Journal
CARCINOGENESIS
Volume 34, Issue 4, Pages 936-942Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgs395
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Funding
- National Natural Science Foundation of China [NSFC-81001275, 81171878, 81222038]
- Fok Ying Tung Foundation for Young Teachers in the Higher Education Institutions of China [131038]
- Program for New Century Excellent Talents in University [NCET10-0388]
- Natural Science Foundation of Hubei [2012FFA011, NSFC-30972534]
- Guangdong Medical Research Foundation [B2012176]
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Recent genome-wide association studies (GWAS) have reported multiple risk loci associated with risk of colorectal cancer (CRC), some of which are involved in the transforming growth factor beta (TGF) signaling pathway. We systematically examined associations of common genetic variations in the TGF signaling pathway and environmental factors with CRC risk using a two-staged case-control study in a Chinese population. A set of 77 single-nucleotide polymorphisms (SNPs) in 10 candidate genes involved in the TGF signaling pathway and several environmental factors including sex, age, smoking and drinking were examined by random forest (RF) to capture the potential genegene and geneenvironment interactions in stage 1 of the study with 443 CRC patients and 480 controls. Three promising SNPs (SMAD7 rs11874392, TGFBR1 rs10988706 and rs6478972) selected by the RF method were genotyped in stage 2 comprising 351 cases and 360 controls for validation. SMAD7 rs11874392 presented consistently significant associations with a risk of CRC at both stages, with odds ratio 1.41 (95% confidence interval 1.211.63) using additive modes in combined analyses. Moreover, the potential interactions between SMAD7 rs11874392, TGFBR1 rs10988706 and rs6478972 were indicated consistently in both stages of the study by using pair-wise interaction and multilocus genotype pattern analysis. Additionally, genesmoking interactions for rs11874392, rs10988706 and rs6478972 were also found to enhance the risk of CRC at both stages, with P for multiplicative interaction equal to 1.16210(6), 8.57410(8) and 9.41010(8) in combined analyses, respectively. This study emphasized the substantial role of the TGF signaling pathway in CRC, especially in interaction with smoking.
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