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.
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.


CONCLUSIONS
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.


CONCLUSIONS
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.
Timpson
Nicholas J
NJ
MRC Centre for Causal Analysis in Translational Epidemiology, Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. n.j.timpson@bris.ac.uk
Brennan
Paul
P
Gaborieau
Valérie
V
Moore
Lee
L
Zaridze
David
D
Matveev
Vsevolod
V
Szeszenia-Dabrowska
Neonilia
N
Lissowska
Jolanta
J
Mates
Dana
D
Bencko
Vladimir
V
Foretova
Lenka
L
Janout
Vladimir
V
Chow
Wong-Ho
WH
Rothman
Nathaniel
N
Boffetta
Paolo
P
Harbord
Roger M
RM
Smith
George Davey
GD
D000328:Adult; D000368:Aged; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000209:etiology*; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000209:etiology*; D043322:Lactase / Q000235:genetics*; D007785:Lactose / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D008892:Milk / Q000009:adverse effects*; D011379:Prognosis; D012307:Risk Factors; D055815:Young Adult
D043322:Lactase; D007785:Lactose
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