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Summary: The aim of this study is to investigate the role of genetic polymorphisms in twelve folate metabolism genes on the risk of lung cancer in Xuan Wei, China, where the lung cancer mortality rate is among the highest and is mainly caused by indoor smoky coal emissions. A total of 122 incident primary lung cancer cases and 122 matched controls were enrolled. Three single nucleotide polymorphisms were associated with increased risk of lung cancer including homozygotes of the C allele of CBS Ala360Ala (OR: 4.02; 95% CI: 1.64–9.87), the 222Val allele of MTHFR (OR: 2.32; 95% CI: 1.34–4.03), and the C allele of SLC19A1 Pro232Pro (OR: 1.83; 95% CI: 1.02–3.28). The distribution of CBS and MTHFR haplotypes differed between cases and controls (P =0.002 and P =0.07, respectively). In summary, three genetic variants in folate metabolism genes are associated with an increased risk of lung cancer in Xuan Wei, China. [Copyright &y& Elsevier]

To evaluate the role of chronic inflammation in the development of gallstones and biliary tract cancer, we examined the risk associated with 62 single nucleotide polymorphisms (SNPs), in 22 inflammation-related genes, in a population-based case-control study conducted in Shanghai, China, where the incidence of biliary tract cancer has been increasing in recent decades. The study included 411 cases with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater), 895 with biliary stones, and 786 controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association of individual SNPs and haplotypes with biliary stones and biliary tract cancer. Of the 62 SNPs examined, 14 were related to the risk of biliary cancer and stones. Specifically, variants in the IL8, IL8RB, RNASEL, and NOS2 genes were associated with biliary stones, whereas VEGF variants were associated with gallbladder cancer. Of the 10 genes with multiple SNPs from which we inferred haplotypes, only one IL8RB haplotype, consisting of 3 SNPs (rs2230054, rs1126579, and rs1126580), was associated with the risk of bile duct cancer (P = 0.003) and biliary stones (P = 0.02), relative to the most frequent haplotype. In summary, common variants in genes that influence inflammatory responses may predispose to gallstones and biliary tract cancer, suggesting the need for future studies into the immunologic and inflammatory pathways that contribute to biliary diseases, including cancer.

Biliary tract cancers, encompassing the gallbladder, extrahepatic bile duct, and ampulla of Vater, are uncommon yet highly fatal malignancies. Gallstones, the primary risk factor for biliary cancers, are linked with hyperlipidemia. We examined the associations of 12 single nucleotide polymorphisms of five genes in the lipid metabolism pathway with the risks of biliary cancers and stones in a population-based case-control study in Shanghai, China. We included 235 gallbladder, 125 extrahepatic bile duct, and 46 ampulla of Vater cancer cases, 880 biliary stone cases, and 779 population controls. Subjects completed an in-person interview and gave blood. Genotyping was conducted by TaqMan assay using DNA from buffy coats. The effects of APOE IVS1+69 (rs440446) and APOB IVS6+360C>T (rs520354) markers were limited to men. Men carrying the G allele of APOE IVS1+69 had a 1.7-fold risk of stones [95% confidence interval (95% CI), 1.2-2.4], a 1.8-fold risk of gallbladder cancer (95% CI, 1.0-3.3), a 3.7-fold risk of bile duct cancer (95% CI, 2.0-7.0), and a 4-fold risk of ampullary cancer (95% CI, 1.4-12.4). Male carriers of the T allele of APOB IVS6+360C>T had a 2-fold risk of bile duct cancer (95% CI, 1.2-3.4). The APOB T-T haplotype (APOB IVS6+360C>T, EX4+56C>T) was associated with a 1.6-fold risk of bile duct cancer (95% CI, 1.1-2.3). Male and female carriers of the T allele of LDLR IVS9-30C>T (rs1003723) had a 1.5-fold risk of bile duct cancer. Our findings suggest that gene variants in the lipid metabolism pathway contribute to the risk of biliary tract stones and cancers, particularly of the bile duct.

Selection and genetic drift can create genetic differences between populations. Cytokines and chemokines play an important role in both hematopoietic development and the inflammatory response. We compared the genotype frequencies of 45 SNPs in 30 cytokine and chemokine genes in two healthy Chinese populations and one Caucasian population. Several SNPs in IL4 had substantial genetic differentiation between the Chinese and Caucasian populations (F ST approximately 0.40), and displayed a strikingly different haplotype distribution. To further characterize common genetic variation in worldwide populations at the IL4 locus, we genotyped 9 SNPs at the IL4 gene in the Human Diversity Panel's (N = 1056) individuals from 52 world geographic regions. We observed low haplotype diversity, yet strikingly different haplotype frequencies between non-African populations, which may indicate different selective pressures on the IL4 gene in different parts of the world. SNPs in CSF2, IL6, IL10, CTLA4, and CX3CR1 showed moderate genetic differentiation between the Chinese and Caucasian populations (0.15 < F ST < 0.25). These results suggest that there is substantial genetic diversity in immune genes and exploration of SNP associations with immune-related diseases that vary in incidence across these two populations may be warranted.

We conducted a population-based case-control study in Xuan Wei, China, where lung cancer rates are among the highest in China due to exposure to indoor coal combustion products, to evaluate the association between polymorphisms in immunoregulatory genes and lung cancer risk. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled in Xuan Wei, China. Fifty single-nucleotide polymorphisms (SNPs) in 23 immunoregulatory genes involved in inflammation were genotyped and analyzed by logistic regression to assess the risk of lung cancer. 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 with the CC genotype [odds ratio (OR) = 2.27, 95% confidence interval (CI) = 1.05-4.91]. The IL8RA Ex2+860 GC or CC (OR = 0.27, 95% CI = 0.11-0.67), ICAM1 Ex2+100 AT or TT (OR = 0.39, 95% CI = 0.18-0.88) and IL12A Ex7+277 GA or AA (OR = 0.43, 95% CI = 0.22-0.84) genotypes were associated with decreased lung cancer risk. The protective effect of the IL8RA variant was stronger among subjects with high cumulative smoky coal use (> or = 130 tons) (OR = 0.11, 95% CI = 0.03-0.44; P(interaction) = 0.03). In conclusion, genetic variation in immunoregulatory genes may play an important role in the development of lung cancer in this population.

There is evidence that chronic inflammation predisposes to biliary tract cancer and that use of non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Although the mechanisms by which NSAIDs lower cancer risk remain unclear, NSAIDs reduce prostaglandin production by blocking prostaglandin-endoperoxide synthase 2 (PTGS2, commonly known as COX-2), an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue. Since variants in the PTGS2 gene may modify the expression or function of its encoded enzyme to modulate the inflammatory response in the biliary tract, we examined the associations of eight PTGS2 polymorphisms (-645C-->T; Ex3 -8G-->C; IVS5 -275T-->G; IVS7 +111T-->C; Ex10 +127T-->C; Ex10 +686 --->ATTAT-->TTATA; Ex10 +837T-->C; Ex10 -90C-->T) with biliary tract cancer and stones in a population-based case-control study conducted in Shanghai, China. Genotyping was performed for 411 patients with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater), 895 patients with biliary stones (673 gallbladder, 222 bile duct), and 786 healthy individuals randomly selected from the population. Significant associations were seen only between the Ex10 +837T-->C marker and bile duct cancer risk. Relative to individuals with the TT genotype, those carrying the C allele (TC or CC genotype) had a 1.8-fold (95% confidence interval: 1.2-2.7) risk of bile duct cancer. Inferred haplotypes including this risk-conferring allele were also associated with increased bile duct cancer risk of similar magnitude. Our results suggest that a common PTGS2 variant increases bile duct cancer risk. Further investigation is needed to confirm and extend our findings in studies of biliary tract cancer that more comprehensively examine PTGS2 and other inflammation-related genes.