Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.
Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.
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肥胖，代谢产物和大肠癌风险：孟德尔随机研究。
DOI：
10.1186/s12916-020-01855-9
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发表时间：
2020-12-17
期刊：
影响因子：
9.3
通讯作者：
Gunter MJ
中科院分区：
文献类型：
--
作者：
Bull CJ;Bell JA;Murphy N;Sanderson E;Davey Smith G;Timpson NJ;Banbury BL;Albanes D;Berndt SI;Bézieau S;Bishop DT;Brenner H;Buchanan DD;Burnett-Hartman A;Casey G;Castellví-Bel S;Chan AT;Chang-Claude J;Cross AJ;de la Chapelle A;Figueiredo JC;Gallinger SJ;Gapstur SM;Giles GG;Gruber SB;Gsur A;Hampe J;Hampel H;Harrison TA;Hoffmeister M;Hsu L;Huang WY;Huyghe JR;Jenkins MA;Joshu CE;Keku TO;Kühn T;Kweon SS;Le Marchand L;Li CI;Li L;Lindblom A;Martín V;May AM;Milne RL;Moreno V;Newcomb PA;Offit K;Ogino S;Phipps AI;Platz EA;Potter JD;Qu C;Quirós JR;Rennert G;Riboli E;Sakoda LC;Schafmayer C;Schoen RE;Slattery ML;Tangen CM;Tsilidis KK;Ulrich CM;van Duijnhoven FJB;van Guelpen B;Visvanathan K;Vodicka P;Vodickova L;Wang H;White E;Wolk A;Woods MO;Wu AH;Campbell PT;Zheng W;Peters U;Vincent EE;Gunter MJ
较高的肥胖程度会增加结直肠癌（CRC）的风险，但这种关系是否因解剖部位或性别而异尚不清楚。此外，介导肥胖对CRC影响的代谢改变尚未完全被了解。
我们研究了肥胖与CRC风险之间因性别和部位而异的关联，以及与肥胖相关的代谢物是否能解释肥胖与CRC的关联。来自体重指数（BMI）和腰臀比（WHR，未根据BMI调整；N = 806,810）的全基因组关联研究的基因变异，以及来自靶向核磁共振代谢组学的123种代谢物（N = 24,925）被用作工具。对BMI和WHR与CRC风险进行了合并性别和性别特异性的孟德尔随机化（MR）分析（在结直肠癌联盟的遗传学与流行病学、结直肠癌跨学科研究以及结肠癌家族登记处中，有58,221例病例和67,694例对照）。对BMI和WHR与代谢物、代谢物与CRC以及在多变量模型中根据代谢物类别调整后的BMI和WHR与CRC进行了合并性别的MR分析。
在性别特异性的MR分析中，较高的BMI（每增加4.2 kg/m²）在男性中与CRC患病几率增加1.23倍（95%置信区间（CI）= 1.08，1.38）相关（逆方差加权（IVW）模型）；在女性中，较高的BMI（每增加5.2 kg/m²）与CRC患病几率增加1.09倍（95% CI = 0.97，1.22）相关。WHR（每增加0.07）在女性中与CRC风险的相关性更强（IVW比值比 = 1.25，95% CI = 1.08，1.43），而在男性中（IVW比值比 = 1.05，95% CI = 0.81，1.36）则较弱。BMI或WHR与104/123种代谢物在错误发现率校正后的P ≤ 0.05水平上相关；有几种代谢物与CRC相关，但方向与肥胖 - CRC正相关的中介作用不一致。在多变量MR分析中，在根据代表性代谢物类别进行调整后，BMI和WHR与CRC的关联并未减弱，例如，BMI与CRC的单变量IVW比值比为1.12（95% CI = 1.00，1.26），当根据低密度脂蛋白颗粒中的胆固醇进行调整时，该比值比变为1.11（95% CI = 0.99，1.26）。
我们的研究结果表明，较高的BMI在男性中更能增加CRC风险，而较高的WHR在女性中更能增加CRC风险。肥胖与许多代谢改变相关，但这些都不能解释肥胖与CRC之间的关联。可能需要更详细的代谢组学测量来阐明其机制途径。
在线版本包含补充材料，可在10.1186/s12916 - 020 - 01855 - 9获取。
Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways. The online version contains supplementary material available at 10.1186/s12916-020-01855-9.