Elevated tHcy in Alzheimer Cause or result of disease

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Smoking, folate and methylenetetrahydrofolate
reductase status as interactive determinants of
colorectal polyps and adenomas

• Telemark Polyp Study-1

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The C677T MTHFR polymorphismand folate
distribution
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Demographic and genetic characteristics of study
population
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Table 2. Clinicopathological diagnoses
Measure of growth given as median (range)
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Occurrence of colorectal polyps and adenomas
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Characteristics in terms of type, number and size
of colorectal polyps and adenomas
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Table 3. Homocysteine and vitamin status
according to gender and smoking
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Table 5. Predictors of plasma homocysteine by
multiple regression
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Odds ratios (95 CI) for the colonoscopic
outcomes for a one level increase in the
independent variable
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Odds ratios (95 CI) for the colonoscopic
outcomes for a one level increase in the
independent variable at low folate
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Odds ratios (95 CI) for the colonoscopic
outcomes for a one level increase in the
independent variable at high folate
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The C677T MTHFR polymorphism as risk factor of
significant lesion of colon-rectum at high and
low and high whole blood folate
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The interaction of smoking, folate status and the
C677T MTHFR polymorphism as risk factors of high
risk adenomas
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The interaction of smoking, folate status and the
C677T MTHFR polymorphism as risk factors of
adenomas 5mm of colon-rectum
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The interaction of smoking, folate status and the
C677T MTHFR polymorphism as risk factors of
hyperplastics polyps of colon-rectum
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Gene-environment interaction in the genetic
pathway to sporadic CRC

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Hypothetical model for the involvement of folate
and MTHFR status in the pathogenesis of
colorectal adenoma and cancer in smokers
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Conclusion

• Folate status and the C677T MTHFR SNP modulate
  the procarcinogenic effect of smoking
• High risk of large or villous or dysplastic
  adenomas were observed in smokers with
• low folate and the CT/TT genotypes
• high folate and the CC genotype
• Similar, but weaker relations were observed with
  hyperplastic polyps

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Relative risk (RR) for colon cancer according to
years since the start of use of multivitamins
containing folic acid in the Nurses Health Study
(1980-1994)
Modified fromGiovannucci et al (1998)Annals
Intern. Med. 129 517-524
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Odds ratio of colorectal cancer by MTHFR genotype
and plasma folate status among United States
physicians
Modified from Ma et al (1997) Cancer Res. 57
1098-1102
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Folate status and colorectal adenomas and cancer.
The evidence

• About 20 case-control studies and 3 prospective
  studies including about 9000 patients
• Most studies (12/16) based on dietary assessment
  demonstrate a relation between folate status and
  risk
• Studies (5) based on measures of folate status in
  blood provide discrepant results
• Most intervention studies (5/7) demonstrate
  reduction of parameters related to carcinogenesis
  by folate
• Modulation of colorectal carcinogenesis by folate
  is supported by animal studies
• Possible mechanisms

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Candidate mechanisms for folate-related
enhancement of carcinogenesis

• Induction of DNA hypomethylation
• Increased chromosomal fragility and/or diminished
  DNA repair
• Secondary choline deficiency
• Diminution in natural killer cell surveillance
• Misincorporation of uridylate for thymidylate in
  DNA synthesis
• Facilitation of tumorigenic virus metabolism

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Folate status has been associated with cancer in

• Lung
• Intervention trials
• Uterine cervix
• Dietary folate, blood folate measurement,
  intervention trials
• Esophagus, stromach and pancreas
• Ecological studies, dietary folate, blood folate,
  intervention trials
• Breast
• Dietary folate
• Colorectum
• Dietary folate, blood folate measurement,
  intervention trials
• S

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The effect of folic acid supplementation on
cervical dysplasia
Changes in cervical dysplasia in patients
receiving either placebo (n25) or folic acid
(n22). Cytological evaluation was made at 4
weeks intervals, and biopsy was at the fourth
visit (3 months of therapy) Butterworth et al
(1982) Am. J. Clin. Nutr. 35 73-82
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The T-allele of the C677T MTHFR polymorphism is
related to high plasma homocysteine and low
serum folate
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Serum and RBC folate in subjects with significant
colon lesion compared with controls