Association Between Polymorphisms In NF-κB Pathway Genes,Environmental Factors And Lung Cancer Risk:A Case-control Study

Objective To explore the environmental risk factor of lung cancer and to investigate the association between polymorphism in NF-k B pathway related gene, micro RNA and lung cancer susceptibility. Furthermore, the environment gene interaction was also studied.Methods1. In total, 1533 pair-matched subjects by gender and age(±3 years) were enrolled in this 1 : 1 matched case-control study. The information on environmental exposure was collected via face to face interview. Univariate and multivariate conditional logistic regression was conducted to identify the environmental risk factor of lung cancer. R package was used to determine the importance among those risk factors by random forest method.2. Bioinformatics were applied to identify potential SNPs in NF-κB related genes,namely NFKBIA, IKBKAP and TAB3, and MALDI-TOF-MS was performed to determine the genotype of selected SNPS. In total, both information on SNP genotype and questionnaire were available among 1094 pair matched subjects( matched by age and gender).Chi-square test was employed to detect the difference in genotype distribution among cases and controls and the association between SNPs and lung cancer risk was calculated by using conditional logistic regression. Unconditional logistic regression was used to perform stratification analysis.3. Linkage disequilibrium in selected SNPs was analyzed by using Haploview, and haplotype was constructed. R package Haplo.stats was used to calculate the haplotype frequency in cases and controls. The generalized linear regression model was established by using haplo.glm package, and the odd ratio was obtained.Results1. The risk factors of lung cancer among Fujian population were identified as follows : environmental pollution near residence, BMI<18.5, insufficient ventilation, cooking oil fume, absence of fume extractor, duration of using fume extractor≤ years, smoking, smoking age ≤18 and >18 years, smoke pack year <30and ≥30, ETS index ≥ 10 person-year, depression, alcohol consumption, lung disease history, familial lung cancer history, major depressive event in 10 years,and salty vegetable consumption. BMI≥24, weekly physical exercise, walking,weekly consumption of raw garlic.2. The results suggested that the OR for genotype TT carriers of NFKBIA rs8904 was0.761(95% CI: 0.598~0.968) when comparing with genotype CC. The crude ratio for genotype CC carriers of IKBKAP rs2230793 was 1.386( 95% CI :1.007~1.907) when comparing with AA+AC genotype. The OR for genotype TT of rs1538660 was 0.713(95% CI:0.515~0.986)when comparing with genotype CC, as for the recessive model, the OR was 0.724(95% CI:0.530~0.988).The OR for genotype TT carrier of rs12894467 was 0.689(95%CI: 0.472~0.987).3. The stratification analysis was performed in accordance with pathological typ e, the carriers of CC genotype of rs2230793 polymorphisms possess 2.29(95%C I:1.03-5.08) fold risk of developing other types of lung cancer when comparin g with carriers of AA genotype, and 2.48(95% CI: 1.13~5.47) fold risk wh en being compared with AA+AC genotype.The OR of carriers of genotype GT of rs1804429 was 0.64(95%CI:0.42~0.99) when comparing with genot ype GG+TT. The genotype TT of rs12894467 rendered a decreased OR of d eveloping SQ for CT genotype was 0.46(95%CI:0.22~0.97) when comp aring with genotype CC+TT.4. The stratification analysis by smoking and ETS showed that in smokers or subjects with ETS, the genotype CT of rs105081 was associated with reduced lung cancer risk with an OR of 0.487(95%CI:0.266~0.892) when comparing with genotype CC, and the OR of genotype CT was 0.511(95%CI :0.279~0.935) when comparing with genotype CC+TT. Genotype CC of IKBKAP was associated with elevated lung cancer risk with an OR of 1.676(95%CI:1.080~2.601) when comparing with genotype AA, and the OR of genotype CC was 1.697(95% CI:1.104~2.608) when comparing with genotype AA+AC. Among the non-smokers,the genotype TT of rs12894467 was associated with reduced lung cancer risk with an OR of 0.650(95%CI:0.428~0.987) when comparing with genotype CC+CT.5. The generalized linear model was established by using haplp.glm module, and the TA haplotype of IKBKAP was associated with reduced lung cancer risk with an OR of 0.862(95%CI:0.753~0.987), and the ORs for CA and TT haplotype were2.260(95% CI:1.533~ 3.331) and 2.260(95%CI:1.533~3.331), respectively,when being compared with CT haplotype.Conclusion1. The major risk factors of lung cancer in Fujian province were identified as follows:smoke pack year, ETS index, cook oil fume, BMI<18.5. BMI≥24, physical exercise, walk, and weekly consumption of raw garlic were identified as protective factors.2. The NFKBIA rs8904 TT,rs1050851 CT, IKBKAP rs1538660 TT, CXCL12rs1804429 GT and mi R-300 rs12894467 TT were associated with reduced lung cancer risk. IKBKAP rs2230793 CC may lead to elevated lung cancer risk.3. The TA haplotype of IKBKAP was associated with reduced lung cancer risk while CA and CT haplotype were positively associated with lung cancer risk.