Novel interleukin-4 and interleukin-1 receptor antagonist gene variations associated with non-cardia gastric cancer in Japan: comprehensive analysis of 207 polymorphisms of 11 cytokine genes.
OBJECTIVE
Helicobacter pylori (H. pylori)-induced chronic atrophic gastritis is a high-risk factor for gastric cancer. Immune responses to H. pylori are involved in gastric mucosal inflammation, and might affect clinical outcome, including the development of gastric cancer. The present study examines the significance of gene polymorphisms of various cytokines in the development of gastric cancer following H. pylori infection.


METHODS
One hundred Japanese non-cardia gastric cancer patients and 93 dyspeptic patients as controls were enrolled in the study (age range 50-75 years). All patients were positive for H. pylori. Genomic DNA was extracted from peripheral whole blood leukocytes, and we comprehensively analyzed 207 single nucleotide polymorphisms (SNP) in 11 cytokine genes; interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (RN), IL-4, IL-4R, IL-8, IL-10, IL-12, TNF-alpha, TNF-beta, and IFN-gamma, using either invader assay (163 SNP), direct sequencing (22 SNP), or PCR-restriction fragment length polymorphism (22 SNP).


RESULTS
Among the 207 SNP examined, the IL-4 gene diplotypes (984 and 2983 AA/GA) had a significant negative association with gastric cancer development (odds ratio =0.3, 95% confidence interval =0.1-0.9). When we adopted the dyspeptic patients over 66 years of age as the controls, the IL-1RN gene diplotypes (-1102 and 6110 CG/GA) also had a significant negative association (odds ratio =0.2, 95% confidence interval =0.1-0.7).


CONCLUSIONS
A comprehensive analysis of 207 SNP of 11 cytokine genes revealed that variations in IL-4 and IL-1RN genes are negatively associated with the risk of developing gastric cancer following H. pylori infection. Distinct host cytokine responses in the gastric mucosa might have a role in H. pylori-induced carcinogenesis.
Seno
Hiroshi
H
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Satoh
Kiichi
K
Tsuji
Shingo
S
Shiratsuchi
Takayuki
T
Harada
Yosuke
Y
Hamajima
Nobuyuki
N
Sugano
Kentaro
K
Kawano
Sunao
S
Chiba
Tsutomu
T
D000368:Aged; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016481:Helicobacter Infections / Q000150:complications* / Q000382:microbiology; D016480:Helicobacter pylori / Q000302:isolation & purification*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics*; D007564:Japan; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology
D016207:Cytokines; C507763:IL1RN protein, human; C508598:IL4 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015847:Interleukin-4