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Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with IBD
  1. J N NIELSEN,
  2. T B LARSEN,
  3. L FREDHOLM,
  4. I BRANDSLUND
  1. Department of Clinical Chemistry
  2. Vejle County Hospital, 7100 Vejle
  3. University of Southern Denmark, Denmark
  4. Department of Gastroenterology
  5. Hvidovre Hospital, 2800 Hvidovre
  6. University of Copenhagen, Copenhagen Denmark
  7. Department of Gastroenterology
  8. Vejle County Hospital, 7100 Vejle
  9. University of Southern Denmark, Denmark
  10. Correspondence to: JN Nielsen. (Email:JNN{at}vs.vejleamt.dk)
    1. P MUNKHOLM
    1. Department of Clinical Chemistry
    2. Vejle County Hospital, 7100 Vejle
    3. University of Southern Denmark, Denmark
    4. Department of Gastroenterology
    5. Hvidovre Hospital, 2800 Hvidovre
    6. University of Copenhagen, Copenhagen Denmark
    7. Department of Gastroenterology
    8. Vejle County Hospital, 7100 Vejle
    9. University of Southern Denmark, Denmark
    10. Correspondence to: JN Nielsen. (Email:JNN{at}vs.vejleamt.dk)
      1. H HEY
      1. Department of Clinical Chemistry
      2. Vejle County Hospital, 7100 Vejle
      3. University of Southern Denmark, Denmark
      4. Department of Gastroenterology
      5. Hvidovre Hospital, 2800 Hvidovre
      6. University of Copenhagen, Copenhagen Denmark
      7. Department of Gastroenterology
      8. Vejle County Hospital, 7100 Vejle
      9. University of Southern Denmark, Denmark
      10. Correspondence to: JN Nielsen. (Email:JNN{at}vs.vejleamt.dk)
        1. D G WEIR,
        2. N MAHMUD,
        3. A MOLLOY,
        4. J SCOTT
        1. Department of Clinical Medicine
        2. Trinity Centre for Health Sciences
        3. St James's Hospital, James's Street
        4. Dublin 8, Republic of Ireland
        5. Email: dweir{at}tcd.ie

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          Editor,—We read with interest the paper by Mahmudet al (

          ) . The study showed an increased prevalence of methylenetetrahydrofolate reductase (MTHFR) C677T variant in patients with inflammatory bowel disease (IBD). The C677T polymorphism is a known genetic cause of mild hyperhomocysteinaemia (hyper-tHcy)1 and may be associated with a variable degree of risk for thromboembolic disease in patients with IBD.2

          To confirm a higher prevalence of the C677T polymorphism, we investigated 99 patients with established IBD for this polymorphism compared with 1084 unselected newborns.3 DNA samples were genotyped for the MTHFR (C677T) mutation. Patients were categorised as homozygous for the thermolabile variant (TT), heterozygous for the wild-type variant (CT), or homozygous for the wild-type (CC).

          Difference in prevalence between IBD patients and controls was compared using the χ2 test. Differences in onset of disease between patients with Crohn's disease (CD) and those with ulcerative colitis (UC) were compared using the Mann-Whitney test.

          A total of 16.2% (16/99) of IBD patients were homozygous for the C677T variant compared with 8.3% (90/1084) in the control group. This difference was statistically significant (p<0.009). When patients were stratified according to CD and UC, we found that homozygosity for the MTHFR C677T variant (TT) was present in 14.0% (7/50) of patients with CD and 18.4% (9/49) of those with UC. Both results were independently significantly higher than in the background population.

          Onset of disease in carriers of the (TT) variant in CD and UC patients was 33.8 and 40.6, respectively, compared with 34.4 and 43.3 in non-carriers. This difference was not statistically significant. There was no correlation between disease activity indices of the IBD patients (Crohn's disease activity index for CD and clinic activity index for UC) and carriers of the (TT) variants. Also, C reactive protein levels in IBD patients was independent of MTHFR gene prevalence.

          Genome wide linkage screen of a large population of IBD patients found evidence of linkage of IBD to the short arm of chromosome 1 in all families investigated. It is interesting that the MTHFR gene is located on chromosome 1 (1p36.3). Additional loci on chromosomes 3, 7, and 16 are linked to IBD.4 The genetic basis of IBD is non-mendelian in nature5 and very complex. Unrecognised factors may therefore be important in the pathogenesis of IBD. Further investigation of other factors is being carried out in our laboratory at present.

          References

          Reply

          Editor,—Thank you for the opportunity to comment on the letter of Dr Nielsen and colleagues. We are pleased that their data have confirmed our findings, as previously recorded (

          ) . We agree with their comment that the genetic basis of inflammatory bowel disease (IBD) is very complex. One point needs to be emphasised, namely that serum homocysteine levels were increased in our patients compared with controls, even when those patients who were homozygous for C677T polymorphism were excluded. This elevated level was present even when the effect of folate deficiency was excluded. This suggests that other polymorphisms as yet undiscovered may be present in one or other of the three enzymes responsible for removal of homocysteine in internal metabolism, namely methylenetetrahydrofolate reductase, methionine synthase, and cystathionine synthase. Accordingly, it is important to emphasise that all patients with IBD should receive regular therapy with 400 μg of folic acid daily.

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