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  • 1
    Keywords: CANCER ; COHORT ; RISK ; GENE ; RISK-FACTORS ; ASSOCIATION ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; HEALTH ; COLON-CANCER ; ALCOHOL ; CONSUMPTION ; FRUIT ; LIFE-STYLE ; MASS INDEX ; CANCER SUSCEPTIBILITY ; METAANALYSIS ; VEGETABLE CONSUMPTION ; LOCI ; GENOME-WIDE ASSOCIATION ; sex ; SCAN ; RISK LOCI ; CHROMOSOME 8Q24
    Abstract: Genome-wide association studies (GWAS) have identified more than a dozen loci associated with colorectal cancer (CRC) risk. Here, we examined potential effect-modification between single-nucleotide polymorphisms (SNP) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at8q23.3 (EIF3H/UTP23), rs6983267 at 8q24 (MYC), rs10795668 at 10p14 (FLJ3802842), rs3802842 at 11q23 (LOC120376), rs4444235 at 14q22.2 (BMP4), rs4779584 at 15q13 (GREM1), rs9929218 at 16q22.1 (CDH1), rs4939827 at 18q21 (SMAD7), rs10411210 at 19q13.1 (RHPN2), and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/nonsteroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal P-interaction = 1.3 x 10(-4); adjusted P = 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption.
    Type of Publication: Journal article published
    PubMed ID: 22367214
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  • 2
    Keywords: CANCER ; NEW-YORK ; POPULATION ; RISK ; colon ; ASSOCIATION ; SUSCEPTIBILITY ; DIFFERENCE ; genetics ; colorectal cancer ; etiology ; COLORECTAL-CANCER ; COLON-CANCER ; heredity ; SNPs ; ALLELES ; analysis ; PHASE ; USA ; GENOME-WIDE ASSOCIATION ; SCAN ; GENETIC RISK
    Abstract: In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early- onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR 1.1; P=5.8 x 10(-10)),showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR 1.19; P=8.6x10(-26)) and 18q21 (rs4939827; OR 1.2; P=7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P 〈 0.008) and rs4939827 (P 〈 0.009). Carrying all six possible risk alleles yielded OR 2.6 (95% CI 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology
    Type of Publication: Journal article published
    PubMed ID: 18372901
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  • 3
    Keywords: DISEASES ; GENE ; METAANALYSIS ; INFERENCE ; 8Q24 ; susceptibility loci ; SCAN ; COMMON VARIANTS ; 5P15.33 ; MULTILOCUS GENOTYPE DATA ; RARE VARIANTS
    Abstract: Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 x 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p 〈 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 x 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 x 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer
    Type of Publication: Journal article published
    PubMed ID: 21761138
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