Doney A S F, Fischer B, Cecil J E, Boylan K, McGuigan F E, Ralston S H, Morris A D, Palmer C N A
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, DD1 9SY, Scotland, UK.
Diabetologia. 2004 Mar;47(3):555-558. doi: 10.1007/s00125-003-1323-1. Epub 2004 Jan 17.
AIMS/HYPOTHESIS: The Pro12Ala polymorphism of peroxisome proliferator-activated receptor (PPAR)gamma has been consistently associated with Type 2 diabetes. The rare Ala12 variant is estimated to reduce the risk of developing Type 2 diabetes by 20 percent. This variant is in linkage disequilibrium with another common variant, T1431. Both have opposing associations with body weight. We therefore examined the association of specific haplotypes marked by these two variants with susceptibility to Type 2 diabetes.
We determined the PPARG genotype of a large Scottish cohort of Type 2 diabetic patients ( n=1997) and compared allele frequencies with a cohort of local children ( n=2444) and a middle-aged, population-based cohort from Scotland ( n=1061).
Frequency of the Ala12 allele was slightly lower in the Type 2 diabetic cohort than in the children [odds ratio (OR)=0.91, p=0.1]. In contrast, the Ala12 variant was under-represented in the Type 2 diabetic population when compared with similarly aged non-diabetic adults (OR=0.74, p=0.0006). When the Ala12 variant was on a haplotype not bearing the 1431T variant, it conferred greater protection (OR=0.66, p=0.003). However, when it was present in haplotypes containing the 1431T variant (70% of Ala12 carriers), this protection was absent (OR=0.99, p=0.94).
CONCLUSIONS/INTERPRETATION: We replicated the finding that the Ala12 variant of PPARgamma affords protection from Type 2 diabetes, and suggest that this protection is modulated by additional common variation at the PPARG locus.
目的/假设：过氧化物酶体增殖物激活受体（PPAR）γ的Pro12Ala多态性一直与2型糖尿病相关。据估计，罕见的Ala12变体可将患2型糖尿病的风险降低20%。该变体与另一个常见变体T1431处于连锁不平衡状态。两者与体重的关联相反。因此，我们研究了由这两个变体标记的特定单倍型与2型糖尿病易感性的关联。
我们确定了一大群苏格兰2型糖尿病患者（n = 1997）的PPARG基因型，并将等位基因频率与一组当地儿童（n = 2444）以及一组来自苏格兰的基于人群的中年人群（n = 1061）进行比较。
2型糖尿病队列中Ala12等位基因的频率略低于儿童队列[优势比（OR）= 0.91，p = 0.1]。相比之下，与年龄相仿的非糖尿病成年人相比，2型糖尿病人群中Ala12变体的比例较低（OR = 0.74，p = 0.0006）。当Ala12变体位于不携带1431T变体的单倍型上时，它提供了更大的保护作用（OR = 0.66，p = 0.003）。然而，当它存在于包含1431T变体的单倍型中时（70%的Ala12携带者），这种保护作用消失（OR = 0.99，p = 0.94）。
结论/解读：我们重复了PPARγ的Ala12变体可预防2型糖尿病这一发现，并表明这种保护作用受到PPARG基因座上其他常见变异的调节。
