Combined effects of MC4R and FTO common genetic variants on obesity in European general populations
Combined effects of MC4R and FTO common genetic variants on obesity in European general populations
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DOI：
10.1007/s00109-009-0451-6
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发表时间：
2009-05-01
影响因子：
4.7
通讯作者：
Froguel, Philippe
中科院分区：
文献类型：
--
作者：
Cauchi, Stephane;Stutzmann, Fanny;Froguel, Philippe
全基因组关联扫描最近发现了 FTO 内含子 1 和 MC4R 188 kb 下游的常见多态性，这些多态性调节体重指数 (BMI) 并与肥胖风险增加相关。尽管它们对肥胖表型的个体贡献不大，但它们的综合影响以及它们与环境因素的相互作用仍有待在从出生到成年的大量普通人群中进行评估。在本研究中，我们分析了 FTO rs1421085 和 MC4R rs17782313 风险等位基因对 BMI、脂肪量、肥胖和随后的 2 型糖尿病 (T2D) 患病率和发病率的独立和综合影响，以及它们与体力活动水平和性别的相互作用，在两个基于欧洲前瞻性人群的队列中，该队列由 4,762 名芬兰青少年 (NFBC 1986) 和 3,167 名法国成年人组成。 （欲望）。与既不携带 FTO 也不携带 MC4R 风险等位基因的参与者（占人口的 20-24%）相比，携带 3 或 4 个风险等位基因的受试者（占人口的 7-10%）在儿童时期患肥胖症的可能性增加了 3 倍。在成人中，它们的综合影响更为温和（类似于风险增加 1.8 倍），并且与脂肪量增加 1.27% 相关（P = 0.001）。前瞻性地，我们证明每个 FTO 和 MC4R 风险等位基因使肥胖和 T2D 发病率分别增加 24% (P = 0.02) 和 21% (P = 0.02)。然而，在调整 BMI 后，对 T2D 的影响消失了。 rs1421085 C 等位基因纯合子新生儿的 Z-BMI 和体重指数分别比无 FTO 风险等位基因的新生儿高 0.1 个单位 (P = 0.02) 和 0.27 g/cm(3) (P = 0.005)。 MC4R rs17782313 C 等位基因与男性肥胖和脂肪量沉积的相关性高于女性（分别为 P = 0.003 和 P = 0.03），并且低体力活动加剧了 FTO 多态性对 BMI 增加和肥胖患病率的影响（分别为 P = 0.008 和 P = 0.01）。因此，在欧洲普通人群中，FTO 和 MC4R 常见多态性的综合效应是相加的，可以预测肥胖和 T2D，并且可能分别受到与体力活动水平和性别的相互作用的影响。
Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20-24% of the populations), subjects with three or four risk alleles (7-10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (similar to 1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm(3) (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.