Mendelian randomization: how it can--and cannot--help confirm causal relations between nutrition and cancer.
Mendelian randomization: how it can--and cannot--help confirm causal relations between nutrition and cancer.
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孟德尔随机分组：它如何 - 不能 - 螺旋 - 证实营养与癌症之间的因果关系。
DOI：
10.1158/1940-6207.capr-08-0070
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Davey-Smith G
中科院分区：
文献类型：
--
作者：
Schatzkin A;Abnet CC;Cross AJ;Gunter M;Pfeiffer R;Gail M;Lim U;Davey-Smith G
营养和癌症的观察性流行病学研究面临着巨大的方法学障碍，包括饮食测量误差和混淆。我们考虑孟德尔随机化是否可以帮助克服这些障碍。孟德尔随机化策略建立在基因分型的准确性和减数分裂时等位基因的随机分类的基础上，涉及寻找营养缺陷模拟基因变体（一种“工具变量”）与癌症结果之间的关联。必要的假设是，基因是独立的癌症，鉴于暴露，也独立于潜在的混杂因素。等位基因变体可以通过其对代谢过程或消费行为的影响来充当饮食和其他营养因素的代理。这样的遗传代理的测量误差很小，通常不会被非遗传特征混淆。潜在信息基因的实例包括LCT（乳糖酶）、ALDH 2（醛脱氢酶）和HFE（血色沉着病），它们分别代表乳制品摄入、酒精饮料饮用和血清铁水平。我们表明，在营养和癌症的孟德尔随机化研究中使用这些和其他基因可能比以前认识到的更复杂，并讨论了可能使工具变量假设无效或使这些研究的解释模糊的因素。营养和癌症的孟德尔随机化研究的样本量要求被证明是潜在的令人生畏的，暴露的强有力的遗传代理是必要的，使这样的研究可行。我们的结论是，孟德尔随机化并不普遍适用，但在适当的条件下，可以补充传统流行病学研究的因果关系的证据。
Observational epidemiologic studies of nutrition and cancer have faced formidable methodologic obstacles, including dietary measurement error and confounding. We consider whether Mendelian randomization can help surmount these obstacles. The Mendelian randomization strategy, building on both the accuracy of genotyping and the random assortment of alleles at meiosis, involves searching for an association between a nutritional exposure-mimicking gene variant (a type of “instrumental variable”) and cancer outcome. Necessary assumptions are that the gene is independent of cancer, given the exposure, and also independent of potential confounders. An allelic variant can serve as a proxy for diet and other nutritional factors through its effects on either metabolic processes or consumption behavior. Such a genetic proxy is measured with little error and usually is not confounded by nongenetic characteristics. Examples of potentially informative genes include LCT (lactase), ALDH2 (aldehyde dehydrogenase), and HFE (hemochromatosis), proxies, respectively, for dairy product intake, alcoholic beverage drinking, and serum iron levels. We show that use of these and other genes in Mendelian randomization studies of nutrition and cancer may be more complicated than previously recognized and discuss factors that can invalidate the instrumental variable assumptions or cloud the interpretation of these studies. Sample size requirements for Mendelian randomization studies of nutrition and cancer are shown to be potentially daunting; strong genetic proxies for exposure are necessary to make such studies feasible. We conclude that Mendelian randomization is not universally applicable, but, under the right conditions, can complement evidence for causal associations from conventional epidemiologic studies.