Meta- and pooled analyses of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer: a HuGE-GSEC review

Abstract

Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

Figure 1.

Schematic presentation of folate metabolism. DHF, dihydrofolate; dTMP, deoxythymidine monophosphate (deoxythymidylate); dUMP, deoxyuridine monophosphate (deoxyuridylate); MTHFR, methylenetetrahydrofolate reductase; THF, tetrahydrofolate. (Modified from Kono and Chen (8)).

Figure 2.

Study-specific (squares) and meta-analysis (diamond) odds ratios for colorectal cancer among persons with the methylenetetrahydrofolate reductase (MTHFR) 677CT genotype—CT versus CC. Meta-analysis estimate for the CT genotype versus the CC genotype: P = 0.57; Q = 32.887; P = 0.240; I² = 15%, 95% confidence interval (CI): 0, 46. Horizontal lines, 95% CI.

Figure 3.

Study-specific (squares) and meta-analysis (diamond) odds ratios for colorectal cancer among persons with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype—TT versus CC. Meta-analysis estimate for the TT genotype versus the CC genotype: P < 0.001; Q = 37.602; P = 0.106; I² = 26%, 95% confidence interval (CI): 0, 53. Horizontal lines, 95% CI.