Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer.
Helicobacter pylori infection, the dominant risk factor for gastric cancers, has been shown to elicit T helper type 1 (Th1) polarized immunological responses. We conducted a population-based study of 305 gastric cancer cases and 427 age- and gender-matched controls in Warsaw, Poland, to evaluate the association with several variants in genes responsible for Th1-cell-mediated response. Genotyping was performed on genomic DNA by TaqMan(TM) assays to determine TNFA (-308 G>A, -417 G>A, -555 G>A, -1036 C>T, -1042 C>A, -1210 T>C), IL1A (-889 C>T), IFNGR2 (Ex7-128 T>C, Ex2-34 C>G and Ex2-16 A>G) and IL12A (IVS2-798 T>A, IVS2-701 C>A and Ex7+277 G>A) polymorphisms. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for sex, age, education and smoking status. Out of six single nucleotide polymorphisms (SNPs) tested in TNFA, gastric cancer risk was significantly associated with the TNFA (-308 G>A) polymorphism, with ORs of 1.4 (95% CI: 1.0-2.0) for the G/A and 2.5 (95% CI: 1.3-4.9) for the A/A genotype carriers, when compared with the more frequent genotype (G/G) (P-trend < 0.001). Among the three tested SNPs in the IFNGR2 gene, only the Ex7-128C>T polymorphism was associated with increased risk, with ORs of 1.5 (95% CI: 1.0-2.3) for T/C and 1.7 (95% CI: 1.1-2.7) for C/C carriers when compared with T/T carriers (P-trend = 0.01). Subjects carrying both IFNGR2 Ex7-128 C/C and TNFA -308 A/A genotypes had the highest risk (OR = 5.5, 95% CI: 1.5-19.4), although the interaction was not statistically significant. IL1A (-889 C>T) and the three examined IL12A variants were unrelated to gastric cancer risk. Our findings suggest that two Th1-related polymorphisms (TNFA -308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer.
Hou
L
L
Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS 8123, Bethesda, MD 20852-7242, USA. lifangh2@mail.nih.gov
El-Omar
E M
EM
Chen
J
J
Grillo
P
P
Rabkin
C S
CS
Baccarelli
A
A
Yeager
M
M
Chanock
S J
SJ
Zatonski
W
W
Sobin
L H
LH
Lissowska
J
J
Fraumeni
J F
JF
Chow
W H
WH
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011044:Poland; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017471:Receptors, Interferon / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
C086185:IFNGR2 protein, human; C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha