Mendelian Randomization: How It Can—and Cannot—Help Confirm Causal Relations between Nutrition and Cancer
- 1 February 2009
- journal article
- review article
- Published by American Association for Cancer Research (AACR) in Cancer Prevention Research
- Vol. 2 (2), 104-113
- https://doi.org/10.1158/1940-6207.capr-08-0070
Abstract
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.Keywords
This publication has 82 references indexed in Scilit:
- Clustered Environments and Randomized Genes: A Fundamental Distinction between Conventional and Genetic EpidemiologyPLoS Medicine, 2007
- A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult ObesityScience, 2007
- The Methylenetetrahydrofolate Reductase 677C→T Polymorphism as a Modulator of a B Vitamin Network with Major Effects on Homocysteine MetabolismAmerican Journal of Human Genetics, 2007
- Insulin, Glucose, Insulin Resistance, and Incident Colorectal Cancer in Male SmokersClinical Gastroenterology and Hepatology, 2006
- Prevalence of Overweight and Obesity in the United States, 1999-2004JAMA, 2006
- Low-Fat Dietary Pattern and Risk of Invasive Breast CancerJAMA, 2006
- The epidemiology of vitamin D and cancer incidence and mortality: A review (United States)Cancer Causes & Control, 2005
- Gene-culture coevolution between cattle milk protein genes and human lactase genesNature Genetics, 2003
- Sample size calculations for population‐ and family‐based case‐control association studies on marker genotypesGenetic Epidemiology, 2003
- The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemiaQJM: An International Journal of Medicine, 1996