Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.
Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.
复制标题
DOI：
10.1371/journal.pgen.1003607
复制
发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Franks PW
中科院分区：
文献类型：
--
作者：
Ahmad S;Rukh G;Varga TV;Ali A;Kurbasic A;Shungin D;Ericson U;Koivula RW;Chu AY;Rose LM;Ganna A;Qi Q;Stančáková A;Sandholt CH;Elks CE;Curhan G;Jensen MK;Tamimi RM;Allin KH;Jørgensen T;Brage S;Langenberg C;Aadahl M;Grarup N;Linneberg A;Paré G;InterAct Consortium;DIRECT Consortium;Magnusson PK;Pedersen NL;Boehnke M;Hamsten A;Mohlke KL;Pasquale LT;Pedersen O;Scott RA;Ridker PM;Ingelsson E;Laakso M;Hansen T;Qi L;Wareham NJ;Chasman DI;Hallmans G;Hu FB;Renström F;Orho-Melander M;Franks PW
通过全基因组关联研究已经确定了许多肥胖基因座。英国的一项研究表明，体力活动可能会减弱其中 12 个基因座的累积效应，但缺乏重复研究。因此，我们测试了这些基因座的总体效应在报告高水平体力活动的欧洲血统成年人中是否减弱。对 111,421 名参与者的 12 个肥胖易感性位点进行了基因分型或估算。通过对每个遗传变异体的 BMI 相关等位基因求和来计算遗传风险评分 (GRS)。使用自填问卷评估身体活动。在每个队列中，在线性和逻辑回归模型中测试了 GRS 和体力活动对 BMI 之间的乘法交互作用，并调整了年龄、年龄2、性别、研究中心（对于多中心研究）以及体力活动和 GRS 的边际项。使用按队列样本量加权的荟萃分析将这些结果结合起来。荟萃分析得出了具有统计显着性的 GRS × 体力活动交互效应估计值 (Pinteraction = 0.015)。然而，统计上显着的交互作用仅在北美队列中表现出来（n = 39,810，Pinteraction = 0.014 vs. n = 71,611，Pinteraction = 0.275）。在二次分析中，FTO rs1121980 (Pinteraction = 0.003) 和 SEC16B rs10913469 (Pinteraction = 0.025) 变体均显示出 SNP × 体力活动相互作用的证据。这项对 111,421 名个体进行的荟萃分析进一步支持了体力活动与肥胖倾向中的 GRS 之间的相互作用，尽管这些发现取决于来自北美的队列的纳入，表明这些结果要么是针对人群的，要么是非因果关系的。我们对 111,421 名欧洲血统成年人进行了分析，以检查体力活动是否可以降低由 12 个单核苷酸多态性引起的肥胖遗传风险，正如之前对 20,000 名英国成年人进行的研究中报道的那样（Li 等人，PLoS Med. 2010）。尽管李等人的研究被广泛引用，但据我们所知，原始报告尚未得到复制。因此，我们试图通过对 111,421 名成年人的综合分析来证实或反驳原始研究的结果。我们的分析产生了统计学上显着的交互效应（Pinteraction = 0.015），证实了原始研究的结果；我们还确定了 FTO 基因座和身体活动之间的相互作用 (Pinteraction = 0.003)，验证了之前的分析 (Kilpelainen 等人，PLoS Med., 2010)，并且我们检测到了 SEC16B 基因座和身体活动之间的新相互作用 (Pinteraction = 0.025)。我们还检查了相互作用分析的功效限制，从而证明研究内和研究间异质性的来源以及数据处理的方式可以抑制荟萃分析中相互作用效应的检测，该荟萃分析结合了许多具有不同特征的队列。这表明，将许多以不同方式测量环境暴露的小型研究结合起来，对于检测基因×环境相互作用可能相对效率较低。
Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age2, sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal. We undertook analyses in 111,421 adults of European descent to examine whether physical activity diminishes the genetic risk of obesity predisposed by 12 single nucleotide polymorphisms, as previously reported in a study of 20,000 UK adults (Li et al, PLoS Med. 2010). Although the study by Li et al is widely cited, the original report has not been replicated to our knowledge. Therefore, we sought to confirm or refute the original study's findings in a combined analysis of 111,421 adults. Our analyses yielded a statistically significant interaction effect (Pinteraction = 0.015), confirming the original study's results; we also identified an interaction between the FTO locus and physical activity (Pinteraction = 0.003), verifying previous analyses (Kilpelainen et al, PLoS Med., 2010), and we detected a novel interaction between the SEC16B locus and physical activity (Pinteraction = 0.025). We also examined the power constraints of interaction analyses, thereby demonstrating that sources of within- and between-study heterogeneity and the manner in which data are treated can inhibit the detection of interaction effects in meta-analyses that combine many cohorts with varying characteristics. This suggests that combining many small studies that have measured environmental exposures differently may be relatively inefficient for the detection of gene × environment interactions.
登录
查看更多内容
影响因子：
158.5
作者：
Cecil, Joanne E.;Tavendale, Roger;Palmer, Colin N. A.
通讯作者：
Palmer, Colin N. A.
影响因子：
13.6
作者：
Peters, Tricia;Brage, Soren;Westgate, Kate;Franks, Paul W.;Gradmark, Anna;Diaz, Maria Jose Tormo;Huerta, Jose Maria;Bendinelli, Benedetta;Vigl, Mattheaus;Boeing, Heiner;Wendel-Vos, Wanda;Spijkerman, Annemieke;Benjaminsen-Borch, Kristin;Valanou, Elisavet;Guillain, Blandine de Lauzon;Clavel-Chapelon, Francoise;Sharp, Stephen;Kerrison, Nicola;Langenberg, Claudia;Arriola, Larraitz;Barricarte, Aurelio;Gonzales, Carlos;Grioni, Sara;Kaaks, Rudolf;Key, Timothy;Khaw, Kay Tee;May, Anne;Nilsson, Peter;Norat, Teresa;Overvad, Kim;Palli, Domenico;Panico, Salvatore;Quiros, Jose Ramon;Ricceri, Fulvio;Sanchez, Maria-Jose;Slimani, Nadia;Tjonneland, Anne;Tumino, Rosario;Feskens, Edith;Riboli, Elio;Ekelund, Ulf;Wareham, Nick
通讯作者：
Wareham, Nick
影响因子：
8.2
作者：
Langenberg, C.;Sharp, S.;Forouhi, N. G.;Franks, P. W.;Schulze, M. B.;Kerrison, N.;Ekelund, U.;Barroso, I.;Panico, S.;Tormo, M. J.;Spranger, J.;Griffin, S.;van der Schouw, Y. T.;Amiano, P.;Ardanaz, E.;Arriola, L.;Balkau, B.;Barricarte, A.;Beulens, J. W. J.;Boeing, H.;Bueno-de-Mesquita, H. B.;Buijsse, B.;Chirlaque Lopez, M. D.;Clavel-Chapelon, F.;Crowe, F. L.;de Lauzon-Guillan, B.;Deloukas, P.;Dorronsoro, M.;Drogan, D.;Froguel, P.;Gonzalez, C.;Grioni, S.;Groop, L.;Groves, C.;Hainaut, P.;Halkjaer, J.;Hallmans, G.;Hansen, T.;Huerta Castano, J. M.;Kaaks, R.;Key, T. J.;Khaw, K. T.;Koulman, A.;Mattiello, A.;Navarro, C.;Nilsson, P.;Norat, T.;Overvad, K.;Palla, L.;Palli, D.;Pedersen, O.;Peeters, P. H.;Quiros, J. R.;Ramachandran, A.;Rodriguez-Suarez, L.;Rolandsson, O.;Romaguera, D.;Romieu, I.;Sacerdote, C.;Sanchez, M. J.;Sandbaek, A.;Slimani, N.;Sluijs, I.;Spijkerman, A. M. W.;Teucher, B.;Tjonneland, A.;Tumino, R.;van der A, D. L.;Verschuren, W. M. M.;Tuomilehto, J.;Feskens, E.;McCarthy, M.;Riboli, E.;Wareham, N. J.
通讯作者：
Wareham, N. J.
影响因子：
4.9
作者：
Loos, RJF;Rankinen, T;Bouchard, C
通讯作者：
Bouchard, C
影响因子：
9.8
作者：
Göring, HHH;Terwilliger, JD;Blangero, J
通讯作者：
Blangero, J