A two-SNP IL-6 promoter haplotype is associated with increased lung cancer risk.
BACKGROUND
Aberrant expression of interleukin-6 (IL-6) may play an important role in lung carcinogenesis. Whether IL-6 promoter haplotypes are associated with lung cancer risk and their functions have not yet been studied. We tested the hypothesis that single-nucleotide polymorphism (SNP) and/or haplotypes of IL-6 promoter are associated with risk of lung cancer.


METHODS
Two functional IL-6 promoter SNPs (-6331T>C and -572C>G) were genotyped in the discovery group including 622 patients and 614 controls, and the results were replicated in an independent validation group including 615 patients and 638 controls. Luciferase reporter gene assays were conducted to examine the function of IL-6 promoter haplotypes.


RESULTS
None of the functional IL-6 promoter SNPs were associated with lung cancer risk in either study. However, a two-SNP CC (-6331C and -572C) IL-6 promoter haplotype was significantly more common among cases than among controls in both groups (P = 0.031 and P = 0.035, respectively), indicating that this haplotype is associated with increased lung cancer risk {adjusted odds ratio [OR], 1.56 [95 % confidence interval (95 % CI), 1.04-2.34] and 1.51 [95 % CI, 1.03-2.22], respectively}. Combined analysis of both studies showed a strong association of this two-SNP haplotype with increased lung cancer risk (adjusted OR, 1.53; 95 % CI, 1.16-2.03; P = 0.003). Comparably, luciferase reporter assays of A549 lung cancer cell lines transfected with the CC haplotype revealed that the two-SNP haplotype had significantly higher IL-6 transcriptional activity compared with cells transfected with the common haplotype.


CONCLUSIONS
This is the first evidence of identifying an IL-6 promoter haplotype (CC) associated with increased risk of lung cancer.
Department of Surgery, The First Affiliated Hospital, Soochow University, 188 Shizi Street, Suzhou 215006, People's Republic of China.
Jun
J
Chen
Reng-Yun
RY
Liu
Lixin
L
Yang
Jun
J
Zhao
Xueying
X
Zhao
Daru
D
Lu
Nengjun
N
Yi
Baohui
B
Han
Xiao-Feng
XF
Chen
Kui
K
Zhang
Jun
J
He
Zhe
Z
Lei
Yifeng
Y
Zhou
Boris
B
Pasche
Xiangdong
X
Li
Hong-Tao
HT
Zhang
D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D015533:Transcriptional Activation
D015850:Interleukin-6