A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk.
BACKGROUND
Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer.


METHODS
This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B(12) metabolism. Genotyping was done using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. Microsatellite instability (MSI) status was determined using standard techniques, and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or codominant model.


RESULTS
In the log additive model, two linked (r(2) = 0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in colorectal cancer risk after correction for multiple testing (odds ratio, 0.87; 95% confidence interval, 0.71-0.94; P = 0.029; and odds ratio, 0.87; 95% confidence interval, 0.71-0.95; P = 0.034 for rs1677693 and rs1643659, respectively). These two linked (r(2) = 0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced colorectal cancer risk only among individuals not using multivitamin supplements.


CONCLUSIONS
Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect colorectal cancer risk except in non-multivitamin users.


CONCLUSIONS
This study suggests that multivitamin supplement use may modify the association between folate pathway genes and colorectal cancer risk in a post-folic-acid-supplemented population.
Levine
A Joan
AJ
USC Keck School of Medicine, Department of Preventive Medicine, Genetic Epidemiology, NRT 1450 Biggy Street Room 1509A, Los Angeles, CA 90033, USA. ajoanlev@usc.edu
Figueiredo
Jane C
JC
Lee
Won
W
Conti
David V
DV
Kennedy
Kathleen
K
Duggan
David J
DJ
Poynter
Jenny N
JN
Campbell
Peter T
PT
Newcomb
Polly
P
Martinez
Maria Elena
ME
Hopper
John L
JL
Le Marchand
Loic
L
Baron
John A
JA
Limburg
Paul J
PJ
Ulrich
Cornelia M
CM
Haile
Robert W
RW
D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism* / Q000517:prevention & control; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014481:United States / Q000453:epidemiology; D014805:Vitamin B 12 / Q000378:metabolism
D005492:Folic Acid; D014805:Vitamin B 12