Genetic variability in the MTHFR gene and colorectal cancer risk using the colorectal cancer family registry.
BACKGROUND
The MTHFR C677T TT genotype is associated with a 15% to 18% reduction in colorectal cancer risk, but it is not clear if other variants of the gene are associated with colorectal cancer risk.


METHODS
We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and colorectal cancer risk using a large family-based case-control study of 1,750 population-based and 245 clinic-based families from the Colon Cancer Family Registry. We assessed 22 TagSNPs, selected based on pairwise r(2) >95%, using the Haploview Tagger and genotyped the TagSNPs on the Illumina GoldenGate or Sequenom platforms. The association between single nucleotide polymorphisms and colorectal cancer was assessed using log-additive, codominant, and recessive models.


RESULTS
From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased colorectal cancer risk overall [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.63-1.04; and OR, 0.82; 95% CI, 0.64-1.07, respectively]. The 677 TT genotype was associated with a decreased risk of microsatellite-stable/microsatellite-low tumors (OR, 0.69; 95% CI, 0.49-0.97) and an increased risk of microsatellite-high tumors (OR, 2.22; 95% CI, 0.91-5.43; P(interaction) = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (P(interaction) = 0.02). No other single nucleotide polymorphism was associated with risk overall or within subgroups.


CONCLUSIONS
The 677 TT and 1298 CC genotypes may each be associated with a decrease in colorectal cancer risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to colorectal cancer risk.
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
Poynter
Jenny N
JN
Conti
David
D
Duggan
David J
DJ
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
D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D004032:Diet; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D053842:Microsatellite Instability; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D012307:Risk Factors
D014408:Biomarkers, Tumor; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)