Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer

Abstract

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

Fig 1. The association between CRC and alcohol consumption (non-/occasional drinkers [reference group]; light-to-moderate drinkers [a]; and heavy drinkers[b]).

Men and women were analyzed separately in each study and age and study site (if applicable) were adjusted in model. Non-/occasional drinkers: drinking < 1 gram of alcohol per day; light-to-moderate drinkers: drinking 1–28 grams of alcohol per day ([a] alcoholc1-28g/d); and heavy drinkers: drinking >28 grams of alcohol per day ([b] alcoholc>28g/d). OR: odds ratio; N = total number of subjects; case = number of cases. Colon23: Hawaii Colorectal Cancer Studies 2 and 3; DACHS: Darmkrebs: Chancen der Verhütung durch Screening; DALS: Diet, Activity and Lifestyle Study; HPFS: Health Professionals Follow-up Study; HPFS_AD: Health Professionals Follow-up Study for colorectal adenoma; MEC: Multiethnic Cohort Study; NHS: Nurses’ Health Study; NHS_AD: Nurses’ Health Study for colorectal adenoma; PHS: Physicians’ Health Study; PLCO: Prostate, Lung, Colorectal and Ovarian Cancer; Screening Trial; VITAL: VITamins And Lifestyle; WHI: Women’s Health Initiative. het.pval: p value of heterogeneity.

Fig 2. The association between CRC and smoking (ever vs. never smokers [a]; pack-years of smoking [b]).

Never smokers were assigned the value 0 for pack-years of smoking. OR: odds ratio; OR for pack-years of smoking is based on per 20 pack-years increase. Age, sex (if applicable), and study site (if applicable) were adjusted in model. ASTERISK: The French Association STudy Evaluating RISK for sporadic colorectal cancer; CCFR: Colon Cancer Family Registry; Colon23: Hawaii Colorectal Cancer Studies 2 and 3.; DACHS: Darmkrebs: Chancen der Verhütung durch Screening; DALS: Diet, Activity and Lifestyle Study; HPFS:Health Professionals Follow-up Study; HPFS_AD: Health Professionals Follow-up Study for colorectal adenoma; MEC: Multiethnic Cohort Study; NHS: Nurses’ Health Study; NHS_AD: Nurses’ Health Study for colorectal adenoma; OFCCR: Ontario Familial Colorectal Cancer Registry; PMH-CCFR: Postmenopausal Hormone study- Colon Cancer Family Registry; PLCO: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; VITAL: VITamins And Lifestyle; WHI: Women’s Health Initiative. CCFR is a collaborating study with GECCO. smk_ever: ever smokers; smk_pkyr20: pack-years of smoking; het.pval: p value of heterogeneity.

Fig 3. Regional association plot for the interaction analyses between moderate alcohol drinking and SNPs at 9q22.32/HIATL1.

The–log10 of p values (left y-axis) are plotted against the SNP genomic position based on NCBI build 37 (x-axis); the estimated recombination rate from 1000 Genomes Project European populations are on the right y-axis and plotted in blue. The most significant SNP was denoted with purple diamond. SNPs are colored to reflect correlation with the most significant SNP. Gene annotations are from the UCSC genome browser. Gene FAM22F is also known as NUTM2F.

Fig 4. Forest plot for meta-analysis of interaction analysis for rs9409565 and light-to-moderate drinking among men (a), women (b) and combined (c).

Odds ratios (ORs) and 95% confidence intervals (95% CI) are presented for the multiplicative interaction between each additional copy of the count (or tested) allele (C) and light-to-moderate vs. non/occasional drinkers. The box sizes are proportional in size to the inverse of the variance for each study, and the lines visually depict the confidence interval. Results from the fixed-effects meta-analysis are shown as diamonds. The width of the diamond represents the confidence interval. P value of heterogeneity for (a), (b), and (c) is 0.93, 0.78, and 0.96, respectively.