Association Of Genetic Variants Of Complement Regulatory Factors With Lung Cancer Risk And Their Regulate Mechanisms

Objectives Membrane-bound complement regulatory proteins(mCRPs)inhibit complement activation and play an important role in the development and progression of tumor.This study aims to investigate the role of mCRPs genetic variants in the development of non-small cell lung cancer(NSCLC).Methods A hospital-based case-control study was conducted in 706 patients with NSCLC from Tangshan Gongren hospital and 706 cancer-free healthy controls from December 2012 to January 2014 in Chinese population.Based on the Han Chinese in Beijing(CHB)population data from Ensembl,we selected the promoter SNPs of mCRPs with the minor allele frequency(MAF)greater than 5%.Web-based TRANSFAC was used for predicting transcription factor binding site.Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).We conduct a dual-luciferase reporter gene assay to assess the effect of polymorphism on transcriptional activity of the gene.The differences in demographic variables and the distribution of genotype between cases and controls were tested by c2test.Unconditional logistic regression was used to analyze the associations of gene variant with the risk of lung cancer by odds ratio(OR)and their 95% confidence interval(95% CI)with adjustments for age,gender,and pack-year of smoking.Luciferase activity data were tested by t test.Results In this study,3 SNPs in the promoter of mCRPs(CD46 rs1970530,CD55rs2564978,CD59 rs79077373)were selected to evaluate the association of genetic variants of CRPs with the risk of NSCLC.We found that significantly higher lung cancer risk was linked with CD55 rs2564978 CC genotype(OR = 1.52,95% CI = 1.11-2.07)or CT genotypes(OR = 1.34,95% CI = 1.05-1.71),compared to the TT genotype.Our data didn't show any significant association of CD46 rs1970530 and CD59 rs79077373 polymorphism with the NSCLC susceptibility.Stratified analysis showed that rs2564978 CC was associated with NSCLC risk among males(OR = 1.69,95% CI = 1.14-2.49)and older subjects(OR = 1.75,95% CI = 1.08-2.82).When stratified by smoking status,the risk effect of rs2564978 CC was more evident among smokers(OR = 2.01,95% CI =1.18-3.43)than non-smokers(OR = 1.30,95% CI = 0.88-1.90).We also conducted the stratified analysis by NSCLC histological types and found that CD55 rs2564978 CC increased the risk of adenocarcinoma with OR(95% CI)of 1.35(1.01-1.80).However,we didn't find CD55 rs2564978 polymorphsim effect on the risk of squamous-cell carcinoma (CC versus TT,OR=0.06,95%CI=0.99~2.30,P=0.057)and other types(CC versus TT,OR = 2.36,95%CI = 0.70 ~ 7.95,P=2.361).The reporter gene expression driven by rs2564978T-containing CD55 promoter was 1.48-fold,1.96-fold and 1.93-fold higher than those driven by the rs2564978C-containing CD55 promoter in A549,NCI-H2030 and NCI-H23 cells(P = 0.045,0.010 and < 0.001).Conclusions These findings indicate that CD55 rs2564978 polymorphism may contribute to an increased risk of NSCLC in Chinese population and further demonstrate that CD55 plays a significant role in the development of NSCLC.