The -251T allele of the interleukin-8 promoter is associated with increased risk of gastric carcinoma featuring diffuse-type histopathology in Chinese population.
OBJECTIVE
Persistent interleukin-8 (IL-8) production contributes to chronic inflammation of the stomach. The proinflammatory IL-1beta polymorphisms, which enhance the cytokine production, are associated with increased risk of gastric cancer. The -251A/T polymorphism of the IL-8 promoter is involved in several human diseases. Particularly, the -251A is associated with decreased risk of colorectal cancer. We aimed to determine whether the -251 allele resulting in high IL-8 expression was associated with increased risk of gastric carcinoma.


METHODS
The -251A/T promoters were cloned and analyzed by luciferase assay. Binding of nuclear proteins to the -251A/T promoters was analyzed by electrophoretic mobility shift assay. The -251A/T promoters were differentiated by PCR-RFLP. Comparison of gastric cancer risk between the -251A/T promoters was done by a case-control study.


RESULTS
The -251T allele possessed transcriptional activity 2- to 5-fold stronger than the -251A counterpart. Electrophoretic mobility shift assay showed that the -251A promoter had strong ability to bind to an unknown protein or multiprotein complex. The -251T allele was associated with increased risk of noncardia (P(trend) = 0.012) and cardia (P(trend) = 0.029) carcinomas. Gastric carcinoma patients with the low-risk AA genotype had a tendency to sustain intestinal-type carcinomas (chi(2) = 6.816; P = 0.033); however, the high-risk -251T allele was associated with >2-fold increased risk of diffuse-type (AA versus AT + TT: odds ratio, 2.52; 95% confidence interval, 1.16-5.49; P = 0.017) and mixed-type (AA versus AT + TT: odds ratio, 2.22; 95% confidence interval, 1.12-4.40; P = 0.019) carcinomas.


CONCLUSIONS
The IL-8 -251T allele is significantly associated with increased risk of gastric carcinoma, particularly the diffuse and mixed types in Chinese population.
Lee
Wei-Ping
WP
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan. wleemc@yahoo.com
Tai
Dar-In
DI
Lan
Keng-Hsin
KH
Li
Anna Fen-Yau
AF
Hsu
Hou-Ching
HC
Lin
En-Ju
EJ
Lin
Yi-Ping
YP
Sheu
Meei-Ling
ML
Li
Chung-Pin
CP
Chang
Full-Young
FY
Chao
Yee
Y
Yen
Shang-Heu
SH
Lee
Shou-Dong
SD
D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D016009:Chi-Square Distribution; D002681:China; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D016481:Helicobacter Infections / Q000235:genetics / Q000382:microbiology; D016480:Helicobacter pylori; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics / Q000382:microbiology / Q000473:pathology*; D014407:Tumor Cells, Cultured
D016209:Interleukin-8