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Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities.

ABSTRACT: Identification of unintended drug effects, specifically drug repurposing opportunities and adverse drug events, maximizes the benefit of a drug and protects the health of patients. However, current observational research methods are subject to several biases. These include confounding by indication, reverse causality and missing data. We propose that Mendelian randomization (MR) offers a novel approach for the prediction of unintended drug effects. In particular, we advocate the synthesis of evidence from this method and other approaches, in the spirit of triangulation, to improve causal inferences concerning drug effects. MR addresses some of the limitations associated with the existing methods in this field. Furthermore, it can be applied either before or after approval of the drug, and could therefore prevent the potentially harmful exposure of patients in clinical trials and beyond. The potential of MR as a pharmacovigilance and drug repurposing tool is yet to be realized, and could both help prevent adverse drug events and identify novel indications for existing drugs in the future.

SUBMITTER: Walker VM

PROVIDER: S-EPMC5837479 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities.

Walker Venexia M VM Davey Smith George G Davies Neil M NM Martin Richard M RM

International journal of epidemiology 20171201 6

Identification of unintended drug effects, specifically drug repurposing opportunities and adverse drug events, maximizes the benefit of a drug and protects the health of patients. However, current observational research methods are subject to several biases. These include confounding by indication, reverse causality and missing data. We propose that Mendelian randomization (MR) offers a novel approach for the prediction of unintended drug effects. In particular, we advocate the synthesis of evi ...[more]

PMID: 29040597

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Project description:BACKGROUND: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. METHODS: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. RESULTS: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. CONCLUSION: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.

Dataset Information

Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities.

Publications

Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities.

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