COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials
COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials
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DOI：
10.1093/jnci/djy204
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发表时间：
2019-07-01
影响因子：
10.3
通讯作者：
Chasman, Daniel, I
中科院分区：
文献类型：
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作者：
Hall, Kathryn T.;Buring, Julie E.;Chasman, Daniel, I
维生素是最常用的补充剂之一（48%的美国成年人）。然而，人们对遗传变异对其有效性和安全性的贡献知之甚少。多种途径连接儿茶酚-O-甲基转移酶（COMT）的维生素E补充剂，α-生育酚，和cancer.Methods在这里，我们确定了COMT是否发挥药理遗传学作用，在两个随机试验中的α-生育酚补充剂对癌症的预防。在妇女基因组健康研究（WGHS，N=23294）的试验加上10年试验后随访（总体）期间，检查了编码非同义缬氨酸至甲硫氨酸取代的常见COMT rs 4680（val 158 met）的药物遗传学效应，该研究是一项为期10年的α-生育酚和阿司匹林试验，试验后随访10年。结果在α-生育酚β-胡萝卜素癌症预防研究（ATBC，N=29133）的病例/对照（N=2396/2235）亚组中得到验证。主要结果是癌症总数。还检查了女性中常见的癌症类型（结直肠癌、乳腺癌、肺癌、子宫癌和淋巴瘤/白血病）的发生率。所有的统计检验都是双侧的。结果rs 4680基因型分层的随机效应荟萃分析，在WGHS和ATBC的整个时期，显示与安慰剂相比，α-生育酚的差异效应：met/met（风险比[HR] = 0.88; 95%置信区间[CI] = 0.80 - 0.97; P=.01），瓦尔/met（HR = 0.99; 95% CI = 0.92 - 1.06; P= 0.74）和瓦尔/瓦尔（HR = 1.18; 95% CI = 1.06 - 1.31; P= 0.002），COMT与α-生育酚相互作用具有统计学显著性（P-相互作用
Background Vitamins are among the most frequently used supplements (48% of US adults). However, little is known about contributions of genetic variation to their efficacy and safety. Multiple pathways link catechol-O-methyltransferase (COMT) to the vitamin E supplement, alpha-tocopherol, and cancer.Methods Here we determined if COMT exerted pharmacogenetic effects on cancer prevention in two randomized trials of alpha-tocopherol supplementation. Pharmacogenetic effects of common COMT rs4680 (val158met), which encodes a nonsynonymous valine-to-methionine substitution, were examined in the trial plus a 10-year post-trial follow-up (overall) period of The Women's Genome Health Study (WGHS, N=23294), a 10-year alpha-tocopherol and aspirin trial with 10years post-trial follow-up. Results were validated in a case/control (N=2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC, N=29133). The primary outcome was total cancers. Rates of cancer types prevalent in women (colorectal, breast, lung, uterine, and lymphoma/leukemia) were also examined. All statistical tests were two-sided.Results Random-effects meta-analysis of rs4680 genotype strata, in WGHS and ATBC overall periods, revealed differential alpha-tocopherol effects compared with placebo: met/met (hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.80 to 0.97; P=.01), val/met (HR = 0.99; 95% CI = 0.92 to 1.06; P=.74), and val/val (HR = 1.18; 95% CI = 1.06 to 1.31; P=.002) with a statistically significant COMT by alpha-tocopherol interaction (P-interaction