Association between a promoter polymorphism (rs2192752, –1028A/C) of interleukin 1 receptor,type I (IL1R1) and location of papillary thyroid carcinoma in a Korean population

The interleukin 1 receptor, type I (IL1R1) is important in the pathogenesis of cancer. We investigated whether single nucleotide polymorphisms (SNPs) of IL1R1 contribute to the development of papillary thyroid carcinoma (PTC), in addition to the clinicopathological features such as the size, number, location, extrathyroidal invasion and metastasis of PTC. Three promoter SNPs (rs949963 ?615G/A, rs2192752 ?1028A/C and rs3917225 ?1099A/G) in IL1R1 were genotyped using direct sequencing in 118 patients with PTC and 347 controls. The odds ratio (OR), 95% confidence interval (CI) and P value were analysed using SNPStats and SNPAnalyzer Pro. For the exact results, Fisher’s exact test and Bonferroni correction (P^c) were performed. The three promoter SNPs of IL1R1 were not associated with PTC development. For the clinicopathological features of PTC, rs2192752 was associated with location (one lobe versus both lobes): dominant model, OR = 3.11, 95% CI = 1.39–6.96, P^c = 0.015; log‐additive model, OR = 2.79, 95% CI = 1.38–5.66, P^c = 0.0087. The C allele frequency of rs2192752 was higher in the both lobes group (28.0%) than the one lobe group (12.3%) (OR = 2.77, 95% CI = 1.40–5.48, P^c = 0.009). However, rs949963 and rs3917225 were not correlated with clinicopathological features including location of PTC. The IL1R1 promoter SNP rs2192752 may contribute to the location of PTC, and the C allele of rs2192752 may be a risk factor for the development of PTC in both lobes.     

Tankyrase 1 polymorphism associated with an increased risk in developing non-small cell lung cancer in a Chinese population: a proof-of-principle study

Objectives: Tankyrase 1 (TNKS1), a poly (ADP-ribose) polymerase, regulates telomere length and apoptosis in cells, overexpression of which occurred in non-small cell lung cancer (NSCLC). This study investigated TNKS1 single-nucleotide polymorphisms (SNPs) for association with a risk in NSCLC development in a Chinese population. Methods: NSCLC cases and healthy controls of 500 each were recruited for genotyping of 24 TNKS1 SNPs. The association between genotype and NSCLC risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) with multivariate unconditional logistic regression analyses. Haploview software was to analyze association between haplotypes and NSCLC risk. Results: TNKS1 rs6601328 A allele was associated with a lower risk in developing NSCLC and adenocarcinoma (ADC) (OR=0.71; 95% CI, 0.51-0.99 and OR=0.70; 95% CI, 0.50-0.99), whereas TNKS1 rs11991621 C allele (OR=1.44; 95% CI, 1.03-2.03), rs11991621 C/C (OR=1.44, 95% CI, 1.03-2.35; P=0.03), and rs10503380 G/G (OR= 1.56, 95% CI, 1.09-2.50, P=0.02) were associated with a higher risk in developing NSCLC or ADC in females and rs6601328 A/A major allele (OR=1.39; 95% CI, 1.00-1.92; P=0.047) and rs7015700 G/G (OR= 1.51, 95% CI, 1.04-2.21) was associated with an increased NSCLC or ADC risk in males but a reduced NSCLC risk (OR=0.63; 95% CI, 0.42-0.96) and ADC risk (OR=0.64; 95% CI, 0.42-0.97) in females. Haploview showed that there were three Haplotype Blocks associated with NSCLC risk. However, TNKS1 rs12541709 C/C was associated with protective effect against ADC (OR=0.75; 95% CI, 0.56-0.99; P=0.04) in this Chinese population. Conclusion: TNKS1 SNPs (rs11991621 rs10503380, and rs7015700) were associated with NSCLC risk, whereas rs6601328 and rs12541709 inversely associated with NSCLC or ADC risk in this Chinese population.     

Genetic association of the ApoB and ApoA1 gene polymorphisms with the risk for alcohol-induced osteonecrosis of femoral head

Polymorphisms of apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1) gene and ApoB/ApoA1 Ratio were associated with lipid metabolism disorders in previous reports. The aim of this study assess whether variation of ApoB, ApoA1 gene are associated or not with alcohol-induced osteonecrosis of femoral head (ONFH). In a case-control study, we genotyped 4 single-nucleotide polymorphisms (SNPs) in ApoB and ApoA1 genes in 209 alcohol-induced ONFH patients and 300 healthy control subjects in Han Chinese population using χ² test and genetic model analysis. The analysis revealed that the frequencies of ApoB and ApoA1 genotypes were significantly different in alcohol-induced ONFH patients than in controls. We identified rs1042034, rs676210 and rs673548 in ApoB gene were associated with decreased risk of alcohol-induced ONFH using recessive model analysis (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.19-0.99; P = 0.042), the OR, CI, P value of three SNPs were the same after adjusted for gender + age. We also identified rs632153 in ApoA1 gene was associated with increased risk of alcohol-induced ONFH using allele model (OR, 1.83; 95% CI, 1.16-2.88; P = 0.008) and log-additive model (adjusted OR, 1.77; 95% CI, 1.00-3.14; P = 0.046), analysis respectively. Haplotype analysis demonstrated no difference between ApoB and alcohol-induced ONFH. Polymorphisms of the ApoB and ApoA1 gene are associated with alcohol-induced ONFH in the Han Chinese population.     

Toll- like receptor 2 polymorphism and IL-6 profile in relation to disease progression in chronic HBV infection: a case control study in Egyptian patients

Chronic hepatitis B (CHB) has a wide range of outcomes depending on host immune responses mainly Toll-like receptors (TLRs) signaling and released cytokines. Toll-like receptor 2 (TLR2) single nucleotide polymorphisms (SNPs) and interleukin 6 (IL-6) may influence the course of CHB. We aimed to elucidate the relation between TLR-2 polymorphism, IL-6 profile, and CHB progression. We analyzed TLR-2 polymorphism (SNP; rs3804099) in 185 CHB patients and 60 controls using TaqMan allelic discrimination assay. Serum IL-6 levels were assessed by ELISA. IL-6 levels were considerably higher in active CHB and cirrhotic patients compared with inactive carriers and controls (P < 0.001). IL-6 showed positive correlation with ALT and advanced fibrosis in active CHB patients (r = 0.31, P = 0.02). A significant positive correlation was noticed between IL-6 and HBV DNA PCR in all CHB groups. TT genotype of rs3804099/TLR-2 was significantly more prevalent in inactive carriers compared to active hepatitis patients (P = 0.04, OR = 0.39 and 95% CI: 0.16–0.95). Both heterozygous CT and mutant TT genotypes were significantly more frequent among inactive carriers compared to cirrhotic patients (P = 0.01, OR = 0.33, 95% CI: 0.13–0.81 and P = 0.009, OR = 0.32, 95% CI: 0.13–0.77). TT genotype was significantly related to lower IL-6 levels in active hepatitis and cirrhotic groups (P = 0.005 and P = 0.001, respectively) showing that TLR mutations would be associated with milder hepatitis activity and lower possibility for disease progression. There may be a positive association between TLR2 rs3804099 polymorphism and hepatitis B activity. IL-6 is a good indicator of CHB disease progression.

     

Association of genetic polymorphisms on BTNL2 with susceptibility to and prognosis of dilated cardiomyopathy in a Chinese population

Background: Dilated cardiomyopathy (DCM) is one type of primary myocardial disease, partly caused by immunity dysfunctions. BTNL2 (butyrophilin-like 2) has already been confirmed to be involved in the etiology of autoimmune disorders and GWAS (genome wide association study) has also identified mutants of a SNP (single nucleotide polymorphism) near BTNL2 could modulate risk of coronary heart disease (also cardiomyopathy). The current study, therefore, was aimed to investigate whether polymorphisms within or around BTNL2 would be correlated with susceptibility to and prognosis of DCM. Material and methods: Peripheral blood samples were gathered from 82 DCM patients and 75 healthy controls. Nine tag-SNPs within or near BTNL2 were obtained from HapMap Database and previously published studies. Eligible haplotypes were gained on the basis of SHesis software. Genotyping of SNPs was implemented with aid of Sequenom MassArray iPLEX platform and subsequently analyzed via MALDI-TOF mass spectrometry. The odd ratios and their 95% confidence interval (95% CI) were utilized to evaluate the correlations between SNPs/haplotypes and DCM risks. Finally, Cox proportional hazard models and Kaplan-Meier curves were performed to assess association of SNPs/haplotypes with prognosis of DCM patients. The statistical analyses were conducted with SPSS 19.0 software. Results: Under the allelic model, rs3763313 (A > C), rs9268494 (C > A), rs9268492 (C > G) and rs9268402 (A > G) were remarkably associated with susceptibility to grade IV of DCM classified by NYHA (New York heart association) (OR = 0.43, 95% CI: 0.22-0.84; P = 0.018; OR = 0.49, 95% CI: 0.27-0.91; P = 0.024; OR = 0.50, 95% CI: 0.27-0.94; P = 0.035; OR = 0.53, 95% CI: 0.28-0.97; P = 0.048). Haplotype C-C-A-T (rs9268492, rs9268494, rs3763313 and rs3763317 synthesized) was also regarded as a protective factor for DCM patients compared with carriers of other haplotypes (OR = 0.50, 95% CI: 0.26-0.97, P = 0.038). Moreover, the univariate survival analysis and multivariate Cox regression analysis both indicated noticeable correlations between rs9268402 and haplotype C-C-A-T and prognosis of DCM patients (NYHA IV), respectively (Long-Rank P = 0.029, HR: 0.241, 95% CI: 0.089-0.650, P = 0.005; Long-Rank P = 0.036; HR = 0.126, 95% CI: 0.035-0.457, P = 0.002). Nonetheless, rs3763313 was found only associated with prognosis of DCM patients (NYHA IV) expressed in the Kaplan-Meier curve (P = 0.009). Conclusion: The genetic mutations within or around BTNL2 (rs3763313, rs9268494, rs9268492 and rs9268402) could alter susceptibility to grade IV of DCM in a Chinese population, and the 2 SNPs (rs3763313 and rs9268402) therein added with haplotype C-C-A-T might separately predict the prognosis of DCM patients. However, additional studies regarding diverse ethnicities need to be furthered to validate our results.     

Association of PTEN gene polymorphisms with liver cancer risk

Objective: To find out if there are any relationship between three single nucleotide polymorphisms (SNPs) of phosphatase and tensin homolog (PTEN) gene (rs1234213, rs1234220, and rs2299939) and the susceptibility of liver cancer. Methods: Genotypes of the three SNPs in the PTEN gene were achieved utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Comparison of genotypes and alleles distribution differences between the case and the control subjects was accomplished with χ² test. The analysis of linkage disequilibrium (LD) and haplotypes of the three SNPs was performed using SHEsis software. We adopted odds ratios (ORs) with 95% confidence intervals (95% CIs) to show the relative risk of liver cancer. Results: TC genotype and C allele of rs1234220 polymorphism showed much more frequently in cases than in controls, reflecting that the TC genotype and the C allele may be linked to the increased risk of liver cancer (OR=2.225, 95% CI=1.178-4.204; OR=1.941, 95% CI=1.124-3.351). Rs2299939 polymorphism showed an opposite result that the GT genotype probably reduce the risk of liver cancer (OR=0.483, 95% CI=0.259-0.900). Statistical significance was not found in the distribution differences of the genotypes of rs1234213 between two groups. LD and haplotype analysis results of the three SNPs showed that the T-C-G haplotype frequency was much higher in cases than in healthy objects, which proved that the T-C-G haplotype might be a susceptibility haplotype for liver cancer (OR=3.750, 95% CI=1.396-10.077). Conclusions: PTEN gene polymorphisms might relate to liver cancer risk.     

Genetic variations in toll-like receptor pathway and lung function decline in Cystic Fibrosis patients

The toll-like receptor (TLR) family maintains pulmonary homeostasis by pathogen recognition, clearance and regulation of inflammation. Genes affecting inflammation response play a key role in modifying Cystic fibrosis (CF) lung disease severity. We assessed the impact of single nucleotide polymorphisms (SNPs) of TLR genes (TLR1 to TLR10, CD14, lipopolyssacharide-binding protein (LBP)) on lung function in CF patients. Each SNP was tested for time-dependent effect on FEV1, using six genetic models. In addition, we investigated associations between SNP genotypes and extreme subject specific slopes of FEV1 decline. Variant alleles of polymorphisms of TLR2 rs1898830, rs5743708, and rs3804100 demonstrated a consistent association with lung disease severity (p = 0.008, p = 0.006 and p = 0.029 respectively). Patients homozygous for variant C allele of TLR5 polymorphism rs5744174 are more frequently associated with extreme fast FEV1 decline (OR: 20 (95% Confidence Interval:1.85–216.18)). Patients homozygous AA for TLR1 polymorphism rs5743551 are more frequently associated with faster decline of FEV1 compared to heterozygous genotype (OR:7.33 (95% CI:1.63–33.11). Our findings indicate that variations in TLR1, TLR2 and TLR5 genes may influence CF lung function decline. Further functional analysis is required to provide new insights into the pathogenesis of TLRs in CF lung disease severity.     

Association between Promoter Polymorphisms of TFF1, TFF2, and TFF3 and the Risk of Gastric and Diffuse Gastric Cancers in a Korean Population

Gastric cancer is one of the most common cancers in the world. The aims of this study were to evaluate the association between polymorphisms in TFF gene family, TFF1, TFF2, and TFF3 and the risk of gastric cancer (GC) and GC subgroups in a Korean population via a case-control study. The eight polymorphisms in TFF gene family were identified by sequencing and genotyped with 377 GC patients and 396 controls by using TaqMan genotyping assay. The rs184432 TT genotype of TFF1 was significantly associated with a reduced risk of GC (odds ratio, [OR) = 0.45; 95% confidence interval, [CI] = 0.25-0.82; P = 0.009), more protective against diffuse-type GC (OR = 0.20; 95% CI = 0.05-0.89; P = 0.035) than GC (OR = 0.34; 95% CI = 0.14-0.82; P = 0.017) in subjects aged < 60 yr, and correlated with lymph node metastasis negative GC and diffuse-type GC (OR = 0.44; 95% CI = 0.23-0.86; P = 0.016 and OR = 0.20; 95% CI = 0.05-0.87; P = 0.031, respectively). In addition, a decreased risk of lymph node metastasis negative GC and diffuse-type GC was observed for rs225359 TT genotype of TFF1 (OR = 0.46, 95% CI = 0.24-0.88; P = 0.020 and OR = 0.21, 95% CI = 0.05-0.88; P = 0.033, respectively). These findings suggest that the rs184432 and rs225359 polymorphisms in TFF1 have protective effects for GC and contribute to the development of GC in Korean individuals.

Graphical Abstract

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Single nucleotide polymorphisms of HER2 related to osteosarcoma susceptibility

Aims: The purpose of this study was to investigate the correlation between single necleotide polymorphisms (SNPs) of human epidermal growth factor receptor-2 (HER2) gene with osteosarcoma susceptibility in Chinese Han population. Methods: 90 patients with osteosarcoma and 100 healthy controls who were frequency-matched with the former by age and gender were enrolled for a case-control study. 5 SNPs of HER2, namely rs2952155, rs1810132, rs2952156, rs1136201 and rs1058808, were tested by Sequenom time of flight mass spectrometry technique. The linkage disequilibrium and haplotype were analyzed using haploview software. The risk intensity of osteosarcoma was expressed by odds ratio (OR) with 95% confidence interval (CI) which was calculated by chi-squared text. Hardy-Weinberg equilibrium (HWE) was also evaluated by chi-squared text. Results: HER2 gene rs1136201 and rs1058808 polymorphisms were associated with the increased risk of osteosarcoma (P=0.04 and 0.02, respectively). Allele G in rs1136201 was 1.67 higher risk for osteosarcoma in cases than the control group (OR=1.67, 95% CI=1.11-2.51) and G allele of rs1058808 polymorphism also significantly increased osteosarcoma susceptibility (OR=2.06, 95% CI=1.27-3.22). The haplotype analysis showed that haplotype C-T-G-G might be a susceptible haplotype to osteosarcoma (OR=1.74, 95% CI=1.01-3.00). HWE test was eligible in controls (P>0.05). Conclusion: HER2 gene rs1136201 and rs1058808 polymorphisms and haplotype C-T-G-G may be related to osteosarcoma susceptibility in Chinese Han population, indicating that the interaction of gene polrmorphism plays an role in osteosarcoma risk.     

Association of Polymorphism rs1045411 in the HMGB1 Gene with Cancer Risk: Evidence from a Meta-analysis

The high-mobility group box protein 1 (HMGB1) rs1045411 polymorphism has been demonstrated to be associated with cancer risk in some studies. However, the results regarding this topic are inconsistent. A meta-analysis was applied to elucidate the association between the HMGB1 rs1045411 polymorphism and cancer risk. Ten relevant studies were subjected to our analysis, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. In total, of 3,918 cases and 5,296 controls were included in this study. The pooled ORs were calculated using a random-effects or fixed-effects model according to the heterogeneity. The pooled results revealed that TT genotype was significantly related to increased cancer risk in the comparisons of TT vs. CC+TC (OR=1.35; 95% CI: 1.09-1.67; p=0.005). Though no statistical significance was achieved between HMGB1 rs1045411 polymorphism and cancer risk in other four genetic models (T vs. C: OR=1.08, 95% CI 0.90-1.30; TC vs. CC: OR=1.01, 95% CI 0.82-1.24; CC vs. TC+TT: OR=0.95, 95% CI 0.77-1.18; TT vs. CC: OR=1.42; 95% CI 0.98-2.05), a trend of increased risk could be drawn. In the subgroup analysis by type of malignancy and ethnicity, no obvious difference was found in the tumour risk regarding the HMGB1 rs1045411 polymorphism amongst the cancer types except for breast cancer (OR=1.94; 95% CI: 1.05-3.59; p=0.03) and hepatocellular carcinoma (OR=1.82; 95% CI: 1.15-2.88; p=0.01), while rs1045411 polymorphism was positively associated with risks of cancer amongst Hans (OR=1.37; 95% CI: 1.11-1.69; p=0.004) rather than Caucasians (OR=0.89; 95% CI: 0.26-3.02; p=0.01). These results suggest that the HMGB1 rs1045411 polymorphism might be associated with increased cancer risk.     

CX3CR1 polymorphisms and the risk of age-related macular degeneration

Background: Age-related macular degeneration (AMD), a most common eye disease, can lead to irreversible visual impairment. Age, genetic and environmental factors have been implicated in AMD. Chemokine (C-X3-C motif) receptor 1 (CX3CR1) gene polymorphisms could influence the susceptibility of AMD. Methods: We tested the association between AMD and single nocleotide polymorphisms (SNPs) of CX3CR1 gene (rs3732378 and rs3732379) in 102 cases and 115 controls from China. Genotypes were determined by MassArray genotyping assay method. Association between CX3CR1 gene polymorphisms and AMD were examined by χ² test and logistic regression. Results: Genotype distribution of CX3CR1 gene polymorphisms were in accordance with HWE examination. No obvious differences were observed in the genotypes of rs3732378 polymorphism between case and control groups (P>0.05), but A allele of it could increase the risk of AMD (P=0.025, OR=2.391, 95% CI=1.092-5.237). Both TT genotype and T allele of rs3732379 were significantly associated with the susceptibility of AMD (P=8.663, OR=8.663, 95% CI=1.044-71.874; P=0.021, OR=2.076, 95% CI=1.104-3.903). Age, gender and smoking status were used as common confounders to adjust the association between CX3CR1 gene polymorphism and AMD risk. Then we found that rs3732378 had no obvious association with AMD susceptibility. TT genotype of rs3732379 related to the occurrence of AMD, but the association was not significant (P=0.050, OR=8.274, 95% CI=1.002-69.963). T allele of rs3732379 might increase the susceptibility of AMD (P=0.029, OR=2.033, 95% CI=1.077-3.838). Conclusion: T allele of rs3732379 might have a positive association with the susceptibility of AMD.     

The FAS ligand promoter polymorphism,rs763110 (?844C>T), contributes to cancer susceptibility: evidence from 19 case–control studies

The potentially functional polymorphism, rs763110 (−844C>T), in the promoter region of the FAS ligand (FASL) gene, has been implicated in cancer risk, but individually published studies show inconclusive results. To derive a more precise estimation of the association between the FASL rs763110 and risk of cancer, we performed a meta-analysis of 19 published studies that included 11 105 cancer cases and 11 372 controls. We used odds ratios (ORs) and 95% confidence intervals (CIs) to assess the strength of the associations. Overall, the rs763110 CT and TT variant genotypes were associated with a significantly reduced cancer risk of all cancer types in different genetic models (homozygote comparison: OR=0.80, 95% CI: 0.68–0.95, P_{heterogeneity}=0.001; heterozygote comparison: OR=0.82, 95% CI: 0.72–0.95, P_{heterogeneity}<0.001; dominant model comparison: OR=0.82, 95% CI: 0.71–0.94, P_{heterogeneity}<0.001; and recessive model comparison: OR=0.88, 95% CI: 0.81–0.96, P_{heterogeneity}=0.074). In the stratified analyses, the risk remained for studies of the smoking-related cancers and Asian populations, or population-based studies in all the genetic models. Although some modest bias could not be eliminated, this meta-analysis suggests that the FASL rs763110 T allele has a possible protective effect on cancer risk.     

Association of Single Nucleotide Polymorphisms in Toll-like Receptor Genes With Asthma Risk: A Systematic Review and Meta-analysis

PurposeAsthma is a complex disease, with contributions from multiple genes, various genetic backgrounds, and environmental factors. Many human epidemiological studies have demonstrated that single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes are inconsistently associated with asthma risk. Some have demonstrated differences concerning the study design and effect size, and conflicting results have been reported. A meta-analysis is necessary to determine the magnitude of this association.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search and meta-analysis of the literature was conducted to estimate the association of SNPs in TLR genes with asthma risk. We screened the medical literature based on the following keyword searches in MEDLINE and EMBASE databases: ''TLR'', ''polymorphism'', ''asthma'', and their combinations.ResultsMeta-analysis of eight studies on TLR4 Asp299Gly showed a marginal association of TLR4 with asthma risk (odds ratio [OR]=0.814 [95% confidence interval [CI], 0.652-1.016; P=0.069]) in the recessive model. TLR4 Thr399Ile was not associated with asthma risk under any genetic model. Meta-analysis of four studies on TLR2 Arg753Gln indicated that TLR2 might be significantly associated with asthma in the dominant and codominant models (P=0.029, P=0.030, and P=0.009, respectively). TLR9 -1237 was marginally associated with asthma risk (OR=0.408 [95% CI, 0.163-1.021; P=0.065]) in the codominant model. Analysis using the allele contrast model showed that the major TLR9 -1237 T allele tended to be a significant protective factor with OR=0.689 (95% CI, 0.471-1.007; P=0.055).ConclusionsThe results showed that TLR4 Asp299Gly, TLR2 Arg753Gln, and TLR9-1237 might contribute significantly to asthma susceptibility. Future genetic association studies would consolidate these findings.     

Prognostic assessment of apoptotic gene polymorphisms in non-small cell lung cancer in Chinese

Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypothesis, we selected 38 potentially functional single nucleotide polymorphisms (SNPs) from 12 genes (BAX, BCL2, BID, CASP3, CASP6, CASP7, CASP8, CASP9, CASP10, FAS, FASLG and MCL1) involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer (NSCLC) patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival (P < 0.05). After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC (BID rs8190315: P = 0.003; CASP9 rs4645981: P = 0.007 and FAS rs1800682: P = 0.016). A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG (adjusted HR = 0.65, 95% CI: 0.49-0.88), CASP9 rs4645981 AA (HR = 0.22, 95% CI: 0.07-0.69) and FAS rs1800682 GG (adjusted HR = 0.67, 95% CI: 0.46-0.97). Time-dependent receptor operation curve (ROC) analysis revealed that the area under curve (AUC) at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not significantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.     

Renal cell carcinoma risk is associated with the interactions of APOE,VHL and MTHFR gene polymorphisms

Objective: The study was designed to explore the association of renal cell carcinoma (RCC) with VHL (rs779805), MTHFR (rs1801133) and APOE (rs8106822 and rs405509) polymorphisms, investigate the interactions among the single nucleotide polymorphisms (SNPs), and explore roles of the interactions in the pathogenesis of RCC in Chinese Han population. Methods: 81 RCC patients and 80 healthy controls were included in the study. Polymerase chain reaction (PCR) and direct sequencing methods were used in the analysis on the genotypes of APOE, VHL and MTHFR gene polymorphisms. Multifactor dimensionality reduction (MDR) method was adopted to conduct gene-gene interaction analysis. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized to evaluate the correlation between gene-gene interactions and RCC risk. Results: Significant correlations were found between RCC risk and 3 SNPs (rs8106822, rs779805 and rs1801133). Genotype AA and allele A of APOE rs8106822 were significantly associated with RCC susceptibility (OR=2.65, 95% CI=1.05-6.69). Meanwhile, we found that the frequencies of genotype GG and allele G were much higher in case group, compared with controls (P<0.05 for both) and they appeared to be risk factors for RCC (OR=2.90, 95% CI=1.22-6.87; OR=1.78, 95% CI=1.14-2.27). While, allele T of MTHFR rs1801133 could decrease the risk of RCC (OR=0.62, 95% CI=0.40-0.97). MDR analysis showed that gene-gene interactions among APOE, VHL and MTHFR SNPs were closely related with RCC susceptibility. Conclusion: APOE, VHL and MTHFR gene polymorphisms were related to the risk of RCC. The interactions among APOE, VHL and MTHFR genes could increase the risk of RCC.     

SERPINE2 Polymorphisms and Chronic Obstructive Pulmonary Disease

A number of genome-wide linkage analyses have identified the 2q33.3-2q37.2 region as most likely to contain the genes that contribute to the susceptibility to chronic obstructive pulmonary disease (COPD). It was hypothesized that the SERPINE2 gene, which is one of the genes located at the 2q33.3-2q37.2 region, may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, the association of four SERPINE2 single nucleotide polymorphisms (SNPs; rs16865421A>G, rs7583463A>C, rs729631C>G, and rs6734100C>G) with the risk of COPD was investigated in a case-control study of 311 COPD patients and 386 controls. The SNP rs16865421 was associated with a significantly decreased risk of COPD in a dominant model for the polymorphic allele (adjusted odds ratio [OR]=0.66, 95% confidence interval [CI]=0.45-0.97, P=0.03). In haplotype analysis, the GACC haplotype carrying the polymorphic allele at the rs16865421 was associated with a significantly decreased risk of COPD when compared to the AACC haplotype (adjusted OR=0.58, 95% CI=0.38-0.89, P=0.01), and this effect was evident in younger individuals (adjusted OR=0.30, 95% CI=0.14-0.64, P=0.002). This study suggests that the SERPINE2 gene contributes to the susceptibility to COPD.     

Association and heterogeneity at the GAPDH locus in Alzheimer's disease

Glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) and its paralogs were implicated in late-onset Alzheimer's disease (LOAD), although the strength and direction of association have not been consistent. We genotyped 3 previously reported single nucleotide polymorphisms (SNPs; rs3741916-GAPDH 5′ UTR, rs2029721-pGAPD, and rs4806173-GAPDHS) in 3 case-control series (2112 cases and 3808 controls). Rs3741916 showed the strongest LOAD association (p = 0.003). The minor allele of rs3741916 showed a protective effect in our combined series (odds ratio [OR] = 0.87%, 95% confidence interval [CI] = 0.79-0.96). This is consistent with results from the 2 published follow-up studies and in opposite direction of the original report. Meta-analysis of the published series with ours suggests presence of heterogeneity (Breslow-Day p < 0.0001). Meta-analysis of only the follow-up series including ours revealed a significant protective effect for the minor allele of rs3741916 (OR = 0.85%, 95% CI = 0.76-0.96, p = 0.009). Our results support the presence of LOAD variants and heterogeneity at the GAPDH locus. The most promising rs3741916 variant is unlikely to be functional given opposing effects in different series. Identification of functional variant(s) in this region likely awaits deep sequencing.     

Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium

Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4R_rs2107356 and IL8_rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4R_rs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8_rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12B_rs3212227 and IFNγ_rs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12B_rs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγ_rs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4R_rs2107356 and IFNγ_rs2069705 SNPs was stronger in allo-HSCT (IL4R_rs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγ_rs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγ_rs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [P_{LPS-96 h}], 0.057; P value for 96 h of treatment with phytohemagglutinin [P_{PHA-96 h}], 0.036; P_{LPS+PHA-96 h} = 0.030; P_{PHA-72 h} = 0.045; P_{LPS+PHA-72 h} = 0.018; P_{LPS-96 h} = 0.058; P_{LPS+PHA-96 h} = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P_{−2 log likehood ratio test} = 5.2 · 10⁻⁴ and P_{50.000 permutation test} = 9.34 · 10⁻⁵). These findings suggest that the IFNγ_rs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.     

The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease

Background: It has been reported that one single nucleotide polymorphisms (SNPs) rs5743708 in TLR2 gene might be associated with the susceptibility to tuberculosis disease. Owing to mixed and inconclusive results, we conducted a meta-analysis to systematically summarize and clarify the association between the rs5743708 gene polymorphism in the TLR2 gene and the risk of tuberculosis disease. Methods: A systematic search of studies on the association of the rs5743708 gene polymorphism in the TLR2 gene with susceptibility to tuberculosis disease was conducted in PubMed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. Results: A total of nineteen case-control studies from 13 articles on rs2910164 and 3 studies on the rs5743708 gene polymorphism in the TLR2 gene and the risk of tuberculosis disease were included. A significant relationship between the rs5743708 gene polymorphism in the TLR2 gene and tuberculosis disease was discovered in an allelic genetic model (OR: 2.801, 95% CI: 2.130-3.683, P=0.000), a homozygote model (OR: 5.795, 95% CI: 1.982-16.941, P=0.001), a heterozygote model (OR: 2.628, 95% CI: 1.888-3.569, P=0.000), a dominant genetic model (OR: 2.786, 95% CI: 2.003-3.877, P=0.000) and a recessive genetic model OR: (5.568, 95% CI: 1.907-16.255, P=0.002). In sub-group analysis base on ethnicity, significance was observed between the Caucasian group and the Asian group. Conclusions: The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease. Individuals with the rs5743708 gene polymorphism in the TLR2 gene are under a higher risk for tuberculosis disease.