Franks P W, Jablonski K A, Delahanty L, Hanson R L, Kahn S E, Altshuler D, Knowler W C, Florez J C
Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umea University Hospital, Umea, Sweden.
Diabetologia. 2007 Dec;50(12):2451-60. doi: 10.1007/s00125-007-0826-6. Epub 2007 Sep 27.
AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor gamma (PPARgamma), encoded by the PPARG gene, regulates insulin sensitivity and adipogenesis, and may bind polyunsaturated fatty acids (PUFA) and thiazolidinediones in a ligand-dependent manner. The PPARG proline for alanine substitution at position 12 (Pro12Ala polymorphism) has been related with obesity directly and via interaction with PUFA.
We tested the effect-modifying role of Pro12Ala on the 1 year change in obesity-related traits in a randomised clinical trial of treatment with metformin (n = 989), troglitazone (n = 363) or lifestyle modification (n = 1,004) vs placebo (n = 1,000) for diabetes prevention in high-risk individuals.
At baseline, Ala12 carriers had larger waists (p < 0.001) and, in a subset, more subcutaneous adipose tissue (SAT; lumbar 2/3; p = 0.04) than Pro12 homozygotes. There was a genotype-by-intervention interaction on 1-year weight change (p = 0.01); in the placebo arm, Pro12 homozygotes gained weight and Ala12 carriers lost weight (p = 0.001). In the metformin and lifestyle arms, weight loss occurred across genotypes, but was greatest in Ala12 carriers (p < 0.05). Troglitazone treatment induced weight gain, which tended to be greater in Ala12 carriers (p = 0.08). In the placebo group, SAT (lumbar 2/3, lumbar 4/5) decreased in Ala12 allele carriers, but was unchanged in Pro12 homozygotes (p < or = 0.005). With metformin treatment, SAT decreased independently of genotype. In the lifestyle arm, SAT (lumbar 2/3) reductions occurred across genotypes, but were greater in Ala12 carriers (p = 0.03). A genotype-by-PUFA intake interaction on reduction in visceral fat (lumbar 4/5; p = 0.04) was also observed, which was most evident with metformin treatment (p < 0.001).
CONCLUSIONS/INTERPRETATION: Within the Diabetes Prevention Program, the Ala12 allele influences central obesity, an effect which may differ by treatment group and dietary PUFA intake (ClinicalTrials.gov ID no: NCT00004992).
目的/假设：由PPARG基因编码的过氧化物酶体增殖物激活受体γ（PPARγ）调节胰岛素敏感性和脂肪生成，并可能以配体依赖的方式结合多不饱和脂肪酸（PUFA）和噻唑烷二酮。PPARG基因第12位脯氨酸被丙氨酸取代（Pro12Ala多态性）与肥胖直接相关，并通过与PUFA相互作用而关联。
在一项针对高危个体预防糖尿病的随机临床试验中，我们测试了Pro12Ala对肥胖相关性状1年变化的效应修饰作用，该试验比较了二甲双胍治疗组（n = 989）、曲格列酮治疗组（n = 363）或生活方式干预组（n = 1,004）与安慰剂组（n = 1,000）。
在基线时，Ala12携带者的腰围更大（p < 0.001），并且在一个亚组中，其皮下脂肪组织（SAT；腰2/3；p = 0.04）比Pro12纯合子更多。在1年体重变化方面存在基因型与干预的相互作用（p = 0.01）；在安慰剂组中，Pro12纯合子体重增加，而Ala12携带者体重减轻（p = 0.001）。在二甲双胍组和生活方式干预组中，各基因型均出现体重减轻，但Ala12携带者减轻最多（p < 0.05）。曲格列酮治疗导致体重增加，Ala12携带者的体重增加趋势更明显（p = 0.08）。在安慰剂组中，Ala12等位基因携带者的SAT（腰2/3、腰4/5）减少，而Pro12纯合子则无变化（p ≤ 0.005）。二甲双胍治疗时，SAT减少与基因型无关。在生活方式干预组中，各基因型的SAT（腰2/3）均减少，但Ala12携带者减少更多（p = 0.03）。还观察到基因型与PUFA摄入量对内脏脂肪减少（腰4/5；p = 0.04）的相互作用，在二甲双胍治疗时最为明显（p < 0.001）。
结论/解读：在糖尿病预防计划中，Ala12等位基因影响中心性肥胖，这种影响可能因治疗组和饮食中PUFA摄入量而异（ClinicalTrials.gov注册号：NCT00004992）。
