Abstract
BackgroundGenome-wide association studies (GWAS) have identified more than 40 colorectal cancer susceptibility loci, but only a small fraction of heritability was explained. To account for missing heritability, we investigated gene-environment interactions (G × Es) between GWAS-identified single-nucleotide polymorphisms (SNPs) and established risk or protective factors for colorectal cancer using both case-only and case-control study designs.MethodsData on 703 colorectal cancer cases and 1406 healthy controls from the National Cancer Center in Korea were used. We tested interactions between 31 GWAS-identified SNPs and 13 established risk or protective factors for colorectal cancer (family history, body mass index, history of colorectal polyps, inflammatory bowel disease, and diabetes mellitus, alcohol drinking, smoking, regular exercise, regular aspirin use, postmenopausal hormone replace therapy, red meat and processed meat intake, and dairy consumption). Logistic regression models were used to assess G × Es for colorectal cancer risk.ResultsThe SNP rs4444235 at 14q22.2 interacted with regular exercise in colorectal cancer (pcase-only = 2.4 × 10− 3, pcase-control = 1.5 × 10− 3). The risk allele (C) of rs4444235 increased the risk of colorectal cancer in regularly exercising individuals (OR = 1.47, 95% CI = 1.02–2.10) but decreased the risk in non-exercising individuals (OR = 0.76, 95% CI = 0.62–0.94). Furthermore, the G × E between the SNP rs2423279 at 20p12.3 and regular aspirin use was statistically significant (pcase-only = 7.7 × 10− 3, pcase-control = 1.6 × 10− 3). The additive effect of the risk allele (T) of rs2423279 on colorectal cancer risk was increased among regular aspirin users (OR = 4.62, 95% CI = 1.97–10.80).ConclusionOur results suggest that SNP rs4444235 at 14q22.2 and SNP rs2423279 at 20p12.3 may interact with regular exercise and aspirin use in colorectal carcinogenesis.
Highlights
Genome-wide association studies (GWAS) have identified more than 40 colorectal cancer susceptibility loci, but only a small fraction of heritability was explained
Genome-wide association studies (GWASs) have identified more than 40 genetic susceptibility regions related to colorectal cancer risk with a nominal genome-wide significance threshold (p-value = 5 × 10− 8) [3], the common Single-nucleotide polymorphism (SNP) discovered by previous GWAS only accounted for 0.65% of the heritability of colorectal cancer, resulting in remaining missing heritability [2]
The caseonly design on G × Es is considered an alternative to case-control design due to potential false positives by unverified assumption of independence between genetic and environmental factors, it allows for more efficient estimation and more powerful association tests to be performed on G × Es than case-control design [16]
Summary
Genome-wide association studies (GWAS) have identified more than 40 colorectal cancer susceptibility loci, but only a small fraction of heritability was explained. To account for missing heritability, we investigated gene-environment interactions (G × Es) between GWAS-identified single-nucleotide polymorphisms (SNPs) and established risk or protective factors for colorectal cancer using both case-only and case-control study designs. Genome-wide association studies (GWASs) have identified more than 40 genetic susceptibility regions related to colorectal cancer risk with a nominal genome-wide significance threshold (p-value = 5 × 10− 8) [3], the common SNPs discovered by previous GWAS only accounted for 0.65% of the heritability of colorectal cancer, resulting in remaining missing heritability [2]. The caseonly design on G × Es is considered an alternative to case-control design due to potential false positives by unverified assumption of independence between genetic and environmental factors, it allows for more efficient estimation and more powerful association tests to be performed on G × Es than case-control design [16]
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