As shown in , colorectal cancer cases were more likely to be obese (23% vs 11% had BMI ≥ 30 kg/m2), more likely to consume alcohol (57% vs 52%), and generally consume more red and processed meat and less dairy than controls. Little to no difference was observed for dietary fiber intake between the cases and their matched controls. A higher proportion of cases than controls had a family history of colorectal cancer (12% vs 10%) and had ever smoked (60% vs 54%). Hours spent in moderate or vigorous physical activity were similar. The median levels for the plasma B vitamins were lower for cases than controls, except for methylmalonic acid. CRP levels were higher for cases.
Characteristics* of the Colorectal Cancer Cases and Matched Controls
presents the crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between each of the plasma B vitamins and the risk of colorectal cancer. Subjects in the upper quartiles for folate levels tended to show a reduced risk of CRC [adjusted OR (95% CI) for Q4 vs. Q1: 0.61 (0.33–1.13); p for trend: 0.097]. A significant inverse trend was observed for PLP levels, with ORs of 1.00, 0.84 (0.51–1.40), 0.62 (0.37–1.03), 0.49 (0.29–0.83); p for trend: 0.009. Because PLP and folate levels were correlated (Spearman correlation coefficient: 0.40), we further adjusted the risk estimates for plasma folate (last column in ). The association between PLP and CRC remained significant. No significant trends were observed for Vitamin B12, methylmalonic acid or homocysteine. We also ran a model for subjects with low vitamin B12 status, defined as vitamin B12 <148pmol/L or methlymalonic acid >210 nmol/L (223 cases, 407 controls), compared to all others. The adjusted OR for CRC was 1.27 (0.73–2.20). There was a reduced risk suggested for increasing levels of cysteine, but this trend was not statistically significant. Further adjustment for intakes of red meat, fish and dairy did not change the risk estimates.
Odds Ratios (95% Confidence Intervals) for Colorectal Cancer by Levels of Various Plasma B Vitamins
The main effect for MTHFR C677T was not significant [OR for TT vs. CC+CT genotype: 0.95 (0.52–1.73)]. Similarly, no statistically significant association was found with plasma CRP [multivariate-adjusted ORs for increasing quartiles (≤0.30, 0.31–0.80, 0.81–2.20, >2.2 mg/l): 1.00, 0.88 (0.52–1.49), 1.00 (0.61–1.62) and 1.19 (0.71–2.00), p for trend=0.33] or alcohol intake [multivariate-adjusted ORs for non-drinkers, ≤3.3 g/d, 3.3–16.4 g/d, >16.4: 1.00, 1.24 (0.79–1.96), 1.27 (0.78–2.06), 1.37 (0.81–2.31), p for trend: 0.35] in this nested-case control study.
shows the joint effects between B vitamins and, separately, alcohol, CRP, and the MTHFR 677TT genotype in relation to the risk of CRC. An interaction between plasma folate and alcohol intake was observed (pinteraction= 0.050), with a significantly decreased CRC risk observed with a high plasma folate (>15.3 ng/ml) only among subjects with an alcohol intake of ≤0.74 g/day [OR: 0.55 (0.31–0.95), compared to individuals with a low alcohol intake and a lower plasma level] (). Plasma folate, comparing subjects with high vs. low levels, was not associated with a reduced risk among subjects with an alcohol intake over the median [OR: 1.12 (0.62–2.04)]. This interaction with alcohol intake was also suggested for PLP (pinteraction= 0.072), where among light drinkers, the association with plasma PLP >51.5 pmol/ml, compared to a lower level [OR: 0.43 (0.26–0.74),] was stronger than among heavier drinkers [OR: 0.84 (0.50–1.40)]. No interaction was found between CRP and PLP, using for PLP either the median value (51.5 pmol/ml) (pinteraction= 0.42) or the cutpoint usually used for deficiency (30 pmol/ml) (pinteraction= 0.66). Unexpectedly, we observed a significant interaction between plasma CRP and vitamin B12 (pinteraction= 0.027), with the suggestion of an increased CRC risk with higher vitamin B12 levels among subjects with high CRP levels [OR: 1.50 (0.92–2.44)]. We also observed the suggestion of an interaction between PLP and MTHFR C677T on the risk of CRC (pinteraction= 0.08), with a stronger reduced risk among TT carriers with plasma PLP above the median, compared to those with PLP ≤ median [OR: 0.25 (0.08–0.80)], than among subjects with the CT or CC genotype [OR: 0.74 (0.47–1.15)]. A similar relationship was suggested for plasma folate, with ORs of 0.37 (0.11–1.21) and 0.92 (0.55–1.51) for high vs. low folate levels among TT carriers and CT/CC carriers, respectively.
Interactions of Alcohol, CRP and MTHFR C677T with Selected Plasma B-Vitamins in Relation to Risk of Colorectal Cancer
We also tested the interaction between plasma folate and PLP on the risk of CRC. The CRC OR for subjects with both PLP and folate levels above the median, compared to those with both levels ≤ median, was 0.55 (0.33–0.93) and the pinteraction was 0.93.
Stratified analyses by sex, anatomic subsites (colon, rectum), or race/ethnicity did not reveal any heterogeneity in the association of CRC with plasma PLP. A similar analysis stratified by multivitamin supplement use suggested a stronger effect among non-users [ORs for increasing tertiles of PLP: 1.00, 0.85 (0.41–1.77), 0.34 (0.13–0.92), p trend: 0.03] than users [1.00, 0.72 (0.41–1.26), 0.70 (0.40–1.22), p trend: 0.32]; however, the test for interaction was not significant (pinteraction= 0.52). Exclusion of cases diagnosed during the first year of follow-up did not materially change the risk estimates.