Polymorphisms in immunoregulatory genes, smoky coal exposure and lung cancer risk in Xuanwei, China Free

1751

There is increasing recognition that inflammatory pathways contribute to malignant transformation including cancer. We conducted a population-based case-control study in Xuanwei, China, where lung cancer rates are among the country's highest, and where lung cancer risk is strongly associated with exposure to indoor coal combustion products. We evaluated the role of polymorphisms in immunoregulatory genes in lung cancer development. A total of 122 incident lung cancercases and 122 individually matched controls were enrolled. Fifty single nucleotide polymorphisms (SNPs) in 23 immunoregulatorygenes involved in inflammation (CCR5, ICAM1, IFNG, IFNGR, IL1A/B, IL1RN, IL4, IL4R, IL5, IL8, IL8RA/B, IL10, IL10RA, IL12A/B, IL13, IL16, LTA, MIF, TGFB, and TNF) were genotyped. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression, adjusting for sex, age, smoking and smoky coal use. Haplotype analyses were conducted for selected genes with two or more SNPs using the haplo.stat package, which uses an expectation-maximization algorithm to estimate haplotypes from genotype data. A global test of association for 42 SNPs, which excluded eight SNPs that were in very tight linkage disequilibrium with other SNPs, was statistically significant (P=0.01), suggesting that overall genetic variation in this pathway contributes to lung cancer risk. In addition, the IL1B -1060TT (i.e., -511TT) genotype was associated with increased lung cancer risk compared to the CC genotype (OR=2.27, 95% CI=1.05-4.91). The IL8RA Ex2+860GC or CC (OR=0.27, 95% CI=0.11-0.67), ICAM1 Ex2+31 AT or TT (OR=0.39, 95% CI=0.18-0.88), and IL12A Ex+227 GA or AA (OR=0.43, 95% CI=0.22-0.84)genotypes were significantly associated with decreased lung cancer risk. The protective effect of the IL8RA variant was predominant among subjects with high cumulative smoky coal use (≥130 tons) (OR=0.11, 95% CI=0.03-0.44; P_interaction=0.03). Haplotype analysis did not reveal associations beyond what was apparent in the single SNP analyses. In conclusion, genetic variation in immunoregulatory genes may play an important role in the development of lung cancer in this population. These findings should be replicated in other populations exposed to indoor fuel combustion products, and extended by analysis of other genetic variants in the inflammatory pathway.