Abstract 2193: Colorectal cancer risk associated with alcohol intake is modified by common genetic variants in one-carbon metabolism: the Multiethnic Cohort Study

Abstract

Abstract Background: Epidemiologic studies have observed that higher alcohol intake is associated with an increased risk of colorectal cancer and that the effects of alcohol may vary by common genetic polymorphisms in one-carbon metabolism enzymes, most notably MTHFR. Experimental studies demonstrated alcohol may impair the activity of some of the enzymes involved in the pathway. We examined common functional genetic variants in key one-carbon metabolism enzymes and their interactions with alcohol intake in association with the risk of colorectal cancer in a prospective study. Materials and Methods: We conducted a study within the Multiethnic Cohort on 1,670 incident colorectal cancer (932 male, 738 female) cases and 2,532 controls that were frequency-matched based on baseline age (45-75), sex and race/ethnicity (African American, white, Japanese American, Latino and Native Hawaiian). Alcohol intake was estimated from a self-administered food frequency questionnaire. Reported functional variants were genotyped in BHMT, CBS, CHDH, MTHFD1, MTHFR, MTR, MTRR, PEMT, and TCN2, using TaqMan assays. Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations adjusted for age, sex, and race/ethnicity. Results: In the nested case-control subset, as in the entire cohort, alcohol intake was associated with an elevated risk of colorectal cancer [ORs for <7g or 0.5 drink/day and ≥ 7g/day intake compared to non-drinking were 1.16 (95% CI: 0.99, 1.35) and 1.30 (1.11, 1.54), respectively; p-trend=0.001]. We found an association of colorectal cancer with rs1801133 in MTHFR [OR=0.81 (0.66, 0.99) for TT vs. CC/CT], as reported earlier, and also with rs1801131 [MTHFR; OR=1.36 (1.02, 1.86) for CC vs. AA/AC] and rs12676 [CHDH; OR=0.84 (0.70, 0.99) for AC/CC vs. AA]. There was a significant interaction between alcohol intake and genetic variants rs1801133 (p-interaction=0.02) and rs1801131 (p-interaction=0.04) in MTHFR, rs12676 (CHDH; p-interaction=0.0002), and rs234706 (CBS; p-interaction=0.002). Alcohol-associated colorectal cancer risk increases were observed only among individuals with the following genotypes: rs1801133 TT [ORs for <7g/day and ≥ 7g/day intake compared to non-drinking: 1.78 (1.11, 2.85), 2.11 (1.25, 3.56)], rs1801131 AA [ORs=1.18 (1.00, 1.30), 1.35 (1.14, 1.59)], rs12676 AA [ORs=1.23 (1.03, 1.47), 1.44 (1.20, 1.74) and rs234706 GG [ORs=1.21 (1.00, 1.46), 1.48 (1.21, 1.81)]. Conclusions: Our findings provide further support that alcohol intake may increase the risk of colorectal cancer in part through its antagonistic effects on one-carbon metabolism, especially among carriers of susceptibility genotypes for key enzymes. Citation Format: Unhee Lim, Lynne R. Wilkens, Maarit Tiirikainen, Carol J. Boushey, Laurence N. Kolonel, Loic Le Marchand. Colorectal cancer risk associated with alcohol intake is modified by common genetic variants in one-carbon metabolism: the Multiethnic Cohort Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2193. doi:10.1158/1538-7445.AM2014-2193