Holy Smokes—An Interaction!
Authors: Braxton D. Mitchell
Journal: Circulation (2017)

Combining genomewide association studies in large meta-analyses has been a valuable tool for identifying genetic susceptibility loci over the past 10 years.In this issue of Circulation, Saleheen and colleagues 1 use these large data sources for a deeper level analysis to identify gene by environment (G × E) interactions.The focus of their investigation is to determine whether the effects of any known coronary heart disease (CHD)-associated loci are modified by smoking behavior.At least 46 loci robustly associated with CHD have been identified to date. 2 Identifying G × E interactions for CHD has been challenging given that the main effects of the known CHD-associated loci tend to be small and in aggregate account for <10% of CHD heritability. 2 The remaining heritability is assumed to come from a variety of sources, including rare variants, G × G and G × E interactions, epigenetic effects, and nonadditive effects.Imprecision of environmental exposure measurements further erodes the ability to detect G × E interactions so that large sample sizes are required.In this study, the authors utilized the large CARDIoGRAMplusC4C Consortium (Coronary ARtery DIsease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Consortium).The authors helped their cause by focusing on 45 loci previously reported to associate with CHD risk plus 5 previously associated with smoking behavior to avoid having to pay a huge penalty for testing hundreds of thousands of variants across the entire genome.The authors did not replicate the interaction result by splitting their sample into a discovery and validation set but, following best practices, 3,4 chose to analyze the full dataset to optimize power.In this study, Saleheen et al 1 report an interaction of smoking with a variant within ADAMTS7.They analyzed a subset of ≈61 000 CHD cases and 80 000 controls from 30 of the CARDIoGRAM studies for whom smoking histories were available.Overall, the ADAMTS7 rs7178051 T allele was associated with a 7% lower risk of CHD.However, in smokers, each copy of the T allele was associated with a 12% lower risk in never smokers compared with only a 5% lower risk in ever smokers (interaction P-value <8.7×10 -5 ), translating to a 60% loss of CHD protection in tobacco users.This result is particularly remarkable given the crude measurement of smoking exposure-that is, subjects were simply classified as ever smokers (>100 cigarettes lifetime) or never smokers because detailed smoking histories were not available in all studies.Had a more refined dosage or lifetime measure of smoking been available, one wonders whether an even stronger interaction effect might have been found.ADAMTS7 was first identified in 2011 as a CHD susceptibility locus in 2 large meta-analyses, 5,6 1 of which showed the ADAMTS7 association to be specific for angiographic CHD. 5 This gene is a member of the ADAMTS family of secreted zinc metalloproteinases and degrades cartilage oligomeric matrix protein.Its precise role in CHD is not clear, although knocking out ADAMTS7 in mice has previously been asso-Holy Smokes-An Interaction!