Applying Mendelian randomization to appraise causality in relationships between nutrition and cancer.

Dietary factors are assumed to play an important role in cancer risk, apparent in consensus recommendations for cancer prevention that promote nutritional changes. However, the evidence in this field has been generated predominantly through observational studies, which may result in biased effect estimates because of confounding, exposure misclassification, and reverse causality. With major geographical differences and rapid changes in cancer incidence over time, it is crucial to establish which of the observational associations reflect causality and to identify novel risk factors as these may be modified to prevent the onset of cancer and reduce its progression. Mendelian randomization (MR) uses the special properties of germline genetic variation to strengthen causal inference regarding potentially modifiable exposures and disease risk. MR can be implemented through instrumental variable (IV) analysis and, when robustly performed, is generally less prone to confounding, reverse causation and measurement error than conventional observational methods and has different sources of bias (discussed in detail below). It is increasingly used to facilitate causal inference in epidemiology and provides an opportunity to explore the effects of nutritional exposures on cancer incidence and progression in a cost-effective and timely manner. Here, we introduce the concept of MR and discuss its current application in understanding the impact of nutritional factors (e.g., any measure of diet and nutritional intake, circulating biomarkers, patterns, preference or behaviour) on cancer aetiology and, thus, opportunities for MR to contribute to the development of nutritional recommendations and policies for cancer prevention. We provide applied examples of MR studies examining the role of nutritional factors in cancer to illustrate how this method can be used to help prioritise or deprioritise the evaluation of specific nutritional factors as intervention targets in randomised controlled trials. We describe possible biases when using MR, and methodological developments aimed at investigating and potentially overcoming these biases when present. Lastly, we consider the use of MR in identifying causally relevant nutritional risk factors for various cancers in different regions across the world, given notable geographical differences in some cancers. We also discuss how MR results could be translated into further research and policy. We conclude that findings from MR studies, which corroborate those from other well-conducted studies with different and orthogonal biases, are poised to substantially improve our understanding of nutritional influences on cancer. For such corroboration, there is a requirement for an interdisciplinary and collaborative approach to investigate risk factors for cancer incidence and progression.

Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study.

OBJECTIVE: A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10-8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 0.234-0.988]; P=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105-0.868]; P=0.026). CONCLUSIONS: Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.

Causal effect of alcohol consumption on hyperuricemia using a Mendelian randomization design.

AIM: We used a Mendelian randomization analysis to assess the causal effect of alcohol consumption on hyperuricemia in Koreans. METHODS: The Korean Cancer Prevention Study-II (KCPS-II) Biobank cohort consisted of 156 701 healthy Korean aged 20 years or older. Clinical data including serum uric acid, alcohol consumption, and other related confounding variables were collected at baseline. The 27 single nucleotide polymorphisms (SNP) including rs671 in aldehyde dehydrogenase 2 (ALDH2) were obtained from a genome-wide association study of alcohol consumption in the KCPS-II Biobank among 11 678 men and women in 2017. Both unweighted and weighted genetic risk score (wGRS) were calculated using 10 SNPs selected based on linkage disequilibrium. RESULTS: As strong instrumental variables, both rs671 and wGRS were associated with an increased amount of alcohol drinking in men and women. Alcohol consumption was also positively associated with hyperuricemia risk in men (P < .001) and women (P = .014). Both rs671 major G allele and wGRS were not associated with hyperuricemia. In Mendelian randomization analysis, the causal relationship between any alcohol consumption and hyperuricemia was found only in men, albeit non-significant after correction for multiple testing. The associations did not change after excluding heavy drinkers or the elderly. CONCLUSIONS: These results provide evidence that alcohol consumption is causally associated with risk of hyperuricemia in Korean men and support its role as a risk determinant.

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.