相互作用。数据表明，当膳食P:S比例较低时，丙氨酸携带者的体重指数高于脯氨酸纯合子，但当膳食比例较高时，则出现相反的情况。这种基因-营养素相互作用强调了在缺乏非遗传暴露数据的情况下研究常见多态性影响的困难，并可能解释了先前研究结果的异质性。
