|(G;G)||2||no increased risk of colorectal cancer correlated with consumption of processed meats|
|(G;T)||2.5||slightly (17%) higher risk of colorectal cancer correlated with consumption of processed meats|
|(T;T)||3.1||higher (by 39%) risk for colorectal cancer correlated with consumption of processed meats|
rs4143094 is a SNP identified by a genome-wide diet-gene interaction analysis (GxE), and was found to be associated with increased risk of colon cancer correlated to the dietary variable of processed meat consumption. It is located on chromosome 10p14, 7.2kb upstream of GATA binding protein 3 (GATA3), in the promoter region of the gene [PMID 24743840]
rs4143094 was identified in a screen of 2.7 million SNPs for the risk of colorectal cancer, by combining 10 studies comparing 9287 cases and 9117 controls. Data was obtained from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and analyzed by conventional case-control logistic regression for multiplicative interactions between SNPs and dietary factors.[PMID 24743840]
rs4143094 was the most significantly implicated SNP in 10p14 for processed meat consumption linked with occurrence of colorectal cancer. The risk allele (T) has an ORinteraction=1.17, p=8.73E-09 with evidenced heterogenetity by p=0.78. When stratifying by genotype, rs4143094-TG has OR=1.2, 95% CI=1.13-1.26; rs4143094-TT has an OR=1.39, 95% CI=1.22-1.59; and the minor/null genotype rs4143094-GG has an OR=1.03, 95% CI=0.98-1.07. Several other SNPs in the 10p14 region were correlated to the same phenotype, (rs485411, risk allele C, ORinteraction=1.18; Pinteraction=1.72E-08; rs1269486, risk allele A, ORinteraction=1.18, Pinteraction=7.53E-08) though rs4143094 was highlighted due to having the most significant P-value.[PMID 24743840]
Colorectal cancer is the third most leading cause of cancer death in men and women [PMID 22237781], and consumption of processed meat has been linked to increased risk of its development [PMID 20663065], [PMID 20495462]. rs4143094 is upstream of GATA3, a gene associated with Th2 cell differentiation [PMID 20969588], which is upregulated in ulcerative colitis [PMID 22467146], a risk factor for colorectal cancer [PMID 17919486]. Though the mechanism by which GATA3 suppression may lead to increased risk of colorectal cancer is unknown, its suppression has been previously linked to breast, colorectal, and lung cancers [PMID 3092280].
DOJ 10.1371/journal.pgen.1004228 Association between risk of colorectal cancer associated with processed meat.
rs4143094 on chromosome 10p14 is about 7.2kb upstream of GATA3 gene. GATA3 belongs to the GATA family of transcription factors. Its functional role includes regulation of luminal epithelial cell differentiation, development of T cell, and differentiation of T helper (Th) cell. Genes in the GATA family are involved in several types of cancers including breast cancer, prostate cancer, and of particular interest to this entry, colorectal cancer [PMID 19798694] [PMID 23428429] [PMID 23348900] [PMID 21779441]. According to dbSNP, rs4143094 has two alleles, G (major allele) and T (minor allele). The minor allele has a frequency of 0.2337 across all populations.
A recent genome-wide association study (GWAS), using data from Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), discovered a strong correlation between rs4143094 and risk of colorectal cancer when ingesting red and processed meat [PMID 24743840]. In the study, approximately 2.7M SNPs were tested across 9,287 case and 9,117 control subjects, all with European ancestry.
The result shows that rs4143094 is associated with risk of colorectal cancer (P = 8.73e-9), with T being the risk allele. Specifically, individuals with TG and TT genotypes are increased for occurrence of colorectal cancer with odds ratio (OR) of 1.2 and 1.39, respectively. rs4143094 resides in a 9.5 kb linkage-disequilibrium (LD) block (r2 > 0.8) containing 19 highly correlated SNPs. The third most significant among these SNPs, rs1269486, is located 1420 bases upstream of GATA3 and is in a region of open chromatin (DNA hypersensitivity). Experimental evidence suggests binding activity of Pol2 and transcription factors c-Fos, JunD, and c-Jun in this region [PMID 23193274]. Many other SNPs in the LD block reside in GATA3-antisense RNA1 (GATA3-AS1). GATA3-AS1 may regulate GATA3 transcript activity, although further experimental evidence is required.
Apart from the SNP, this study also observed that red and processed meat consumption increases risk for colorectal cancer with OR of 1.15 and 1.11, respectively. For this secondary result, the author proposed the following pathway: processed meat triggers pro-tumorigenic inflammatory or immunological response, whose recovery depends upon the expression of GATA3 gene. Further experimental evidence is required to confirm this hypothesis.