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Int J Mol Epidemiol Genet 2012;3(4):333-360

Original Article
The case-only independence assumption: associations between genetic
polymorphisms and smoking among controls in two population-based studies

M Elizabeth Hodgson, Andrew F Olshan, Kari E North, Charles L Poole, Donglin Zeng, Chiu-Kit Tse, Tope O Keku, Joseph
Galanko, Robert Sandler, Robert C Millikan

Departments of Epidemiology and Biostatistics, Gillings School of Global Public Health, Center for Gastrointestinal Biology and
Disease, Lineberger Comprehensive Cancer Center, School of Medicine, Carolina Center for Genome Sciences, University of
North Carolina, Chapel Hill, North Carolina 27599, USA.

Received July 16, 2012; Accepted October 19, 2012; Epub November 15, 2012; Published November 30, 2012

Abstract: The independence assumption for a case-only analysis of statistical interaction, i. e. that genetic (G) and
environmental exposures (E) are not associated in the source population, is often checked in surrogate populations.
Few studies have examined G-E association in empirical data, particularly in controls from population-based studies,
the type of controls expected to provide the most valid surrogate estimates of G-E association. We used controls
from two population-based case-control studies to evaluate G-E independence for 43 selected genetic polymorphisms
and smoking behavior. The odds ratio (ORz) was used to estimate G-E association and, therefore, the magnitude
of bias introduced into the case-only odds ratio (COR). Odds ratios of moderate magnitude [mmORz], defined
as ORz≤0.7 or ORz>=1.4, were found at least one of the six smoking measures (ever, former, current, cig/day, years
smoked, pack-years) for 45% and 59% of the SNPs examined in the control groups of two independently conducted
North Carolina studies, respectively. Consequently, case-only estimates of G-E interaction in the context of a multiplicative
benchmark would be biased for these SNPs and smoking measures. MmORzs were found more often for
smoking amount than smoking status. We recommend that a stand-alone case-only study should only be conducted
when G-E independence can be verified for each polymorphism and exposure metric with population-specific data.
Our results suggest that ORz is specific to each underlying population rather than an estimate of a ‘universal’ ORz
for that SNP and smoking measure. Further, misspecification of smoking is likely to introduce bias into the COR.

Keywords: Case-only, controls, gene-environment interaction, genetic polymorphisms, smoking

Address all correspondence to:
M Elizabeth Hodgson
Departments of Epidemiology
University of North Carolina
1310 Crabapple Lane, Raleigh NC 27607.
E-mail: m.elizabeth.hodgson@gmail.com