Can lactase persistence genotype be used to reassess the relationship between renal cell carcinoma and milk drinking? Potentials and problems in the application of Mendelian randomization

Abstract

Background: Increased risk of renal cell carcinoma (RCC) with milk consumption has been reported from observational studies. Whether this represents a causal association or is a result of confounding or bias is unclear. We assessed the potential for using genetic variation in lactase persistence as a tool for the study of this relationship.

Methods: Using a large, hospital-based case-control study, we used observational, phenotypic, and genetic data to determine whether the MCM6 -13910 C/T(rs4988235) variant may be used as a nonconfounded and unbiased marker for milk consumption.

Results: Consumption of milk during adulthood was associated with increased risk of RCC [odds ratio (OR), 1.35; 95% confidence interval (95% CI), 1.03-1.76; P=0.03]. Among controls, consumption of milk was associated with the lactase persistence genotype at rs4988235 (OR, 2.39; 95% CI, 1.81-3.15; P=6.9x10(-10)); however, the same genotype was not associated with RCC (OR, 1.01; 95% CI, 0.83-1.22; P=0.9). In controls, milk consumption was associated with confounding factors, including smoking and educational attainment, whereas genotypes at rs4988235 showed negligible association with confounding factors.

Conclusion: The absence of an association between the MCM6 genotype and RCC suggests that observational associations between milk consumption and RCC may be due to confounding or bias.

Impact: Although these data suggest that associations between milk consumption and RCC may be spurious, if the association between genotype and behavioral exposure is weak, then the power of this test may be low. The nature of intermediate risk factor instrumentation is an important consideration in the undertaking and interpretation of this type of causal analysis experiment.

Figure 1. Mendelian randomization framework for the analysis of RCC risk by milk consumption

In this framework, the observational association between milk drinking and RCC is scrutinized by the use of genetic variation that is related to the exposure of interest (milk drinking) and potentially to the outcome of risk (RCC), but not to other possibly confounding factors. As such, genotype may act here as an “instrument” for the reassessment of the originally tentative observational finding.