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Gene–smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single-nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene–smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies of NSCLC, which included 13 327 cases and 13 328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5 × 10−8 for identifying significant gene–smoking interactions and 1 × 10–6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene–smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.54–0.74, P = 3.31 × 10–8], and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95% CI: 0.63–0.82, P = 8.10 × 10–7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95% CI: 0.51–0.73, P = 7.55 × 10–8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations. [ABSTRACT FROM AUTHOR]

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819TNS3 at 7p12.3 (P = 3.90 × 10−9) and rs1143149SEPT7 at 7p14.2 (P = 9.75 × 10−9), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819TNS3: Pinteraction = 8.0 × 10−4; rs1143149SEPT7: Pinteraction = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.Methods: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis.Results: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584).Conclusions: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with cancer risk, several of which have shown pleiotropic effects across cancers. Therefore, we performed a systematic cross-cancer pleiotropic analysis to detect the effects of GWAS-identified variants from non-lung cancers on lung cancer risk in 12,843 cases and 12,639 controls from four lung cancer GWASs. The overall association between variants in each cancer and risk of lung cancer was explored using sequential kernel association test (SKAT) analysis. For single variant analysis, we combined the result of specific study using fixed-effect meta-analysis. We performed functional exploration of significant associations based on features from public databases. To further detect the biological mechanism underlying identified observations, pathway enrichment analysis were conducted with R package "clusterProfiler." SNP-set analysis revealed the overall associations between variants of 8 cancer types and lung cancer risk. Single variant analysis identified 6 novel SNPs related to lung cancer risk after multiple correction (P fdr < 0.10), including rs1707302 (1p34.1, OR = 0.93, 95% CI: 0.90–0.97, P = 7.60 × 10−4), rs2516448 (6p21.33, OR = 1.07, 95% CI: 1.03–1.11, P = 1.00 × 10−3), rs3869062 (6p22.1, OR = 0.91, 95% CI: 0.86–0.96, P = 7.10 × 10−4), rs174549 (11q12.2, OR = 0.90, 95% CI: 0.87–0.94, P = 1.00 × 10−7), rs7193541 (16q23.1, OR = 0.93, 95% CI: 0.90–0.96, P = 1.20 × 10−4), and rs8064454 (17q12, OR = 1.07, 95% CI: 1.03–1.11, P = 4.30 × 10−4). The eQTL analysis and functional annotation suggested that these variants might modify lung cancer susceptibility through regulating the expression of related genes. Pathway enrichment analysis showed that genes modulated by these variants play important roles in cancer carcinogenesis. Our findings demonstrate the pleiotropic associations between non-lung cancer susceptibility loci and lung cancer risk, providing important insights into the shared mechanisms of carcinogenesis across cancers. [ABSTRACT FROM AUTHOR]

Background: The association of ABO blood groups with gastric cancer risk was proposed decades ago, but the results have been inconsistent.Methods: We used two single nucleotide polymorphisms to determine ABO genotype in 4932 gastric cancer cases and 6158 controls of Chinese descent, and evaluated the associations of ABO blood groups and genotypes with risk of gastric cancer using multivariable logistic regression models. We also systematically reviewed published literature and performed a meta-analysis of all relevant studies.Results: In the case-control study, compared with blood group O, both blood group A and AB were associated with increased gastric cancer risk (for group A, odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.02-1.24; for group AB, OR = 1.18, 95% CI: 1.02-1.36, respectively). Analyses of ABO genotypes revealed associations of AO and AB with risk of gastric cancer compared with OO genotype. Consistent with the case-control study, meta-analysis of 40 studies including 33,613 cases and 2,431,327 controls demonstrated that blood group A (OR = 1.19, 95% CI: 1.13-1.25) and AB (OR = 1.09, 95% CI: 1.03-1.16) were associated with increased risk of gastric cancer.Conclusions: Our analyses validated the association of blood group A with risk of gastric cancer, and suggested that blood group AB was also associated with gastric cancer risk. Functional investigations are warranted to elucidate the exact mechanism of ABO blood groups in gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Even though genome-wide association studies (GWASs) have identified dozens of single nucleotide polymorphisms (SNPs) affecting the susceptibility to lung cancer, only a tiny fraction of heritability can be explained. Regulating the expression of surrounding genes is one of the important mechanisms for SNPs to exert their effect. So it is necessary to systematically evaluate the associations between expression quantitative trait loci (eQTL) and lung cancer risk. In this study, a two-stage case–control design was used to evaluate the associations of eQTL SNPs (eSNPs) defined by GTEx in normal lung tissues with the risk of lung cancer based on two GWAS datasets, including 7127 cases and 6818 controls. Promising variants were replicated in an independent population with 1026 lung cancer cases and 1006 controls. Functional annotations of the identified eSNPs and related genes were performed based on multiple public databases. Finally, we identified two potential eSNPs associated with the risk of lung cancer in 3q28 [rs505974, OR = 0.90 (0.86 – 0.94), P = 6.51 × 10−6] and 21q22.3 [rs79589812, OR = 1.38 (1.21 – 1.58), P = 2.46 × 10−6]. Subgroup analysis showed rs505974 might interact with smoking behaviour. Gene-set enrichment and pathway analysis revealed that rs505974 may affect the susceptibility to lung cancer via regulating the expression of CLDN16, which may be involved in the chemical carcinogenesis pathway, whereas rs79589812 may regulate the expression of SPATC1L, which may be involved in the base excision repair pathway. These results provide an overview of the associations between eSNPs and lung cancer in Asian populations. [ABSTRACT FROM AUTHOR]

Summary: Previously, we identified UBE2L3 as a susceptibility gene for chronic hepatitis B virus (HBV) infection through genome‐wide association study. Here, we analysed the association between genetic variants of UBE2L3 and the susceptibility to HBV‐related hepatocellular carcinoma (HCC) and further explored its role in HCC. This case‐control study included 1344 subjects who cleared HBV, 1560 HBV carriers and 1057 HBV‐related HCC patients. Two single nucleotide polymorphisms (SNPs) were genotyped, including rs2266959 and rs4821116. Logistic regression analysis was performed to compute the odds ratio (OR) and 95% confidence interval (CI). We further analysed the expression of UBE2L3 and its association with pathological features based on The Cancer Genome Atlas (TCGA) data and our tissue microarray. Proliferation and migration assays were performed in hepatoma cell lines with or without UBE2L3 knockdown. Further RNA‐seq analysis was performed to explore the underlying oncogenic mechanism. The variant genotypes of rs4821116 in UBE2L3 were associated with decreased risk for HCC and chronic HBV infection. Moreover, based on both TCGA and our tissue microarray data, higher levels of UBE2L3 expression were correlated with higher tumour grade, advanced tumour stage and poor survival. In vitro analysis revealed that UBE2L3 may promote hepatocyte proliferation and migration. RNA‐seq analysis showed that UBE2L3 was inversely correlated with CDKN2B, a negative regulator of cell cycle, and CLDN1, loss of which may promote cancer metastasis. In conclusion, UBE2L3 may also be a susceptibility gene in HBV‐related HCC, and it may promote HCC proliferation and migration by negatively regulating CDKN2B and CLDN1. [ABSTRACT FROM AUTHOR]

Coal worker's pneumoconiosis (CWP) is a debilitating and progressive occupational lung disease resulted fromlong-term inhalation of airborne silica-containing coalmine dust. Both environmental factors and genetic variations contribute to CWP. Our previous genome-wide association study (GWAS) revealed a tiny fraction of variants with the top associations in Chinese Han population. To identify novel susceptibility loci of CWP, functional variants with suboptimal associations in the GWAS scan were further studied here. Imputation was firstly performed to access the associations between ungenotyped variants and CWP risk and suboptimal associations with p < 1.0 x 10-3 were annotated with genotype-tissue expression (GTEx) and dbNSFP. Further, expression quantitative trait loci (eQTL) and nonsynonymous variants were validated within an independent cohort with 703 CWP cases and 705 exposed controls. Comprehensively functional annotations were performed for identified single nucleotide polymorphism(SNPs) based on multiple bioinformatics databases and websites. We found 4 CWP risk-associated eQTL SNPs, including rs10797062 at 1q23.2 (p = 6.91 x 10-4, OR = 1.28), rs1667614 at 2q13.1 (p = 1.48 x 10-4, OR = 0.53), rs2540438 at 2q33.1 (p = 2.13 x 10-3, OR = 1.33) and rs2274554 at 13q31.1 (p = 9.01 x 10-5, OR = 1.35). Based on the results from GTEx, the identified variants were significantly associated with host genes in lung tissues: rs10797062- ATP1A4 (p = 8.60 x 10-11), rs1667614-FNBP1P1 (p = 1.00 x 10-20), rs2540438-ALS2CR12 (p = 1.90 x 10-7), and rs2274554-RBM26 (p = 5.00 x 10-6). Joint effect analysis showed the risk of CWP was significantly increased with the number of risk variant alleles in an allele-dosagemanner (ptrend = 2.20 x 10-12). Enrichment pathway analysis suggested coexpressed genes of ATP1A4, FNBP1P1 and RBM26 were enriched in Ubiquitin mediated proteolysis pathway simultaneously. These results may provide a deeper understanding of the genetic predisposition of CWP. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have identified a large amount of single-nucleotide polymorphisms (SNPs) associated with complex traits. A recently developed linear mixed model for estimating heritability by simultaneously fitting all SNPs suggests that common variants can explain a substantial fraction of heritability, which hints at the low power of single variant analysis typically used in GWAS. Consequently, many multi-locus shrinkage models have been proposed under a Bayesian framework. However, most use Markov Chain Monte Carlo (MCMC) algorithm, which are time-consuming and challenging to apply to GWAS data. Here, we propose a fast algorithm of Bayesian adaptive lasso using variational inference (BAL-VI). Extensive simulations and real data analysis indicate that our model outperforms the well-known Bayesian lasso and Bayesian adaptive lasso models in accuracy and speed. BAL-VI can complete a simultaneous analysis of a lung cancer GWAS data with ~3400 subjects and ~570,000 SNPs in about half a day. [ABSTRACT FROM AUTHOR]

NBN plays a crucial role in carcinogenesis as a core component for both homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA double-strand breaks (DSBs) repair pathways. Genetic variants in the NBN gene have been associated with multiple cancers risk, suggesting pleiotropic effect on cancer. We hypothesized that genetic variants in the NBN gene may modify the risk of gastric cancer. To test this hypothesis, we evaluated the association between four potentially functional single nucleotide polymorphisms in NBN and gastric cancer risk in a case–control study of 1,140 gastric cancer cases and 1,547 controls in a Chinese population. We found that the A allele of rs10464867 (G>A) was significantly associated with a decreased risk of gastric cancer (odds ratio [OR] = 0.81, 95% confidence interval [95% CI] = 0.71–0.94; P = 4.71×10−3). Furthermore, the association between A allele of rs10464867 and decreased risk of gastric cancer was more significantly in elder individuals (per-allele OR = 0.72[0.59–0.88], P = 1.07×10−3), and male individuals (per-allele OR = 0.73[0.62–0.87], P = 3.68×10−4). We further conducted a haplotype analysis and identified that the NBN Ars10464867Grs14448Grs1063053 haplotype conferred stronger protective effect on gastric cancer (OR = 0.76[0.65–0.89], P = 6.39×10−4). In summary, these findings indicate that genetic variants at NBN gene may contribute to gastric cancer susceptibility and may further advance our understanding of NBN gene in cancer development. [ABSTRACT FROM AUTHOR]

Caspase recruitment domain family, member 8 (CARD8) can coordinate innate and adaptive immune responses and sensitize cells to apoptosis, which may participate in tumorigenesis of virus-induced hepatocellular carcinoma (HCC) and cervical cancer. By bioinformatics analyses, we identified several single nucleotide polymorphisms (SNPs) within a new identified long non-coding RNA (lncRNA) as expression quantitative trait loci (eQTLs) for CARD8. In this study, we therefore hypothesized that CARD8 eQTLs SNPs within lncRNA may influence the risk of HCC and cervical cancer. We performed two independent case-control studies of 1,300 cases with HBV-positive HCC and 1,344 normal controls, together with 1,486 cervical cancer patients and 1,536 control subjects to test the association between eQTLs SNP (rs7248320) for CARD8 and the risk of HCC and cervical cancer. The variant genotype of rs7248320 was significantly associated with increased risk of HCC and cervical cancer [GG vs. AA/GA: adjusted odds ratio (OR) = 1.28, 95% confidence interval (CI) = 1.03–1.61, P = 0.028 for HCC; adjusted OR = 1.34, 95% CI = 1.09–1.66, P = 0.006 for cervical cancer]. Moreover, the effect of rs7248320 on cervical cancer risk was more prominent in premenopausal women. Further interactive analysis detected a significantly multiplicative interaction between rs7248320 and menopausal status on cervical cancer risk (P = 0.018). These findings suggest that CARD8 eQTLs SNP may serve as a susceptibility marker for virus-related HCC and cervical cancer. [ABSTRACT FROM AUTHOR]

Purpose: Genetic basis of Developmental dysplasia of the hip (DDH) remains largely unknown. To find new susceptibility genes for DDH, we carried out a genome-wide association study (GWAS) for DDH. Methods: We enrolled 386 radiology confirmed DDH patients and 558 healthy controls (Set A) to conduct a genome-wide association study (GWAS). Quality-control was conducted at both the sample and single nucleotide polymorphism (SNP) levels. We then conducted a subsequent case-control study to replicate the association between a promising loci, rs6060373 in UQCC gene and DDH in an independent set of 755 cases and 944 controls (set B). Results: In the DDH GWAS discovering stage, 51 SNPs showed significance of less than 10-4, and another 577 SNPs showed significance of less than 10-3. In UQCC, all the 12 genotyped SNPs showed as promising risk loci. Genotyping of rs6060373 in set A showed the minor allele A as a promising risk allele (p = 4.82*10-7). In set A, the odds ratio of allele A was 1.77. Genotyping of rs6060373 in Set B produced another significant result (p = 0.0338) with an odds ratio of 1.18 for risk allele A. Combining set A and set B, we identified a total p value of 3.63*10-6 with the odds ratio of 1.35 (1.19–1.53) for allele A. Conclusion: Our study demonstrates common variants of UQCC, specifically rs6060373, are associated with DDH in Han Chinese population. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies (GWAS) have identified dozens of single nucleotide polymorphisms (SNPs) associated with type 2 diabetes risk. We have previously confirmed the associations of genetic variants in HHEX, CDKAL1, VEGFA and FTO with type 2 diabetes in Han Chinese. However, the cumulative effect and predictive value of these GWAS identified SNPs on the risk of type 2 diabetes in Han Chinese are largely unknown. Methodology/Principal Findings: We conducted a two-stage case-control study consisting of 2,925 cases and 3,281controls to examine the association of 30 SNPs identified by GWAS with type 2 diabetes in Han Chinese. Significant associations were found for proxy SNPs at KCNQ1 [odds ratio (OR) = 1.41, P = 9.91 × 10–16 for rs2237897], CDKN2A/CDKN2B (OR = 1.30, P = 1.34 × 10–10 for rs10811661), CENTD2 (OR = 1.28, P = 9.88 × 10-4 for rs1552224) and SLC30A8 (OR = 1.19, P = 1.43 × 10-5 for rs13266634). We further evaluated the cumulative effect on type 2 diabetes of these 4 SNPs, in combination with 5 SNPs at HHEX, CDKAL1, VEGFA and FTO reported previously. Individuals carrying 12 or more risk alleles had a nearly 4-fold increased risk for developing type 2 diabetes compared with those carrying less than 6 risk alleles [adjusted OR = 3.68, 95% confidence interval (CI): 2.76–4.91]. Adding the genetic factors to clinical factors slightly improved the prediction of type 2 diabetes, with the area under the receiver operating characteristic curve increasing from 0.76 to 0.78. However, the difference was statistically significant (P < 0.0001). Conclusions/Significance: We confirmed associations of SNPs in KCNQ1, CDKN2A/CDKN2B, CENTD2 and SLC30A8 with type 2 diabetes in Han Chinese. The utilization of genetic information may improve the accuracy of risk prediction in combination with clinical characteristics for type 2 diabetes. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do genetic variants in known canonical pathways that have been widely suggested to affect spermatogenesis confer susceptibility to non-obstructive azoospermia (NOA)? SUMMARY ANSWER Rs1406714 in CHD2, rs2126986 in GNAO1 and rs7226979 in BCL2 were associated with NOA in Han Chinese men at a significant level after multiple testing corrections. WHAT IS KNOWN ALREADY Previous genome-wide association studies (GWASs) have identified three loci for NOA, whereas less attention has been given to those markers that did not exceed the genome-wide significance threshold. STUDY DESIGN, SIZE, DURATION We conducted a two-stage association study containing 1653 NOA cases and 2329 controls to investigate the susceptibility markers for NOA. PARTICIPANTS/MATERIALS, SETTING, METHODS Imputation and pathway-based approaches can be applied to identify additional causal makers with small effects on NOA. We performed a candidate pathway-based association study using imputed-genotyping data for 24 238 single nucleotide polymorphisms estimated from NOA GWAS. Remarkably, 40 markers were associated with NOA in both imputation analysis and NOA GWAS (Stage 1) after linkage disequilibrium analysis and selected for validation (Stage 2) in another population. MAIN RESULTS AND THE ROLE OF CHANCE Based on the literature, genes from 11 biological pathways known or hypothesized to be important in spermatogenesis were selected. Combined analysis using directly genotyped data for Stages 1 and 2 revealed that rs1406714 in CHD2 was associated with decreased risk of NOA [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68–0.89, Pmeta = 1.7E−04], whereas rs2126986 in GNAO1 and rs7226979 in BCL2 were both risk makers for NOA (rs2126986: OR = 1.28, 95% CI = 1.15–1.41, Pmeta = 2.3E−06; rs7226979: OR = 1.21, 95% CI = 1.11–1.33, Pmeta = 4.5E−05). LIMITATIONS, REASONS FOR CAUTION Our analysis of genes in the pathways studied was not exhaustive. WIDER IMPLICATIONS OF THE FINDINGS Our study opens new avenues for the identification of other novel causal markers that are related to NOA. It will also provide a new paradigm for understanding the etiology of male infertility and contribute to the development of targeted therapies. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by National Basic Research Program of China (973 Program, 2011CB944304); National Science Fund for Outstanding Young Scholars (81322039); National Natural Science Foundation (31371524); Distinguished Young Scholars of Jiangsu Province (BK20130041); The Program for Postgraduates Research Innovation in University of Jiangsu Province (CXZZ12-0600). Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). There were no competing interests. [ABSTRACT FROM AUTHOR]

Background: MiR-106b-25 cluster, hosted in intron 13 of MCM7, may play integral roles in diverse processes including immune response, tumorigenesis and progression. A single nucleotide polymorphism (SNP), rs999885, is located in the promoter region of MCM7. Our previous study showed that the A to G base change of rs999885 may provide an increased risk for HCC in HBV persistent carriers by altering the expression of the miR-106b-25 cluster. However, it is unknown whether rs999885 is associated with prognosis of intermediate or advanced HBV-related hepatocellular carcinoma (HCC) patients. Methods: The SNP, rs999885, was genotyped by using the TaqMan allelic discrimination Assay in 414 intermediate or advanced HCC patients. Log-rank test and Cox proportional hazard models were used for survival analysis. Results: The variant genotypes of rs999885 were associated with a significantly decreased risk of death for intermediate or advanced HCC [additive model: adjusted hazard ratio (HR)  = 0.76,95% confidence intervals (CI)  = 0.59–0.97]. Further stepwise regression analysis suggested that rs999885 was an independently protective factor for the prognosis of HCC in the final model (additive model: adjusted HR  = 0.72, 95% CI  = 0.56–0.91, P = 0.007). Conclusions: These findings indicate that the A to G base change of rs999885 may provide a protective effect on the prognosis of intermediate or advanced HCC in Chinese. [ABSTRACT FROM AUTHOR]

Background: Oligozoospermia is one of the severe forms of idiopathic male infertility. However, its pathology is largely unknown, and few genetic factors have been defined. Our previous genome-wide association study (GWAS) has identified four risk loci for non-obstructive azoospermia (NOA). Objective: To investigate the potentially functional genetic variants (including not only common variants, but also less-common and rare variants) of these loci on spermatogenic impairment, especially oligozoospermia. Design, Setting, and Participants: A total of 784 individuals with oligozoospermia and 592 healthy controls were recruited to this study from March 2004 and January 2011. Measurements: We conducted a two-stage study to explore the association between oligozoospermia and new makers near NOA risk loci. In the first stage, we used next generation sequencing (NGS) in 96 oligozoospermia cases and 96 healthy controls to screen oligozoospermia-susceptible genetic variants. Next, we validated these variants in a large cohort containing 688 cases and 496 controls by SNPscan for high-throughput Single Nucleotide Polymorphism (SNP) genotyping. Results and Limitations: Totally, we observed seven oligozoospermia associated variants (rs3791185 and rs2232015 in PRMT6, rs146039840 and rs11046992 in Sox5, rs1129332 in PEX10, rs3197744 in SIRPA, rs1048055 in SIRPG) in the first stage. In the validation stage, rs3197744 in SIRPA and rs11046992 in Sox5 were associated with increased risk of oligozoospermia with an odds ratio (OR) of 4.62 (P  =  0.005, 95%CI 1.58-13.4) and 1.82 (P  =  0.005, 95%CI 1.01-1.64), respectively. Further investigation in larger populations and functional characterizations are needed to validate our findings. Conclusions: Our study provides evidence of independent oligozoospermia risk alleles driven by variants in the potentially functional regions of genes discovered by GWAS. Our findings suggest that integrating sequence data with large-scale genotyping will serve as an effective strategy for discovering risk alleles in the future. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) are popular for identifying genetic variants which are associated with disease risk. Many approaches have been proposed to test multiple single nucleotide polymorphisms (SNPs) in a region simultaneously which considering disadvantages of methods in single locus association analysis. Kernel machine based SNP set analysis is more powerful than single locus analysis, which borrows information from SNPs correlated with causal or tag SNPs. Four types of kernel machine functions and principal component based approach (PCA) were also compared. However, given the loss of power caused by low minor allele frequencies (MAF), we conducted an extension work on PCA and used a new method called weighted PCA (wPCA). Comparative analysis was performed for weighted principal component analysis (wPCA), logistic kernel machine based test (LKM) and principal component analysis (PCA) based on SNP set in the case of different minor allele frequencies (MAF) and linkage disequilibrium (LD) structures. We also applied the three methods to analyze two SNP sets extracted from a real GWAS dataset of non-small cell lung cancer in Han Chinese population. Simulation results show that when the MAF of the causal SNP is low, weighted principal component and weighted IBS are more powerful than PCA and other kernel machine functions at different LD structures and different numbers of causal SNPs. Application of the three methods to a real GWAS dataset indicates that wPCA and wIBS have better performance than the linear kernel, IBS kernel and PCA. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified multiple genetic variants associated with risk of esophageal squamous-cell carcinoma (ESCC) in Chinese populations. We examined whether these genetic factors, along with non-genetic factors, can contribute to ESCC risk prediction. We examined 25 single nucleotide polymorphisms (SNPs) and 4 non-genetic factors (sex, age, smoking and drinking) associated with ESCC risk in 9805 cases and 10 493 controls from Chinese populations. Weighted genetic risk score (wGRS) was calculated and logistic regression was used to analyze the association between wGRS and ESCC risk. We calculated the area under the curve (AUC) using receiver operating characteristic curve analysis to measure the discrimination after adding genetic variants to the model with only non-genetic factors. Net reclassification improvement (NRI) was used to quantify the degree of correct reclassification using different models. wGRS of the combined 17 SNPs with significant marginal effect (G SNPs) increased ~4-fold ESCC risk (P = 1.49 × 10−164) and the associations were significant in both drinkers and non-drinkers. However, wGRS of the eight SNPs with significant effect in gene × drinking interaction (GE SNPs) increased ~4-fold ESCC risk only in drinkers (Pinteraction = 8.76 × 10–41). The AUC for a risk model with 4 non-genetic factors, 17 G SNPs, 8 GE SNPs and their interactions with drinking was 70.1%, with the significant improvement of 7.0% compared with the model with only non-genetic factors (P < 0.0001). Our results indicate that incorporating genetic variants, lifestyle factors and their interactions in ESCC risk models can be useful for identifying patients with ESCC. [ABSTRACT FROM AUTHOR]

A recently published genome-wide association study (GWAS) in European populations identified several loci at 4q21, 4q23 and 12q24 that were associated with risk of upper aerodigestive tract (UADT) cancers, including esophageal squamous cell carcinoma (ESCC). In the current study, we conducted a case-control study in a Chinese population including 2,139 ESCC cases and 2,273 controls to evaluate the associations of six reported single nucleotide polymorphisms (SNPs) (rs1494961, rs1229984, rs1789924, rs971074, rs671 and rs4767364) with risk of ESCC. We found significant association with risk of ESCC for four SNPs, including rs1494961 in HEL308 at 4q21 [odds ratio (OR) = 1.15, 95 % confidence interval (CI) = 1.05-1.26], rs1229984 in ADH1B at 4q23 (OR = 1.24, 95 % CI = 1.13-1.36) and rs1789924 near ADH1C at 4q23 (OR = 1.20, 95 % CI = 1.03-1.39), and rs671 in ALDH2 at 12q24 (OR = 0.83, 95 % CI = 0.75-0.91). Combined analysis of these four SNPs showed a significant allele-dosage effect on ESCC risk for individuals with different number of risk alleles ( P trend = 2.23 × 10). Compared with individuals with '0-2' risk allele, those carrying '3', '4' or '5 or more' risk alleles had 1.42-, 1.66-, or 1.76-fold risk of ESCC, respectively. Thus, our findings indicate that rs1494961 at 4q21, rs1229984 and rs1789924 at 4q23, and rs671 at 12q24 may be used as genetic biomarkers for ESCC susceptibility in Chinese population. [ABSTRACT FROM AUTHOR]

We conducted a genome-wide scan of SNPs to identify variants associated with length of survival in 1,331 individuals with esophageal squamous-cell carcinoma (ESCC), with associations validated in 2 independent sets including 1,962 individuals with this cancer. We identified rs1050631 in SLC39A6 as associated with the survival times of affected individuals, with the hazard ratio for death from ESCC in the combined sample being 1.30 (95% confidence interval (CI) = 1.19−1.43; P = 3.77 × 10−8). rs7242481, located in the 5′ UTR of SLC39A6, disturbs a transcriptional repressor binding site and results in upregulation of SLC39A6 expression. Immunohistochemical staining of ESCC tissues showed that higher expression of SLC39A6 protein was correlated with shorter length of survival in individuals with advanced ESCC (P = 0.013). Knockdown of SLC39A6 expression suppressed proliferation and invasion in ESCC cells. These results suggest that SLC39A6 has an important role in the prognosis of ESCC and may be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Genome-wide association study (GWAS) is a promising approach for identifying common genetic variants of the diseases on the basis of millions of single nucleotide polymorphisms (SNPs). In order to avoid low power caused by overmuch correction for multiple comparisons in single locus association study, some methods have been proposed by grouping SNPs together into a SNP set based on genomic features, then testing the joint effect of the SNP set. We compare the performances of principal component analysis (PCA), supervised principal component analysis (SPCA), kernel principal component analysis (KPCA), and sliced inverse regression (SIR). Simulated SNP sets are generated under scenarios of 0, 1 and ≥2 causal SNPs model. Our simulation results show that all of these methods can control the type I error at the nominal significance level. SPCA is always more powerful than the other methods at different settings of linkage disequilibrium structures and minor allele frequency of the simulated datasets. We also apply these four methods to a real GWAS of non-small cell lung cancer (NSCLC) in Han Chinese population [ABSTRACT FROM AUTHOR]

Purpose: Platinum-based chemotherapy is the most common treatment for patients with advanced non-small cell lung cancer (NSCLC). Genetic polymorphisms in the base excision repair (BER) pathway are suspected to influence the response of patients to this type of therapy. In this study, we investigated whether nonsynonymous single nucleotide polymorphisms (SNPs) in the BER pathway were associated with the response, progression-free survival (PFS) and overall survival (OS) of NSCLC patients following platinum-based chemotherapy. Methods: We used TaqMan to genotype four SNPs ( APE1 Asp148Glu, PARP1 Va1762Ala, XRCC1 Arg194Trp and XRCC1 Arg399Gln) in 147 patients with advanced NSCLC who had undergone routine platinum-based chemotherapy. Results: Logistic regression analysis showed that subjects with the XRCC1-399 A allele had a significantly better response to platinum-based chemotherapy than those with the XRCC1-399 GG genotype (AA/AG vs. GG: adjusted OR = 2.35, 95 % CI = 1.11-5.00). Furthermore, multivariate Cox proportional hazard regression analysis showed that the PARP1-762 CC genotype was a significantly unfavorable prognostic factor for PFS (CC vs. CT/TT: adjusted HR = 1.90, 95 % CI = 1.02-3.52). In contrast, the APE1-148 GG genotype was a significantly protective prognostic factor for OS (GG vs. TT: adjusted HR = 0.33, 95 % CI = 0.12-0.92). Conclusions: We found that XRCC1 Arg399Gln, PARP1 Va1762Ala and APE1 Asp148Glu SNPs in the BER pathway may influence the prognosis of advanced NSCLC patients following platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Occupational exposure to endotoxin is associated with decrements in pulmonary function, but how much variation in this association is explained by genetic variants is not well understood. Objective: We aimed to identify single nucleotide polymorphisms (SNPs) that are associated with the rate of forced expiratory volume in one second (FEV1) decline by a large scale genetic association study in newly-hired healthy young female cotton textile workers. Methods: DNA samples were genotyped using the Illumina Human CVD BeadChip. Change rate in FEV1 was modeled as a function of each SNP genotype in linear regression model with covariate adjustment. We controlled the type 1 error in study-wide level by permutation method. The false discovery rate (FDR) and the family-wise error rate (FWER) were set to be 0.10 and 0.15 respectively. Results: Two SNPs were found to be significant (P<6.29×10−5), including rs1910047 (P = 3.07×10−5, FDR = 0.0778) and rs9469089 (P = 6.19×10−5, FDR = 0.0967), as well as other eight suggestive (P<5×10−4) associated SNPs. Gene-gene and gene-environment interactions were also observed, such as rs1910047 and rs1049970 (P = 0.0418, FDR = 0.0895); rs9469089 and age (P = 0.0161, FDR = 0.0264). Genetic risk score analysis showed that the more risk loci the subjects carried, the larger the rate of FEV1 decline occurred (Ptrend = 3.01×10−18). However, the association was different among age subgroups (P = 7.11×10−6) and endotoxin subgroups (P = 1.08×10−2). Functional network analysis illustrates potential biological connections of all interacted genes. Conclusions: Genetic variants together with environmental factors interact to affect the rate of FEV1 decline in cotton textile workers. [ABSTRACT FROM AUTHOR]

Genetic variants may influence miRNA–mRNA interaction through modulate binding affinity, creating or destroying miRNA-binding sites. Twenty-four single nucleotide polymorphisms (SNPs) that were predicted to affect the binding affinity of breast cancer-related miRNAs to 3′-untranslated regions (UTR) of known genes were genotyped in 878 breast cancer cases and 900 controls in Chinese women. Three promising SNPs (rs10494836, rs10857748 and rs7963551) were further validated in additional 914 breast cancer cases and 967 controls. The variant allele (C) of rs7963551 at 3′-UTR of RAD52 showed a consistently reduced breast cancer risk in two stages with a combined odds ratio (OR) of 0.84 [95% confidence interval (CI) = 0.75–0.95], which was more prominent among women with early age at first live birth (OR = 0.71, 95% CI = 0.58–0.87). A significant interaction was observed between rs7963551 and age at first live birth on breast cancer risk (P for interaction = 0.04). Luciferase activity assay showed a higher expression level for rs7963551 C allele as compared with A allele (P = 5.19×10–3 for MCF-7 cell lines), which might be due to a reduced inhibition from a weakened binding capacity of miRNA to 3′-UTR of RAD52 harboring C allele. These findings indicate that rs7963551 located at hsa-let-7 binding site may alter expression of RAD52 through modulating miRNA–mRNA interaction and contribute to the development of breast cancer in Chinese women. [ABSTRACT FROM AUTHOR]

A genome-wide association study, conducted among women of European ancestry, has identified two single-nucleotide polymorphisms (SNPs) rs4415084 (T>C) and rs10941679 (A>G) at chromosome 5p12 were associated with risk of breast cancer, suggesting that genetic variants in this region may have a role in the development of breast cancer. To investigate the associations between SNPs at 5p12 and risk of breast cancer in the Chinese population, we conducted a fine-mapping in 5p12 using a haplotype-tagging SNP approach and genotyped these SNPs with a case-control study consisting of 878 cases and 900 controls. We found that the two risk SNPs reported in the European population were neither associated with breast cancer risk in our Chinese population, nor did the fine-mapping SNPs after controlling multiple comparison. [ABSTRACT FROM AUTHOR]

A single nucleotide polymorphism (SNP) rs999737 at 14q24.1 was identified as a susceptibility marker of breast cancer in a genome-wide association study of the European population, which was also confirmed by some of the following studies in populations of European descent. However, rs999737 is very rare or nonpolymorphic in non-Europeans including Chinese, and the role of other genetic variants at 14q24.1 has not been evaluated in populations of non-European descent. In this study, we first selected 21 common tagging SNPs (minor allele frequency [MAF] >0.05 in the Chinese population) by searching the Hapmap database, covering a linage disequilibrium region of more than 70 Kb at 14q24.1, and then conducted a two-stage study (stage I: 878 cases and 900 controls; stage II: 914 cases and 967 controls) to investigate the associations between these tagging SNPs and risk of breast cancer in a Chinese population. In stage I, two SNPs (rs2842346 and rs17828907) were identified to be significantly associated with breast cancer risk ( p=0.030 and 0.027 for genotype distributions, respectively). However, no significant associations were found between these two SNPs and breast cancer risk in either stage II or the combined dataset. These findings suggest that common variants at 14q24.1 might not be associated with the risk of breast cancer in the Chinese population, which will need the replication in additional larger studies. [ABSTRACT FROM AUTHOR]

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) on chromosome 6p21.1 and 6p22.3 as type 2 diabetes (T2D) susceptibility loci in the European and Japanese populations. However, these SNPs have not been well evaluated in Chinese population. Here, we performed a case-control study with 2925 T2D cases and 3281 controls in a Chinese population. We used TaqMan OpenArray and Sequenom MassARRAY to genotype the four SNPs (rs4712523, rs7756992, rs4712524 and rs6931514) in CDKAL1 (cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1) at 6p22.3 and one SNP (rs9472138) near vascular endothelial growth factor A (VEGFA) at 6p21.1. All the five SNPs were significantly associated with T2D risk with overall effects (odds ratio, OR) from 1.19 to 1.29 in the additive genetic model (rs6931514: OR=1.29, 95% confidence intervals (95% CI)=1.19-1.39, P=5.6 × 10−10; rs7756992: OR=1.23, 95% CI=1.15-1.32, P=1.2 × 10−8; rs4712523: OR=1.25, 95% CI=1.15-1.35, P=3.8 × 10−8; rs4712524: OR=1.24, 95% CI=1.15-1.35, P=6.8 × 10−8; rs9472138: OR=1.19, 95% CI=1.05-1.34, P=006). Conditional analysis identified two independent signals (rs6931514 at 6p22.3 and rs9472138 at 6p21.1) that were significantly associated with T2D. Compared with the wild homozygote of rs6931514 and rs9472138, subjects with variant alleles of the two SNPs had increased risk for T2D susceptibility in a dose-response manner (Ptrend=7.4 × 10−12). Our findings indicated that genetic variants of CDKAL1 and VEGFA on chromosome 6 may contribute to T2D risk in Chinese population, especially for rs9472138 at 6p21.1 identified for the first time to significantly increase the T2D risk in Chinese individuals. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies (GWAS) have identified several breast cancer susceptibility loci, and one genetic variant, rs11249433, at 1p11.2 was reported to be associated with breast cancer in European populations. To explore the genetic variants in this region associated with breast cancer in Chinese women, we conducted a two-stage finemapping study with a total of 1792 breast cancer cases and 1867 controls. Methodology/Principal Findings: Seven single nucleotide polymorphisms (SNPs) including rs11249433 in a 277 kb region at 1p11.2 were selected and genotyping was performed by using TaqManH OpenArrayTM Genotyping System for stage 1 samples (878 cases and 900 controls). In stage 2 (914 cases and 967 controls), three SNPs (rs2580520, rs4844616 and rs11249433) were further selected and genotyped for validation. The results showed that one SNP (rs2580520) located at a predicted enhancer region of SRGAP2 was consistently associated with a significantly increased risk of breast cancer in a recessive genetic model [Odds Ratio (OR) = 1.66, 95% confidence interval (CI) = 1.16-2.36 for stage 2 samples; OR = 1.51, 95% CI = 1.16-1.97 for combined samples, respectively]. However, no significant association was observed between rs11249433 and breast cancer risk in this Chinese population (dominant genetic model in combined samples: OR = 1.20, 95% CI = 0.92-1.57). Conclusions/Significance: Genotypes of rs2580520 at 1p11.2 suggest that Chinese women may have different breast cancer susceptibility loci, which may contribute to the development of breast cancer in this population. [ABSTRACT FROM AUTHOR]

Three genome-wide association studies (GWAS) have been conducted on the genetic susceptibility of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), two of which consistently identified tagging single nucleotide polymorphisms (SNPs) around HLA-DQ/DR. In contrast, large multi-centre association studies between HBV genotype, mutations and the risk of HCC are relatively rare, and their interactions with host variants are even less. We performed a multi-centre study of 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers as controls to evaluate the effects of HBV genotype, mutations, GWAS-identified HLA-DQ/DR SNPs (rs9272105 and rs9275319) and their interactions on HCC risk. We found HBV genotype C was more frequent in HBV-related HCC. And 11 HBV hotspot mutations were independently and significantly associated with HCC risk. We also detected significant interactions of rs9272105 with both the HBV genotype and mutations. Through stepwise regression analysis, HBV genotype, the 11 mutations, HLA-DQ/DR SNPs, and the interaction of rs9272105 with mutation A1752G were all entered into the HCC prediction model, and the area under the curve for the panel including the HLA-DQ/DR SNPs, HBV genotype and mutations was 0.840. The HBV genotype, the mutations and the HLA-DQ/DR SNPs may serve as biomarkers for the surveillance of HBV persistent carriers. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapy has been shown to improve the survival of advanced non-small cell lung cancer (NSCLC) patients; the platinum-induced toxicity severely impedes the success of chemotherapy. Genetic variations, such as single nucleotide polymorphisms (SNPs), may contribute to patients' responses to the platinum-based chemotherapy. To identify SNPs that modify the risk of hepatotoxicity in NSCLC patients receiving platinum-based chemotherapy, we performed a genome-wide association scan in 334 subjects followed by a replication study among 375 subjects. Consistent associations with platinum-induced hepatotoxicity risk was identified for SNP rs2838566 located at 21q22.3, as the minor A allele could significantly increase the risk of liver injury (OR = 3.78, 95%CI = 1.99-7.19, P = 4.90 × 10−5 for GWAS scan, OR = 1.89, 95%CI = 1.03-3.46, P = 0.039 for replication, and OR = 2.56, 95%CI = 1.65-3.95, P = 2.55 × 10−5 for pooled population). These results suggested that genetic variants at 21q22.3 may contribute to the susceptibility of platinum-induced hepatotoxicity in NSCLC patients. [ABSTRACT FROM AUTHOR]

Tobacco smoke is the major environmental risk factor underlying lung carcinogenesis. However, approximately one-tenth smokers develop lung cancer in their lifetime indicating there is significant individual variation in susceptibility to lung cancer. And, the reasons for this are largely unknown. In particular, the genetic variants discovered in genome-wide association studies (GWAS) account for only a small fraction of the phenotypic variations for lung cancer, and gene-environment interactions are thought to explain the missing fraction of disease heritability. The ability to identify smokers at high risk of developing cancer has substantial preventive implications. Thus, we undertook a gene-smoking interaction analysis in a GWAS of lung cancer in Han Chinese population using a two-phase designed case-control study. In the discovery phase, we evaluated all pair-wise (591,370) gene-smoking interactions in 5,408 subjects (2,331 cases and 3,077 controls) using a logistic regression model with covariate adjustment. In the replication phase, promising interactions were validated in an independent population of 3,023 subjects (1,534 cases and 1,489 controls). We identified interactions between two single nucleotide polymorphisms (SNPs) and smoking. The interaction p values are 6.73 × 10-6 and 3.84 × 10-6 for rs1316298 and rs4589502, respectively, in the combined dataset from the two phases. An antagonistic interaction (rs1316298-smoking) and a synergetic interaction (rs4589502-smoking) were observed. The two interactions identified in our study may help explain some of the missing heritability in lung cancer susceptibility and present strong evidence for further study of these gene-smoking interactions, which are benefit to intensive screening and smoking cessation interventions. [ABSTRACT FROM AUTHOR]

Introduction: Recently, several genome-wide association studies (GWAS) have identified novel single nucleotide polymorphisms (SNPs) associated with breast cancer risk. However, most of the studies were conducted among Caucasians and only one from Chinese.Methods: In the current study, we first tested whether 15 SNPs identified by previous GWAS were also breast cancer marker SNPs in this Chinese population. Then, we grouped the marker SNPs, and modeled them with clinical risk factors, to see the usage of these factors in breast cancer risk assessment. Two methods (risk factors counting and odds ratio (OR) weighted risk scoring) were used to evaluate the cumulative effects of the five significant SNPs and two clinical risk factors (age at menarche and age at first live birth).Results: Five SNPs located at 2q35, 3p24, 6q22, 6q25 and 10q26 were consistently associated with breast cancer risk in both testing set (878 cases and 900 controls) and validation set (914 cases and 967 controls) samples. Overall, all of the five SNPs contributed to breast cancer susceptibility in a dominant genetic model (2q35, rs13387042: adjusted OR = 1.26, P = 0.006; 3q24.1, rs2307032: adjusted OR = 1.24, P = 0.005; 6q22.33, rs2180341: adjusted OR = 1.22, P = 0.006; 6q25.1, rs2046210: adjusted OR = 1.51, P = 2.40 × 10-8; 10q26.13, rs2981582: adjusted OR = 1.31, P = 1.96 × 10-4). Risk score analyses (area under the curve (AUC): 0.649, 95% confidence interval (CI): 0.631 to 0.667; sensitivity = 62.60%, specificity = 57.05%) presented better discrimination than that by risk factors counting (AUC: 0.637, 95% CI: 0.619 to 0.655; sensitivity = 62.16%, specificity = 60.03%) (P < 0.0001). Absolute risk was then calculated by the modified Gail model and an AUC of 0.658 (95% CI = 0.640 to 0.676) (sensitivity = 61.98%, specificity = 60.26%) was obtained for the combination of five marker SNPs, age at menarche and age at first live birth.Conclusions: This study shows that five GWAS identified variants were also consistently validated in this Chinese population and combining these genetic variants with other risk factors can improve the risk predictive ability of breast cancer. However, more breast cancer associated risk variants should be incorporated to optimize the risk assessment. [ABSTRACT FROM AUTHOR]

CpG-SNPs in gene promoter regions are proposed to be associated with multiple diseases. To date, few studies have focused on the associations between CpG-SNPs in miRNA promoters and the risk of breast cancer. In this study, 138 miRNAs differentially expressed between breast cancer and non-cancer tissues (fold change >2, P  < 0.05) were identified using The Cancer Genome Atlas (TCGA) Research database. In total, 13 SNPs were selected in the promoters of the miRNAs and were evaluated in a case-control study of Chinese women including 1486 cases and 1519 controls. After multivariate logistic regression analysis, we found that three CpG-SNPs: rs1190983, rs155247, and rs62382272, were significantly associated with breast-cancer susceptibility in the population (Additive model: rs1190983: adjusted OR = 0.88, 95% CI: 0.79–0.99, P  = 0.034; rs155247: adjusted OR = 0.83, 95% CI: 0.74–0.93, P  = 0.002; rs62382272: adjusted OR = 1.24, 95% CI: 1.04–1.47, P  = 0.016). eQTL analysis showed that these three SNPs were correlated with the expression of the related miRNAs in TCGA breast cancer tissues ( P  = 0.006,0.009,0.001 for rs1190983, rs155247, and rs62382272). Furthermore, rs1190983 was found to be associated with CpG site (cg20488673) methylation (meQTL) ( P  = 0.004), which was in turn correlated with miR-342 expression ( P  = 0.016). These findings indicated that the three CpG-SNPs in the promoters of miRNAs were likely to possess important biological functions to breast cancer in the Han Chinese population. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) is believed to be both the source and target of reactive oxygen species (ROS), and mtDNA genetic alterations have been reported to be associated with molecular defects in the oxidative phosphorylation (OXPHOS) system. In order to investigate the potentially susceptible mtDNA genetic variants to oligoasthenospermia, we conducted a two-stage study in 921 idiopathic infertile men with oligoasthenospermia and 766 healthy controls using comprehensive molecular analysis. In the screen stage, we used next generation sequencing (NGS) in 233 cases and 233 controls to screen oligoasthenospermia susceptible mitochondrial genetic variants. In total, seven variants (C5601T, T12338C, A12361G, G13928C, A15235G, C16179T and G16291A) were screened to be potentially associated with idiopathic oligoasthenospermia. In the validation stage, we replicated these variants in 688 cases and 533 healthy controls using SNPscan. Our results demonstrated that the genetic alteration of C16179T was associated with idiopathic male infertility (odds ratio (OR) 3.10, 95% CI 1.41–6.79) ( p = 3.10 × 10 − 3 ). To elucidate the exact role of the genetic variants in spermatogenesis, two main sperm parameters (sperm count and motility) were taken into account. We found that C16179T was associated with both low sperm count and motility, with ORs of 4.18 (95% CI 1.86–9.40) ( p = 1.90 × 10 − 4 ) and 3.17 (95% CI 1.40–7.16) ( p = 3.50 × 10 − 3 ), respectively. Additionally, A12361G was found to be associated with low sperm count, with an OR of 3.30 (95% CI 1.36–8.04) ( p = 5.50 × 10 − 3 ). These results indicated that C16179T influenced both the process of spermatogenesis and sperm motility, while A12361G may just only participate in the process of spermatogenesis. Further investigation in larger populations and functional characterizations are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Exposure to particulate matter 2.5 (PM 2.5 ) may result in DNA damage. Histone variant H2AX phosphorylation plays a central role in the response to damaged chromatin. In the current study, we investigated whether H2AX gene polymorphisms account for PM 2.5 -modulated DNA damage levels. A total of 307 healthy urban residents were collected from three cities in southern, central, and northern China, Zhuhai, Wuhan, and Tianjin, respectively. The dust mass concentrations of PM 2.5 were detected by Gilian 5000 pumps, and the DNA damage levels were measured using comet assay. Seven potentially functional single nucleotide polymorphisms (SNPs) of H2AX gene were selected and genotyped by Illumina Infinium ® BeadChip. We found that three SNPs (rs10790283 G > A, rs604714 C > A and rs7759 A > G) were significantly associated with DNA damage levels (adjusted P = 0.002, 0.018 and 0.027, respectively). Significant interactions ( P < 0.05) were observed between certain genetic polymorphisms and PM 2.5 -modulated DNA damage levels. These results suggested that genetic variations of H2AX might be associated with the DNA damage levels in urban residents with different exposure to PM 2.5 . Further studies with large sample size in independent populations merit validating these findings. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) in populations of European ancestry have identified nine single nuclear polymorphisms (SNP) on chromosome 11 related to type 2 diabetes (T2D) susceptibility. Herein, we further evaluate the association of these SNPs and T2D in a Chinese Han population. We performed a case-control study of 2925 T2D cases and 3281 controls to evaluate the association of five SNPs of KCNJ11 , MTNR1B , CENTD2 and LOC387761 and T2D in addition to the previously reported four SNPs of KCNQ1 . Multiple logistic regression was used to evaluate SNP's effect by adjustment for confounding factor age, sex and BMI. In the first stage, SNPs rs1552224 at CENTD2 were significantly associated with T2D and the association was statistically significant in the whole study population (P = 0.001) although it was not replicated in the second stage. rs1552224 and rs2237897 of KCNQ1 showed significant joint effect on T2D and there was a significant decreased risk of T2D with the number increase of risk alleles (P for trend = 3.81 × 10 −17 ). Compared to those without carrying any risk allele, individuals carrying one, two, and three or four risk alleles had a 30.7%, 44.8% and 62.0% decreased risk for developing T2D, respectively. Our finding suggests that genetic variant rs1552224 of CENTD2 on chromosome 11 contributes to an independent effect as well as joint cumulative effect with rs2237897 of KCNQ1 on the risk of T2D in Chinese Han population, and further functional research would be warranted. [ABSTRACT FROM AUTHOR]

Objective The aim of this investigation was to identify pathways involved in pneumoconiosis susceptibility, clarify their potential mechanisms, and generate SNP-to-gene to pathway hypotheses using an analytical pathway-based approach. Methods The identify candidate causal SNPs and pathways (ICSNPathway) was used to perform pathway analysis of a GWAS dataset for pneumoconiosis, which, after quality control filtering, harbored genotypes of 710,999 SNPs in 202 pneumoconiosis cases and 198 exposed controls. The first stage involved the pre-selection of candidate SNPs by linkage disequilibrium analysis and functional annotation of the most significant SNPs; the second stage involved annotation of biological mechanisms for the selected candidate SNPs using improved-gene set enrichment analysis. Results ICSNPathway analysis identified 18 candidate SNPs, involving 13 genes and 30 candidate pathways and revealed 13 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was that rs8120 and rs2292151 alters the role of TICAM1 , a gene involved in various pathways and processes, including positive regulation of tumor necrosis factor (TNF) production, innate immune response-activating signal transduction, positive regulation of the innate immune response, and the biosynthesis of type I interferon (0.001 < p < 0.008; 0.001< false discovery rate (FDR) <0.035). The second strongest mechanism was that rs2230656 modulates HIST3H3 to affect its role in chromatin assembly processes ( p < 0.001; FDR <0.001). The third mechanism was that rs11592462 modulates CDH23 , which regulates organization of the inner ear stereocilia, auditory receptor cell morphogenesis, ear morphogenesis, and cellular homeostasis (0.001 < p < 0.006; 0.001 < FDR < 0.044). Of 13 candidate genes, TICAM1 , HIST3H3 , CA1 , CA3 , PTPRZ1 , and IL27RA are associated with fibrosis. Some of the 30 candidate pathways, which include positive regulation of TNF production, innate immune response-activating signal transduction, and regulation of innate immune response, may be associated with susceptibility to pneumoconiosis. Other candidate genes and pathways were novel or lacking fibrosis-related research. Conclusion By applying ICSNPathway analysis to the pneumoconiosis GWAS data, we identified candidate SNPs, genes such as TICAM1 and HIST3H3, and pathways involved in the positive regulation of TNF production that may contribute to pneumoconiosis susceptibility. Further analyses are needed to validate the results. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Human leukocyte antigens (HLA) play an important role in presenting virus antigens to immune cells that are responsible for the clearance of virus-infected cells and tumor cells. Herein, we evaluated whether genetic variants of HLA-DP and HLA-DQ are associated with cervical cancer risk. Methods: We genotyped four single nucleotide polymorphisms (SNPs) in HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs2856718 and rs7453920) in a two-stage case–control study with a total of 2317 cervical cancer cases and 2109 cancer-free controls using TaqMan allelic discrimination assay. Results: We found consistently significant associations of HLA-DP rs3077 and rs9277535 with increased risks of cervical cancer (dominant genetic model: adjusted OR=1.51, 95% CI=1.32–1.71 for rs3077; adjusted OR=1.29, 95% CI=1.12–1.49 for rs9277535). When combining the effects of HLA-DP rs3077 and rs9277535, subjects carrying “≥1” variant alleles had a 1.55-fold increased risk of cervical cancer (95% CI=1.32–1.81), compared with those carrying “0” variant allele. And cervical cancer risk significantly increased with the increasing number of variant alleles of the two SNPs in a dose-dependent manner (P for trend=4.33×10−10). However, there were no significant associations for HLA-DQ rs2856718 and rs7453920 in our population. Conclusions: These findings indicate that HLA-DP rs3077 and rs9277535 were candidate susceptibility markers for cervical cancer in Chinese females. Further validation studies with different ethnic background, biological function analyses and especially HPV typing together were needed. [Copyright &y& Elsevier]

Summary: Background: A recent genome-wide association study (GWAS) focused on esophageal squamous cell carcinoma (ESCC) has identified several susceptible regions (5q11, 21q22, 6p21 10q23, and 12q24) in Chinese population. We hypothesized that single nucleotide polymorphisms (SNPs) identified in these regions for ESCC were also associated with the risk of head and neck cancer (HNC) which share similar risk factors with ESCC. Methods: To test this hypothesis, we genotyped three SNPs (rs2274223, rs2014300 and rs10484761) in a case–control study with 503 HNC cases and 900 cancer-free controls in a Chinese population. Results: We found that rs2274223 was associated with a significantly increased risk of HNC in our population [GG vs. AA: adjusted odds ratio (OR)=1.86, 95% confidence interval (CI)=1.09–3.16; GG vs. (AG/AA): adjusted OR=1.85, 95% CI=1.09–3.12], and the effect appeared to be more prominent among drinkers (P =0.024) and patients with oral cavity cancer (P =0.019). In contrast, rs2014300 and rs10484761 variant were not observed any significantly association with risk of HNC. Conclusions: These results indicate that rs2274223 may be a marker SNP for HNC susceptibility in Chinese population. [ABSTRACT FROM AUTHOR]

• An improved RF method was proposed to better identify key risk factors in GWAS data. • A total of 24 independent SNVs were identified to be associated with DNA damage levels. • The potential biological mechanism of 24 SNVs in influencing DNA damage levels was explored by mediation analysis and functional annotation analysis. Recent studies have found multiple single nucleotide variants (SNVs) associated with DNA damage. However, previous association analysis may ignore the potential interaction effects between SNVs. Therefore, we used an improved random forest (RF) analysis to identify the SNVs related to personal DNA damage in exon-focused genome-wide association study (GWAS). A total of 301 subjects from three independent centers (Zhuhai, Wuhan, and Tianjin) were retained for analysis. An improved RF procedure was used to systematically screen key SNVs associated with DNA damage. Furthermore, we used genetic risk score (GRS) and mediation analysis to investigate the integrative effect and potential mechanism of these genetic variants on DNA damage. Besides, gene set enrichment analysis was conducted to identify the pathways enriched by key SNVs using the Data-driven Expression Prioritized Integration for Complex Traits (DEPICT). Finally, a set of 24 SNVs with the lowest mean square errors (MSE) were identified by improved RF analysis. Both weighted and unweighted GRSs were associated with increased DNA damage levels (P weight < 0.001 and P unweight < 0.001). Gene set enrichment analysis indicated that these loci were significantly enriched in several biological features associated with DNA damage. These findings suggested the role of SNVs in modifying DNA damage levels. It may be convincing that this improved RF analysis can effectively identify SNVs associated with DNA damage levels. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between genetic variants in Ser-Arg (SR) protein–coding genes and the susceptibility of nonobstructive azoospermia (NOA) in Chinese men. Design: Case-control study. Setting: State Key Laboratory of Reproductive Medicine in Nanjing Medical University conducted the genotyping and examined the expression levels of genes. Patient(s): The study included 962 NOA patients and 1,931 control subjects. Intervention(s): None. Main Outcome Measure(s): Genotyping of 16 single-nucleotide polymorphisms (SNPs) of eight “canonic” SR protein–coding genes were performed with the use of the Illumina Infinium Beadchip platform. Odds ratios were calculated by logistic regression analysis in the additive model. Expression levels were measured by quantitative reverse-transcription polymerase chain reaction. Result(s): Rs17431717 near SFRS9 and rs12046213 near SFRS4 were significantly associated with a decreased risk of NOA, whereas rs10849753 near SFRS9 and rs6103330 in SFRS6 were associated with an increased risk of NOA. Of the two SNPs in SFRS9, only rs17431717 remained significant after conditioning on another. Combined analysis of three promising SNPs (rs17431717, rs12046213, and rs6103330) showed that compared with individuals with “0–2” risk alleles, those carrying “3,” “4,” and “≥5” risk alleles had 1.22-, 1.38-, and 1.90-fold increased risk of NOA, respectively. Conclusion(s): Polymorphisms in SR protein–coding genes may contribute to the risk of NOA in Chinese men. The findings of this study can help us to further understand the etiology of spermatogenic impairment, and they provide more evidence for the role of splicing activity in human spermatogenesis. [ABSTRACT FROM AUTHOR]