Genome-Wide Gene-Smoking Interaction Analysis Identified Signals At RFTN1 And ZC3H11A Gene In Lung Cancer Carcinogenesis

Yafang LI, DARTMOUTH COLLEGE, United States
XIAO X. 1 , AMOS C. 1

1 BIOMEDICAL DATA SCIENCE DEPARTMENT, DARTMOUTH COLLEGE

Purpose: Genome-wide association studies have identified interactions between tobacco smoking and genes on chromosome 15q25.1 and 6q that increase risk of lung cancer. However the identified interactions are still limited because of small effect size and samples size. In this study, we conducted a gene-smoking interaction analysis in a GWAS of lung cancer in Caucasian population to identify latent genes interacting with smoking status.
Methods: We performed the analysis in a three-stage design. In stage I and II, we evaluated all pair-wise (502933) gene-smoking interaction analysis in 1,149 subjects (641 cases and 508 controls) and 2,152 (1082 cases and 1070 controls) using a logistic regression model with adjustment for first three principal components. We then validated the signals at two candidate genes in 30,427 samples (16912 cases and 13513 controls). We also combined all the samples and reported an overall effect. By adopting the same strategy, we also evaluated the gene-smoking interactions in patients with lung adenocarcinoma.
Results:  We identified two SNPs, chr3_16408247_A_T, and chr3_16409729_A_G, in RFTN1 gene on chromosome 3 that interacted with ever & never smoking status (chr3_16408247_A_T : p-value=1.67x10-3, 1.70x10-4 and 2.92x10-4 for stage I-III, combined p-value=3.83x10-7; and chr3_16409729_A_G p-value=1.53x10-3, 1.12x10-4, 8.68x10-5 for stage I-III, combined p-value=5.31x10-8). When restricted to lung adenocarcinoma, we identified six SNPs in ZC3H11A gene on chromosome 1 interacted with smoking status. The SNP with strongest signal has p-value=1.53x10-3, 1.12x10-4, 8.68x10-5 for stage I-III, and 5.31x10-8 , OR=1.5 in combined analysis.
Conclusions: An synergetic gene-smoking interaction were observed at RFTN1 and ZC3H11A genes in lung cancer carcinogenesis. The two interactions identified in this study may help explain the missing heritability in lung susceptibility. This study also indicated the existence of latent gene-environment interactions in lung cancer development and provided strong evidence for further evaluation of gene-smoking interactions.
Funding source: U19 CA148127