Niskanen L, Lindi V, Erkkilä A, Sivenius K, Luoma J, Ylä-Herttuala S, Laakso M, Uusitupa M I j
Department of Clinical Nutrition, and the A.I. Virtanen Institute of Molecular Sciences, University of Kuopio, Kuopio, Finland.
Metabolism. 2003 Feb;52(2):213-7. doi: 10.1053/meta.2003.50039.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a key component in adipocyte differentiation and fat-specific gene expression and may modulate macrophage functions, like proinflammatory activities, and stimulate oxidized low-density lipoprotein (ox-LDL) uptake. We hypothesized that the Pro12Ala polymorphism of the PPAR-gamma2 gene may affect the immune response to ox-LDL. Therefore, we investigated the association of the Pro12Ala polymorphism of the PPAR-gamma2 gene with ox-LDL autoantibodies, as well anticardiolipin antibodies, in a 10-year prospective study. The Pro12Ala polymorphism was genotyped in 119 nondiabetic subjects (age, 45 to 64 years; body mass index [BMI], 19 to 46 kg/m(2)) and 70 type 2 diabetic patients (age, 45 to 65 years; BMI, 19 to 46 kg/m(2)) by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method. Ox-LDL autoantibodies and anticardiolipin antibodies were determined at baseline and after 10 years of follow-up. At baseline, the Pro12Ala polymorphism was not associated with ox-LDL autoantibodies in nondiabetic subjects, whereas type 2 diabetic patients having the Pro12Ala or the Ala12Ala genotypes tended to have higher levels of ox-LDL autoantibodies than did type 2 diabetic patients with the Pro12Pro genotype. At the 10-year follow-up, diabetic subjects having the Ala12 allele had higher ox-LDL autoantibody levels than did diabetic subjects with the Pro12Pro genotype (P =.043 after adjustment for age, gender, BMI, and hemoglobin A(1c) [HbA(1c)] at 5 years). In nondiabetic subjects and regarding anticardiolipin antibodies, no such relationship was observed. We conclude that the Pro12Ala polymorphism of the PPAR-gamma2 gene was associated with increased ox-LDL autoantibodies in type 2 diabetic subjects. Genotype may therefore modulate the oxidative modification of LDL in hyperglycemic milieu.
过氧化物酶体增殖物激活受体γ（PPAR-γ）是脂肪细胞分化和脂肪特异性基因表达的关键成分，可能调节巨噬细胞功能，如促炎活性，并刺激氧化型低密度脂蛋白（ox-LDL）摄取。我们推测PPAR-γ2基因的Pro12Ala多态性可能影响对ox-LDL的免疫反应。因此，在一项为期10年的前瞻性研究中，我们调查了PPAR-γ2基因的Pro12Ala多态性与ox-LDL自身抗体以及抗心磷脂抗体之间的关联。通过聚合酶链反应-单链构象多态性（PCR-SSCP）方法，对119名非糖尿病受试者（年龄45至64岁；体重指数[BMI]，19至46kg/m²）和70名2型糖尿病患者（年龄45至65岁；BMI，19至46kg/m²）的Pro12Ala多态性进行基因分型。在基线和随访10年后测定ox-LDL自身抗体和抗心磷脂抗体。在基线时，非糖尿病受试者中Pro12Ala多态性与ox-LDL自身抗体无关，而具有Pro12Ala或Ala12Ala基因型的2型糖尿病患者的ox-LDL自身抗体水平往往高于具有Pro12Pro基因型的2型糖尿病患者。在10年随访时，具有Ala12等位基因的糖尿病受试者的ox-LDL自身抗体水平高于具有Pro12Pro基因型的糖尿病受试者（在对年龄、性别、BMI和5年时的糖化血红蛋白A1c[HbA1c]进行校正后，P = 0.043）。在非糖尿病受试者中，关于抗心磷脂抗体，未观察到这种关系。我们得出结论，PPAR-γ2基因的Pro12Ala多态性与2型糖尿病受试者中ox-LDL自身抗体增加有关。因此，基因型可能在高血糖环境中调节LDL的氧化修饰。
