Genetic variants on 15q25.1, smoking, and lung cancer: an assessment of mediation and interaction.
Genome-wide association studies have identified variants on chromosome 15q25.1 that increase the risks of both lung cancer and nicotine dependence and associated smoking behavior. However, there remains debate as to whether the association with lung cancer is direct or is mediated by pathways related to smoking behavior. Here, the authors apply a novel method for mediation analysis, allowing for gene-environment interaction, to a lung cancer case-control study (1992-2004) conducted at Massachusetts General Hospital using 2 single nucleotide polymorphisms, rs8034191 and rs1051730, on 15q25.1. The results are validated using data from 3 other lung cancer studies. Tests for additive interaction (P = 2 × 10(-10) and P = 1 × 10(-9)) and multiplicative interaction (P = 0.01 and P = 0.01) were significant. Pooled analyses yielded a direct-effect odds ratio of 1.26 (95% confidence interval (CI): 1.19, 1.33; P = 2 × 10(-15)) for rs8034191 and an indirect-effect odds ratio of 1.01 (95% CI: 1.00, 1.01; P = 0.09); the proportion of increased risk mediated by smoking was 3.2%. For rs1051730, direct- and indirect-effect odds ratios were 1.26 (95% CI: 1.19, 1.33; P = 1 × 10(-15)) and 1.00 (95% CI: 0.99, 1.01; P = 0.22), respectively, with a proportion mediated of 2.3%. Adjustment for measurement error in smoking behavior allowing up to 75% measurement error increased the proportions mediated to 12.5% and 9.2%, respectively. These analyses indicate that the association of the variants with lung cancer operates primarily through other pathways.
Departments of Epidemiology and Biostatistics, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. tvanderw@hsph.harvard.edu
Tyler J
TJ
VanderWeele
Kofi
K
Asomaning
Eric J
EJ
Tchetgen Tchetgen
Younghun
Y
Han
Margaret R
MR
Spitz
Sanjay
S
Shete
Xifeng
X
Wu
Valerie
V
Gaborieau
Ying
Y
Wang
John
J
McLaughlin
Rayjean J
RJ
Hung
Paul
P
Brennan
Christopher I
CI
Amos
David C
DC
Christiani
Xihong
X
Lin
D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15; D005260:Female; D059647:Gene-Environment Interaction; D060005:Genotyping Techniques; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000523:psychology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*