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Increased blood levels of homocysteine have been found to be associated with inflammatory bowel diseased (IBD) in several studies.1,2 The main genetic determinant associated with elevated plasma levels of homocysteine (t-Hcys) is the MTHFR 677C→ T gene polymorphism of methylenetetrahydrofolate reductase, a critical enzyme involved in the remethylation pathway of homocysteine.3 An association of the MTHFR 677T allele with IBD has been reported in Northern Europe1,4 but not in three other series from Italy and France.5–7 Double heterozygosity MTHFR 677CT+1298AC also produces reduced enzyme activity and increased t-Hcys, but its association with IBD has never been studied. Similarly, the association of IBD with transcobalamin (TCN1 776C→G), a genetic determinant that influences transcobalamin levels and t-Hcys, is not known. Transcobalamin is the protein that promotes intestinal transcytosis and cell delivery of vitamin B12, the cofactor of the methionine synthase dependent remethylation pathway.8
In this study, we have evaluated the association of ulcerative colitis (UC) with MTHFR 677C→T, MTHFR1298A→C, and TCN1 776C→G in a series of 72 patients from central China who gave informed consent. This series was compared with 111 age and sex matched controls. The research protocol was approved by the local appointed committee. Extraction of DNA and determination of polymorphisms were performed as described previously by us.8,9 A continuity corrected χ2 test and an ANOVA test were used, respectively, to assess differences in categorical and continuous variables between groups. Odds ratios of independent categorical variables that differed significantly between patients and controls were determined by logistic regression analysis. A p value <0.05 was considered to indicate statistical significance.
The main clinical characteristics are summarised in table 1. Most of the cases were recently diagnosed. None had any thrombotic manifestations. TCN1 776G allele frequency was approximately 1.5-fold higher compared with Caucasians, and we failed to find any association with the risk of UC or severity of disease. MTHFR677T allele frequency in our control group was close to that reported in South Europe and much higher than that of North Europe. There was no significant association of the MTHFR 677TT or 677T allele with the risk of UC. By comparison, this association was significant in two UC series of 52 and 91 cases, respectively, from the UK and Denmark, two countries with a lower MTHFR 677T allele frequency, but not in other series from Italy and France where allele frequency was comparable with that observed in our population. These discrepant results could therefore be related, at least in part, to ethnic variations in 677T allele frequency, as previously observed with Down syndrome, spina bifida, and cardiovascular diseases.10 In contrast, we found a significant association with age at onset. Onset in 677T allele carriers occurred later than that of non-carriers, with respective mean ages of 42.4 (15.7) and 35.4 (13.8) (p = 0.0487).
Our results were different when the two 677TT and 677CT+1298AC genotypes of MTHFR were considered together, that correspond to decreased catalytic activity. Firstly, the difference in frequency between patients and controls was at the limit of significance and this could be related to the limited size of our patient series (table 1). Secondly, these genotypes were associated with an increased risk of extensive UC (whole colon) (table 1), with an odds ratio of 4.92 (95% confidence interval 1.3–18.3; p = 0.017), after adjustment for age and sex.
In conclusion, our study showed that the genotypes of MTFHR, associated with a decrease in enzyme activity, seemed to be more significantly associated with extension of disease than with the primary risk, at least in central China.
Conflict of interest: None declared.