The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition.
Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first prospective study of blood folate levels and gastric cancer. Gastric cancer cases (n=247) and controls (n=631) were matched for study center, age, sex, and time of blood donation. Two common single nucleotide polymorphisms of the MTHFR gene were determined, as were plasma concentrations of folate, cobalamin (vitamin B12), total homocysteine, and methylmalonic acid (cobalamin deficiency marker) in prediagnostic plasma. Risk measures were calculated with conditional logistic regression. Although no relations were observed between plasma folate or total homocysteine concentrations and gastric cancer, we observed a trend toward lower risk of gastric cancer with increasing cobalamin concentrations (odds ratio, 0.79 per SD increase in cobalamin; P=0.01). Further analyses showed that the inverse association between cobalamin and gastric cancer was confined to cancer cases with low pepsinogen A levels (marker of severe chronic atrophic gastritis) at the time of blood sampling. The 677 C-->T MTHFR polymorphism was not associated with gastric cancer, but we observed an increased risk with the variant genotype of the 1298 A-->C polymorphism (odds ratio, 1.47 for CC versus AA; P=0.04). In conclusion, we found no evidence of a role of folate in gastric cancer etiology. However, we observed increased gastric cancer risk at low cobalamin levels that was most likely due to compromised cobalamin status in atrophic gastritis preceding gastric cancer.
Vollset
Stein Emil
SE
LOCUS for Homocysteine and Related Vitamins, Institute of Medicine, University of Bergen, Bergen, Norway. vollset@uib.no
Igland
Jannicke
J
Jenab
Mazda
M
Fredriksen
Ase
A
Meyer
Klaus
K
Eussen
Simone
S
Gjessing
Håkon K
HK
Ueland
Per Magne
PM
Pera
Guillem
G
Sala
Núria
N
Agudo
Antonio
A
Capella
Gabriel
G
Del Giudice
Giuseppe
G
Palli
Domenico
D
Boeing
Heiner
H
Weikert
Cornelia
C
Bueno-de-Mesquita
H Bas
HB
Carneiro
Fátima
F
Pala
Valeria
V
Vineis
Paolo
P
Tumino
Rosario
R
Panico
Salvatore
S
Berglund
Göran
G
Manjer
Jonas
J
Stenling
Roger
R
Hallmans
Göran
G
Martínez
Carmen
C
Dorronsoro
Miren
M
Barricarte
Aurelio
A
Navarro
Carmen
C
Quirós
José R
JR
Allen
Naomi
N
Key
Timothy J
TJ
Bingham
Sheila
S
Linseisen
Jakob
J
Kaaks
Rudolf
R
Overvad
Kim
K
Tjønneland
Anne
A
Büchner
Frederike L
FL
Peeters
Petra H M
PH
Numans
Mattijs E
ME
Clavel-Chapelon
Françoise
F
Boutron-Ruault
Marie-Christine
MC
Trichopoulou
Antonia
A
Lund
Eiliv
E
Slimani
Nadia
N
Ferrari
Pietro
P
Riboli
Elio
E
González
Carlos A
CA
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005757:Gastritis, Atrophic / Q000097:blood / Q000453:epidemiology; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000097:blood / Q000235:genetics*; D008764:Methylmalonic Acid / Q000097:blood; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D014805:Vitamin B 12 / Q000097:blood*
D006710:Homocysteine; D008764:Methylmalonic Acid; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12