Meta-analysis of infection and disease among household contacts of patients with drug-resistant tuberculosis / 中国热带医学

@#Abstract: Objective　To analyze the association between drug resistance and the risk of latent tuberculosis infection and disease among household contacts of patients with pulmonary tuberculosis, and to explore whether the compensatory mutation of drug-resistant Mycobacterium tuberculosis will enhance its pathogenicity or transmission ability. Methods　The English and Chinese databases, including PubMed, web of science, EMBASE, Cochrane library database, CNKI and Wanfang database, were searched by computer from the time of establishment of the database to January 2022. Cohort studies on the risk of infection and disease among household contacts of patients with drug-resistant and sensitive pulmonary tuberculosis were searched and screened according to the inclusion and exclusion criteria. The data were extracted and evaluated by NOS scale, using stata16.0 software meta-analysis to calculate the combined effect of tuberculosis infection and disease risk of family contacts, and carry out heterogeneity test, subgroup analysis and sensitivity analysis. Results　A total of 7 cohort studies involving 9653 TB index cases and 29, 734 house contacts were included. The results of meta-analysis showed that compared with drug-sensitive pulmonary tuberculosis patients, the risk of tuberculosis infection in house contacts of drug-resistant pulmonary tuberculosis patients was increased (OR=1.56, 95%CI=1.25-1.96, P<0.001), but there was no difference in the risk of incidence (RR=1.06, 95%CI=0.80-1.41, P=0.67>0.05). Subgroup analysis showed that the risk of latent tuberculosis infection in house contacts was affected by the study area, and the size of family contacts had an impact on the risk of TB . Sensitivity analysis showed that the results of meta-analysis were robust. Conclusion　Compared with drug sensitive TB patients, household contacts with drug-resistant TB patients had a higher risk of tuberculosis, but there was no difference in the risk of TB among the two groups.

A case report of ocular tuberculosis in a patient with membranous nephropathy.

RATIONALE: Membranous nephropathy (MN), a chronic kidney disease (CKD), due to hypoproteinemia, malnutrition, anemia, long-term intake of immunosuppressive agents, changes in cellular immune state, and decrease in antimicrobial peptides, is a high risk for Mycobacterium tuberculosis (MTB) infection, which can cause tuberculosis (TB). TB manifests by various clinical symptoms. Ocular symptoms is a rare presentation of TB. Here, we describe a case of ocular tuberculosis in a patient with MN. PATIENT CONCERNS: A 63-year-old man with membranous nephropathy (MN) history presented with ocular symptoms. DIAGNOSES: According to the pathological manifestations of ocular tissue biopsy and a positive polymerase chain reaction (PCR) on samples from sputum and bronchoalveolar lavage fluid (BALF), we elicited a diagnosis of disseminated tuberculosis. INTERVENTION: The patient received antituberculous therapy and immunosuppressive therapy. OUTCOMES: The clinical manifestations significantly improved. LESSONS: Clinicians should be aware of the possibility of TB in cases of immunocompromised patients and perform an appropriate diagnostic work-up for TB.

An HLA class II locus, previously identified by a genome-wide association study, is also associated with susceptibility to pulmonary tuberculosis in a Chinese population.

OBJECTIVE: Genome-wide association study (GWAS) in Icelanders identified HLA class II sequence variants on chromosome 6p21 as tuberculosis (TB) susceptibility loci. To evaluate the role of these loci in other populations with different ancestry, we conducted a case-control study in Chinese population. METHODS: We genotyped two genetic variants (rs9272461 and rs9271300) on the reported chromosome 6p21 in 739 pulmonary tuberculosis (PTB) cases and 749 healthy controls from Chinese Han population using TaqMan allelic discrimination assay. Logistic regression was applied to evaluate the association between genetic variants and PTB risk and to estimate corresponding odds ratios (ORs) and 95% confidence intervals (95%CIs). RESULTS: We found that rs9272461 was significantly associated with the risk of PTB in various genetic models (dominant OR = 0.75, 95%CI: 0.61-0.92; recessive OR = 0.64, 95%CI: 0.46-0.90, and additive OR = 0.78, 95%CI: 0.67-0.90). Moreover, in the stratified analysis in additive model, the association was also significant in the old (age ≥ 48 years) (OR = 0.76, 95%CI: 0.62-0.93; P = .008), men (OR = 0.71, 95%CI: 0.59-0.85; P < .001), and new PTB cases (OR = 0.76, 95%CI: 0.65-0.90; P = .001). The association results were similar between the microbiologically negative (OR = 0.78, 95%CI: 0.64-0.94; P = .008) and positive cases (OR = 0.77, 95%CI: 0.64-0.93; P = .008). We did not observe significant association for rs9271300 neither in the overall analysis (additive model: OR = 0.98, 95%CI: 0.85-1.13; P = .776) nor in the stratified analysis. CONCLUSIONS: Our findings indicate that the HLA class II locus also affects the susceptibility to PTB in Chinese population. Further validation studies and function experiments are required to confirm the roles of the discovered variant.

Genetic variants at 18q11.2 and 8q24 identified by genome-wide association studies were not associated with pulmonary tuberculosis risk in Chinese population.

OBJECTIVE: Genome-wide association study (GWAS) recently identified several susceptibility loci in ASAP1 gene on chromosome 8q24 for tuberculosis (TB) in a Russian population, but no relevant studies have been performed to validate these findings. In addition, previous GWAS in Ghana and Gambia found that the variant rs4331426 at 18q11.2 was a susceptibility locus for TB. However, the follow-up studies reported conflicting results. Herein, we investigated the contribution of genetic variants at 8q24 and 18q11.2 to TB in Chinese population. METHODS: We genotyped four genetic variants at 8q24 (rs10956514 and rs11774633) and 18q11.2 (rs4331426 and rs6507226) in a case-control study with 355 newly bacteriologically confirmed pulmonary TB cases and 395 healthy controls using TaqMan allelic discrimination assay. Subsequently, we conducted a meta-analysis including 4 reported studies in Chinese populations and our case-control study with a total of 3118 cases and 3226 controls to further evaluate the relationship between rs4331426 at 18q11.2 and TB risk. RESULTS: We did not find significant association between genetic variants at 8q24 and risk of TB (rs10956514: OR=0.89, 95%CI: 0.72-1.09, P=0.253; rs11774633: OR=0.86, 95%CI: 0.69-1.08, P=0.206). We did not observe significant association for genetic variants at 18q11.2 (rs4331426: OR=0.62, 95%CI: 0.34-1.14, P=0.122; and rs6507226: OR=0.98, 95%CI: 0.80-1.20, P=0.853). Moreover, the pooled results from the Meta-analysis further supported that rs4331426 at 18q11.2 was not associated with TB risk in Chinese population (OR=0.90, 95% CI: 0.63-1.29). CONCLUSIONS: Our findings indicate that TB risk-associated loci at 8q24 and 18q11.2 identified by GWAS from the other populations may not contribute to TB susceptibility in Chinese population.

CD14 -159C/T polymorphism contributes to the susceptibility to tuberculosis: evidence from pooled 1,700 cases and 1,816 controls.

CD14 is a receptor for lipopolysaccharide and plays an important role in innate immune against infections induced by microorganisms. A functional polymorphism in promoter region of CD14 gene, -159C/T, was extensively investigated with tuberculosis (TB) risk, but the association results were inconclusive. We performed a meta-analysis to synthesize association results of CD14 -159C/T polymorphism with TB risk from 8 studies including 1,700 TB cases and 1,816 controls. Based on the heterogeneity between studies evaluated by χ2-based Q test, a fixed- or random-effect model was applied to estimate the pooled odds ratio (OR) and 95% confidence interval (CI). Potential publication bias was evaluated with the funnel plot as well as the linear regression asymmetry test proposed by Egger et al. We found that the -159T allele was significantly associated with an increased risk of TB (OR 1.27, 95% CI 1.01-1.61) as compared with -159C allele. Individuals with -159TT genotype showed a significantly increased risk of TB than those with -159CT/CC genotype (OR 1.52, 95% CI 1.11-2.08). These associations were not attributed to potential publication bias (P>0.05 for Egger's test). The results from this meta-analysis indicate that CD14 -159C/T polymorphism is associated with TB predisposition and may serve as a candidate of susceptibility biomarker for TB.

Association between the CD209 promoter -336A/G polymorphism and susceptibility to tuberculosis: a meta-analysis.

BACKGROUND AND OBJECTIVE: Dendritic cell-specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN), encoded by the CD209 gene, is a major Mycobacterium tuberculosis receptor on human dendritic cells. The potentially functional -336A/G polymorphism in the CD209 promoter region has been associated with susceptibility to tuberculosis (TB), but the results have been inconclusive. We performed a meta-analysis to clarify the relationship between the CD209-336A/G variant and the risk of TB. METHODS: Ten studies involving a total of 2598 TB patients and 2614 control subjects were systematically reviewed, and the data were quantitatively synthesized by meta-analysis. The Q-test was applied to assess the heterogeneity of associations among the studies, and Egger's regression test was used to assess potential publication bias. RESULTS: No significant association was identified between the CD209-336A/G polymorphism and risk of TB (G allele vs A allele: odds ratio (OR) 1.02, 95% confidence interval (CI) 0.90-1.15). Moreover, no significant association was observed in populations of African ethnicity (OR 1.01, 95% CI 0.87-1.17) or among individuals who were negative for the human immunodeficiency virus (OR 0.98, 95% CI 0.84-1.15). CONCLUSIONS: This meta-analysis has indicated that the CD209-336A/G polymorphism may not contribute to susceptibility to TB.

Meta-analysis on the association of TIRAP S180L variant and tuberculosis susceptibility.

The missense variant S180L in TIRAP (Toll-interleukin-1 receptor domain-containing adaptor protein) gene is implicated in attenuating TLRs signal transaction and may affect individual response to Mycobacterium tuberculosis infection. Several studies investigated the association between TIRAP S180L and risk of tuberculosis (TB), but the results were controversial. In this study, we quantitatively synthesized nine studies relevant to the association between TIRAP S180L polymorphism and TB risk with total 6584 TB cases and 7294 controls using meta-analysis. We found that the variant allele Leu180 and heterozygous genotype Ser/Leu were not significantly associated with risk of TB (allelic OR = 0.99, 95%CI: 0.88-1.11; Ser/Leu vs Ser/Ser: OR = 0.99, 95%CI: 0.87-1.13) with heterogeneity P values > 0.05. In subgroup analysis, none of the significant associations were observed for S180L and TB risk in Africans (allelic OR = 0.58, 95%CI: 0.29-1.61; heterozygous OR = 0.65, 95%CI: 0.32-1.32) or Asians (allelic OR = 1.30, 95%CI: 0.97-1.74; heterozygous OR = 1.17, 95%CI: 0.84-1.65) or risk of pulmonary tuberculosis (PTB) (allelic OR = 0.92, 95%CI: 0.69-1.22; heterozygous OR = 0.98, 95%CI: 0.86-1.12). This meta-analysis indicates that TIRAP S180L polymorphism is unlikely to substantially contribute to TB susceptibility.

A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese.

microRNAs (miRNA) are a new class of non-protein-coding, small RNAs that function as tumor suppressors or oncogenes. They participate in diverse biological pathways and function as gene regulators. Recently, we conducted a survey of common single nucleotide polymorphisms (SNP) in miRNA sequences and reported that, among four SNPs (rs2910164, rs2292832, rs11614913, and rs3746444) in pre-miRNAs, rs11614913 in miR-196a2 might affect mature miR-196a expression and target mRNA-binding activity and was significantly associated with non-small cell lung cancer survival. However, it remains largely unknown whether miRNA SNPs may alter lung cancer susceptibility. In the current study, we evaluated associations between the above four SNPs in pre-miRNAs and lung cancer susceptibility in a case-control study of 1,058 incident lung cancer patients and 1,035 cancer-free controls in a Chinese population. We found that miR-196a2 rs11614913 variant homozygote CC was associated with approximately 25% significantly increased risk of lung cancer compared with their wild-type homozygote TT and heterozygote TC (odds ratio, 1.25; 95% confidence interval, 1.01-1.54). However, no significant effects were observed on the association between the other three SNPs and lung cancer risk. These findings suggest that functional SNP rs11614913 in miR-196a2 could also contribute to lung cancer susceptibility.

Putative functional polymorphisms of MMP9 predict survival of NSCLC in a Chinese population.

Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and their over-expression is often associated with unfavorable survival of non-small cell lung cancer (NSCLC). Because genetic variants can alter expression level or biological activity of MMPs, we hypothesized that potentially functional single nucleotide polymorphisms (SNPs) in key MMP genes may be associated with the survival of NSCLC patients. We selected and genotyped 14 putative functional SNPs in six MMP genes (MMP1, MMP2, MMP3, MMP7, MMP9 and MMP12) using PCR-RFLP methods in 561 NSCLC patients. Kaplan-Meier method with the log-rank test and Cox proportional hazard models were used for the survival analyses. The C-1562T, Arg279Gln and Arg668Gln polymorphisms in MMP9 were significantly associated with survival of patients with NSCLC (log-rank p values = 0.032, 0.038 and 0.036, respectively). The C-1562T and Arg668Gln loci were in complete linkage disequilibrium (r(2) = 1). Patients carrying the 668Gln allele had improved survival with a median survival time (MST) of 51.6 months, compared with 21.8 months for those with the 668Arg/Arg genotype (log-rank p = 0.010). In contrast, the 279Gln/Gln genotype was associated with a significantly shortened MST (17.3 months, log-rank p = 0.030) in the recessive model. In the final multivariate Cox regression model, 279Gln/Gln was identified as an independent prognostic factor with an adjusted hazard ratio of 1.60 (95% confidence interval 1.07-2.41). The MMP9 Arg279Gln and Arg668Gln SNPs are potential predictors of survival in NSCLC patients.

Association of human aryl hydrocarbon receptor gene polymorphisms with risk of lung cancer among cigarette smokers in a Chinese population.

BACKGROUND AND OBJECTIVE: Most of the carcinogenic effects of polycyclic aromatic hydrocarbons present in tobacco smoke are mediated by the aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor that regulates tobacco-induced expression of carcinogen metabolic enzymes. We hypothesized that genetic variations in AHR might confer individual susceptibility to lung cancer. METHODS: Eight selected single-nucleotide polymorphisms in AHR were genotyped using the Illumina SNP genotyping BeadLab platform in a case-control study of 500 lung cancer patients and 517 cancer-free controls in a Chinese population. RESULTS: We found that significantly increased lung cancer risk was associated with heterozygous genotypes of rs2158041 (adjusted odds ratio=1.53 and 95% confidence interval=1.17-1.99 for GA, compared with the GG genotype) and rs7811989 (adjusted odds ratio=1.48 and 95% confidence interval=1.13-1.93 for GA, compared with the GG genotype), although these two single-nucleotide polymorphisms were in linkage disequilibrium. Furthermore, haplotype analysis revealed significant differences in haplotype distributions of AHR between cases and controls (Global P=1.38e-5). We also observed statistically significant interaction between the polymorphism rs2066853 (p.Arg554Lys) and cumulative cigarette smoking as a discrete or continuous variable (P=0.033 and 0.019, respectively), and the Lys/Lys genotype conferred an increased risk of lung cancer in the heavy smokers (adjusted odds ratio=3.36 and 95% confidence interval=1.07-10.55). CONCLUSION: These findings suggest that AHR polymorphisms and potential gene-smoking interaction may be involved in the etiology of lung cancer. Further large prospective studies with ethnically diverse populations and functional studies are warranted to validate these findings.

Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women.

Small, noncoding RNA molecules, called microRNAs (miRNAs), are thought to function as either tumor suppressors or oncogenes. Common single-nucleotide polymorphisms (SNPs) in miRNAs may change their property through altering miRNA expression and/or maturation, and thus they may have an effect on thousands of target mRNAs, resulting in diverse functional consequences. However, it remains largely unknown whether miRNA SNPs may alter cancer susceptibility. We evaluated the associations of selected four SNPs (rs2910164, rs2292832, rs11614913, and rs3746444) in pre-miRNAs (hsa-mir-146a, hsa-mir-149, hsa-mir-196a2, and hsa-mir-499) with breast cancer risk in a case-control study of 1,009 breast cancer cases and 1,093 cancer-free controls in a population of Chinese women and we found that hsa-mir-196a2 rs11614913:T>C and hsa-mir-499 rs3746444:A>G variant genotypes were associated with significantly increased risks of breast cancer (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.02-1.48 for rs11614913:T>C; and OR, 1.25; 95% CI, 1.02-1.51 for rs3746444:A>G in a dominant genetic model) in a dose-effect manner (P for trend was 0.010 and 0.037, respectively). These findings suggest, for the first time, that common SNPs in miRNAs may contribute to breast cancer susceptibility. Further functional characterization of miRNA SNPs and their influences on target mRNAs may provide underlying mechanisms for the observed associations and disease etiology.

Genetic variants in GTF2H1 and risk of lung cancer: a case-control analysis in a Chinese population.

GTF2H1, the p62 subunit of the multiprotein complex transcription factor IIH (TFIIH), participates in both the nucleotide excision repair process and transcription control by specifically interacting with a variety of factors important in carcinogenesis. To elucidate the role of genetic variation in GTF2H1 in the etiology of lung cancer, we conducted a case-control study of 500 incident lung cancer cases and 517 controls in a Chinese population by genotyping six common single nucleotide polymorphisms (SNPs) in GTF2H1. An increased risk was associated with the variant genotypes of rs3802967 [adjusted odds ratio (OR)=1.38, 95% confidence interval (CI)=1.04-1.82], rs4150606 (adjusted OR=1.44, 95% CI=1.08-1.92), and rs4150678 (adjusted OR=1.37, 95% CI=1.04-1.81) in a dominant genetic model. The risk for rs3802967C/T+T/T genotypes was more pronounced among males subjects (P=0.002). In contrast, a decreased risk was associated with the rs4150667T/T genotype (adjusted OR=0.59, 95% CI=0.38-0.93) in a recessive model. Haplotype analysis showed that the haplotype "222212" (1 for common alleles and 2 for minor alleles) was associated with increased risk of lung cancer (P=0.03). Further evaluation using luciferase reporter constructs showed that the T allele of rs3802967 had higher luciferase expression, suggesting that the -79C-->T change may affect transcriptional activation of GTF2H1. Taken together, these results suggest that GTF2H1 polymorphisms/haplotypes may contribute to genetic susceptibility to lung cancer.

Methyl-CpG binding domain 1 gene polymorphisms and lung cancer risk in a Chinese population.

Polymorphisms of the methyl-CpG binding domain 1 (MBD1) gene may influence MBD1 activity on gene expression profiles, thereby modulating individual susceptibility to lung cancer. To test this hypothesis, we investigated the associations of four MBD1 polymorphisms and lung cancer risk in a Chinese population. Single locus analysis revealed significant associations between two polymorphisms (rs125555 and rs140689) and lung cancer risk (p=0.011 and p=0.005, respectively). Since the two polymorphisms were in linkage disequilibrium, further haplotype analyses were performed and revealed a significant association with lung cancer (global test p-value=0.0041). Our results suggested that MBD1 polymorphisms might be involved in the development of lung cancer. Validation of these findings in larger studies of other populations is needed.

Genetic variants of miRNA sequences and non-small cell lung cancer survival.

Recent evidence indicates that small noncoding RNA molecules known as microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Mutation, misexpression, and altered mature miRNA processing are implicated in carcinogenesis and tumor progression. Because SNPs in pre-miRNAs could alter miRNA processing, expression, and/or binding to target mRNA, we conducted a systematic survey of common pre-miRNA SNPs and their surrounding regions and evaluated in detail the association of 4 of these SNPs with the survival of individuals with non-small cell lung cancer (NSCLC). When we assumed that disease susceptibility was inherited as a recessive phenotype, we found that the rs11614913 SNP in hsa-mir-196a2 was associated with survival in individuals with NSCLC. Specifically, survival was significantly decreased in individuals who were homozygous CC at SNP rs11614913. In the genotype-phenotype correlation analysis of 23 human lung cancer tissue samples, rs11614913 CC was associated with a statistically significant increase in mature hsa-mir-196a expression but not with changes in levels of the precursor, suggesting enhanced processing of the pre-miRNA to its mature form. Furthermore, binding assays revealed that the rs11614913 SNP can affect binding of mature hsa-mir-196a2-3p to its target mRNA. Therefore, the rs11614913 SNP in hsa-mir-196a2 may be a prognostic biomarker for NSCLC. Further characterization of miRNA SNPs may open new avenues for the study of cancer and therapeutic interventions.

Tagging single nucleotide polymorphisms in MBD4 are associated with risk of lung cancer in a Chinese population.

MBD4 (methyl-CpG binding domain protein 4) was identified as a methyl-CpG binding protein and plays an important role in DNA methylation and carcinogenesis. We hypothesized that genetic variants in MBD4 were associated with lung cancer risk. We selected and genotyped three tagging SNPs (rs2311394, rs140693, and rs2005618) of MBD4 using the illumina SNP genotyping BeadLab platform in a case-control study of 500 incident lung cancer patients and 517 cancer-free controls in a Chinese population. We observed a significantly decreased risk of lung cancer associated with the rs140693 GA genotype (adjusted OR=0.70, 95% CI=0.52-0.93), and the combined rs140693 GA/AA variant genotypes (adjusted OR=0.76, 95% CI=0.58-1.00), compared with the wild-type homozygote rs140693 GG. The reduced lung cancer risk in non-smokers carrying rs140693 GA/AA genotypes was more predominant (adjusted OR=0.56, 95% CI=0.35-0.87). However, there was no statistic evidence of gene-smoking interaction. These findings suggest that genetic variants of MBD4 rs140693 may modulate risk of lung cancer. Further larger case-control and functional studies are needed to validate these findings.

Tagging single nucleotide polymorphisms in phosphoinositide-3-kinase-related protein kinase genes involved in DNA damage "checkpoints" and lung cancer susceptibility.

PURPOSE: DNA damage checkpoints are initiated by its sensor proteins of the phosphoinositide-3-kinase-related protein kinase family, including ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We hypothesized that polymorphisms in these genes may alter the regulation of DNA repair and the risk of lung cancer. EXPERIMENTAL DESIGN: We genotyped 12 tagging single nucleotide polymorphisms (tSNP) in these three phosphoinositide-3-kinase-related protein kinase genes in 500 incident lung cancer cases and 517 controls in a Chinese population by using the Illumina SNP genotyping BeadLab platform. RESULTS: Single locus analyses revealed that some of the heterozygotes or variant homozygotes of DNA-PKcs tSNPs were associated with decreased risks of lung cancer compared with their wild-type homozygotes. In the combined analyses of two tSNPs (rs8178085 and rs12334811) with approaching dose-dependent effect on lung cancer predisposition, subjects carrying two to four risk genotypes were associated with a 43% decreased lung cancer risk compared with subjects carrying zero to one risk genotypes (adjusted odds ratio, 0.53; 95% confidence interval, 0.35-0.80). Moreover, the decreased risk associated with the combined genotypes of rs8178085 and rs12334811 was slightly more pronounced in nonsmokers and in carriers with ataxia-telangiectasia mutated rs228591 variant allele or ataxia-telangiectasia and Rad3-related rs6782400 wild-type homozygous genotype. CONCLUSION: These results indicate, for the first time, that tSNPs in DNA-PKcs may play a protective role in lung cancer development.

Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population.

One-carbon metabolism facilitates the cross-talk between genetic and epigenetic processes, making it a good candidate for studying the risk of lung cancer. To investigate the role of common variants of one-carbon metabolizing genes on lung cancer risk, total 25 single nucleotide polymorphisms (SNPs) in 7 genes were genotyped among 500 incident lung cancer patients and 517 cancer-free controls. An increased risk was suggested for the variant allele carriers of MTHFR rs17037396 [odds ratio (OR)=1.39, 95% confidence interval (CI): 1.00-1.94] and rs3753584 (OR=1.46, 95% CI: 1.03-2.08), compared with subjects with wild homozygote, respectively, and the risk was more pronounced among older individuals (>60 years). In contrast, a decreased risk was observed for TYMS rs2853742 variant allele carriers (OR=0.44, 95% CI: 0.19-0.99) and MTHFD rs2236225 variant allele carriers (OR=0.76, 95% CI: 0.59-0.99). Haplotype analysis revealed that MTHFR "ACCACC" haplotype may contribute to the risk of lung cancer (OR=1.49, 95% CI: 1.03-2.14, local test p value 0.032). A data mining method, multifactor dimensionality reduction (MDR), predicted a four-factor interaction model (rs1801133, rs4659731, rs2273029 and rs699517) with the lowest average prediction error (45.08%, p<0.001). These findings suggest that genetic variants in one-carbon metabolizing genes might modulate the risk of lung cancer. Validation of these findings in larger studies is needed.

Potentially functional polymorphisms of EXO1 and risk of lung cancer in a Chinese population: A case-control analysis.

Exonuclease 1 (EXO1) is an important nucleases involved in mismatch repair system that contributes to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. Potentially functional polymorphisms in EXO1 may alter cancer risks by influencing the repair activity of EXO1. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in EXO1 were associated with risk of lung cancer. To test this hypothesis, we genotyped five common SNPs (rs1776177A/G, rs1047840G/A (Glu589Lys), rs1776148G/A (Gly670Glu), rs9350C/T (Leu757Pro) and rs851797T/C) that tag eight SNPs located at exon regions of EXO1 by using the Illumina high-throughput genotyping platform in 500 incident lung cancer cases and 517 cancer-free controls in a Chinese population. Significant differences of allele and genotype distributions were observed in Glu589Lys (rs1047840) of EXO1 between the cases and controls (P=0.028 and 0.025 for allele and genotype distributions, respectively). Logistic regression analyses revealed that individuals carrying the variant 589Lys allele (589Glu/Lys or 589Lys/Lys) had a significantly increased risk of lung cancer [adjusted odds ratio (OR)=1.41, 95% confidential interval (CI)=1.09-1.84] compared with those who carried the wild-type homozygote (589Glu/Glu). Furthermore, we found that haplotype AAGTT was more frequent in cases than in controls (P<0.001 for both two-sided chi(2)-test and 1000 times permutation tests). These results suggest that the EXO1 Glu589Lys polymorphism and its surrounding regions might be genetic susceptibility markers for lung cancer in this study population.

TGFB1 and TGFBR2 functional polymorphisms and risk of esophageal squamous cell carcinoma: a case-control analysis in a Chinese population.

PURPOSE: Transforming growth factor beta1 (TGF-beta1) and its receptor II (TGF-betaRII) are two key components of TGF-beta signaling and play an important role in carcinogenesis. Several functional polymorphisms were identified in TGFB1 and TGFBR2 and associated with elevated serum or plasma level of TGF-beta1 and enhanced transcription activity of TGFBR2. This population-based case-control study was to evaluate the contribution of functional polymorphisms in TGFB1 C-509T, Leu10Pro and TGFBR2 G-875A to the risk of esophageal squamous cell carcinoma (ESCC). METHODS: Genotyping was performed using the primer-introduced restriction analysis-PCR assay in 255 ESCC cases and 704 cancer-free controls in a Chinese population. RESULTS: The variant genotypes (-509CT/TT) of TGFB1 C-509T were associated with a 63% significantly decreased risk of ESCC (adjusted OR = 0.37, 95% CI = 0.27-0.50) compared with -509CC wild-type homozygote. In addition, a moderately decreased risk of ESCC was related to -875GA (adjusted OR = 0.70, 95% CI = 0.49-0.99) but not -875AA genotype (adjusted OR = 1.09, 95% CI = 0.51-2.35) in TGFBR2, compared with -875GG common genotype. Furthermore, subjects carrying variant genotypes either or both of TGFB1 C-509T and TGFBR2 G-875A had a significantly reduced risk of ESCC (adjusted OR = 0.37, 95% CI = 0.26-0.53 for either one variant genotype and adjusted OR = 0.30, 95% CI = 0.19-0.48 for both variant genotypes) in a dose-response manner (chi (trend) (2) = 33.87, P < 0.001) compared with subjects with both wild-type genotypes. CONCLUSIONS: These results are consistent with our previous findings in gastric cancer and support the hypothesis that genetic variants in TGFB1 and TGFBR2 may modulate the risk of ESCC.

Variant genotypes and haplotypes of the epidermal growth factor gene promoter are associated with a decreased risk of gastric cancer in a high-risk Chinese population.

Epidermal growth factor (EGF), a ligand of the EGF receptor, plays a critical role in the development of gastric cancer. Genetic variants in its promoter region may influence transcription activity and contribute to gastric cancer predisposition. To test this hypothesis, we genotyped three EGF promoter polymorphisms (G61A, G-1380A, and A-1744G) in a case-control study of 675 gastric cancer cases and 704 cancer-free controls. We found that the variant genotypes of EGF 61GA/AA were associated with a significantly decreased risk of gastric cancer (OR = 0.77, 95% CI = 0.61-0.95), when compared with wild-type homozygote 61GG. In the combined analysis with all three loci of EGF, subjects carrying one or more variant loci had a significantly decreased risk of gastric cancer in a dose-response manner (adjusted OR = 0.58, 95% CI = 0.42-0.80 for subjects carrying one variant locus and OR = 0.46, 95% CI = 0.32-0.66 for those carrying two to three variant loci, respectively; trend test: chi(2) = 16.14, P < 0.001). Compared with the most common haplotype GGA, haplotypes AGA, GGG and GAA (each containing one variant allele) were associated with 33%, 29% and 34% significantly decreased risk of gastric cancer (adjusted OR = 0.67, 95% CI = 0.55-0.82 for AGA; OR = 0.71, 95% CI = 0.57-0.88 for GGG and OR = 0.66, 95% CI = 0.52-0.84 for GAA, respectively). Our findings indicate that variant genotypes and haplotypes of EGF promoter might play a role in gastric carcinogenesis.