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Objectives: The polymorphic major histocompatibility complex (MHC) plays a vital role in the immune system and drives predisposition to multiple cancers. A number of lung cancer-related genetic variants in the MHC have been identified in recent genome-wide association studies; however, the causal variants remain unclear., Materials and Methods: In the present study, we conducted a large-scale fine-mapping study of lung cancer in the MHC region of 13,945 unrelated Asian individuals to search for potential causal variants. We used the recently constructed Pan-Asian panel as the reference and imputed eight HLA genes (HLA-A, HLC-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) using SNP2HLA software., Results: We identified one single nucleotide polymorphism, rs12333226 (OR=1.41, P=3.97×10 -7 ), five HLA amino acid polymorphisms in HLA-DRB1 (OR=0.89, P=7.51×10 -6 -8.57×10 -6 ), and one two-digit classic HLA allele HLA-A*11 (OR=0.87, P=9.68×10 -6 ) that were strongly associated with the risk of lung cancer. Rs12333226 was an expression quantitative trait locus of HLA-A and HLA-H in circulating monocytes, and exerted effect on lung cancer risk especially in the younger. HLA-DRβ1 positions 10, 16, and 25 drove the effect of one reported SNP rs2395185. The peptide position analysis identified additional lung cancer susceptibility amino acid positions, including HLA-DRβ1 position 30 and 11 (P omnibus =6.11×10 -5 and 6.91×10 -5 ), HLA-DQa1 47 and 76 (P omnibus =3.96×10 -4 and 1.41×10 -2 ) and HLA-A 152 (P omnibus =4.86×10 -4 ). Most of the peptide positions were located in the peptide-binding grooves and seemed to affect antigen presentation. All the existing and novel variants explained approximately 2.37% of the phenotypic variances, while 21.10% was attributed to the variants identified in this study., Conclusion: We identified seven novel bi-allelic variants and five polymorphic amino acid positions in HLA-DRβ1, HLA-DQα1, and HLA-A that confer a risk of lung cancer. This finding provides evidence for the substantial contributions of HLA class I and II molecules to lung cancer susceptibility., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background. Interleukin 1 receptor associated kinases (IRAKs) play a central role in TLR signaling pathway. Scarce literature has investigated the association of potential functional genetic variants of IRAKs with Hepatitis B Virus- (HBV-) related hepatocellular carcinoma (HCC). Methods. A case-control study with 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers was conducted to evaluate the effects of common missense variants of IRAK family members on HCC. Proliferation assays and real-time polymerase chain reactions were carried out to evaluate the functions. Multivariable adjusted logistic regression was adopted to estimate effect size and identify risk factors. Results. Association analysis indicated that rs4251545 A allele of IRAK4 (p.Ala428Thr) was positively associated with HBV-related HCC risk (OR = 1.30, 95% CI: 1.09–1.54, P=0.003). Functional annotation indicated that rs4251545 reduced its own expression in liver (P=0.031). Further molecular functional analysis detected that rs4251545 increased the proliferation rate of L02 cells (P<0.05). Meanwhile, rs4251545 reduced mRNA expressions of IL-6, IL-8, CXCL-1, and CXCL-2 in L02 cells (P<0.01). Conclusion. rs4251545 of IRAK4 (p.Ala428Thr) modified the susceptibility to HBV-related HCC via increased proliferation rate and reduced production of inflammatory cytokines and chemokines. Further well-designed experiments are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Background: Suppressor of cytokine signaling 3 (SOCS3) has been identified as an inhibitor of JAK/STAT pathway that plays a significant role in carcinogenesis. SOCS3 and JAK2 polymorphisms may influence the gene expression or function, contributing to the disease susceptibility; however, such effect has not been evaluated in head and neck squamous cell carcinoma (HNSCC).Methods: A case-control study was performed to test the associations of SOCS3 and JAK2 polymorphisms with risk of HNSCC in 576 cases and 1552 cancer-free controls from China. Seven potentially functional polymorphisms predicted by bioinformatics tools were genotyped using Infinium BeadChip platform. The association between genotypes and HNSCC risk was estimated by computing odds ratios (ORs) and 95% confidence intervals (CIs) in univariate and multivariate logistic regression models.Results: We found that rs2280148 located at 3'-untranslated region of SOCS3 was significantly associated with an increased risk of HNSCC (additive model: adjusted OR = 1.21, 95% CI = 1.03-1.43, P = 0.021). Moreover, rs8064821 located in the promoter region of SOCS3 was linked with a decreased risk of the cancer (additive model: adjusted OR = 0.83, 95% CI = 0.71-0.97, P = 0.022). Combined analysis of these variants by the number of risk alleles showed a significant locus-dosage effect on the risk of HNSCC (Ptrend = 0.006).Conclusions: We provided the first evidence that SOCS3 polymorphisms may influence the risk of HNSCC, which could be applied as novel biomarkers to identify individuals at high risk of the disease. [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]

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]

A recent genome-wide association study (GWAS) has identified a new subset of susceptibility loci of Tetralogy of Fallot (TOF), one form of cyanotic congenital heart disease (CHD), on chromosomes 10p11, 10p14, 12q24, 13q31, 15q13 and 16q12 in Europeans. In the current study, we conducted a case-control study in a Chinese population including 1,010 CHD cases [atrial septal defect (ASD), ventricular septal defect (VSD) and TOF] and 1,962 controls to evaluate the associations of these loci with risk of CHD. We found that rs2228638 in NRP1 on 10p11 was significantly increased the risk of TOF (OR = 1.52, 95% CI = 1.13–2.04, P = 0.006), but not in other subgroups including ASD and VSD. In addition, no significant associations were observed between the other loci and the risk of ASD, VSD or TOF. Our results suggested that the genetic variants on 10p11 may serve as candidate markers for TOF susceptibility in Chinese population. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related deaths worldwide. By now, genome-wide association studies (GWAS) have identified numerous loci associated with the risk of developing lung cancer. However, these loci account for only a small fraction of the familial lung cancer risk. We hypothesized that epistasis may contribute to the missing heritability. To test this hypothesis, we systematically evaluated the association of epistasis of genetic variants with risk of lung cancer in Han Chinese cohorts. We conducted a pairwise genetic interaction analysis of 591370 variants, using BOolean Operation-based Screening and Testing (BOOST), in an ongoing GWAS of lung cancer that includes 2331 cases and 3077 controls. Pairs of epistatic loci with PBOOST ≤ 1.00×10−6 were further evaluated by a logistic regression model (LRM) with covariate adjustment. Four promising epistatic pairs identified at the screening stage (PLRM ≤ 2.86×10−13) were validated in two replication cohorts: the first from Beijing (1534 cases and 1489 controls) and the second from Shenyang and Guangzhou (2512 cases and 2449 controls). Using this combined analysis, we identified an interaction between rs2562796 and rs16832404 at 2p32.2 that was significantly associated with the risk of developing lung cancer (PLRM = 1.03×10−13 in total 13 392 subjects). This study is the first investigation of epistasis for lung cancer on a genome-wide scale in Han Chinese. It addresses part of the missing heritability in lung cancer risk and provides novel insight into the multifactorial etiology of lung cancer. [ABSTRACT FROM PUBLISHER]

Genetic variants in human microRNA (miRNA) genes may alter mature miRNA processing and/or target selection, and likely contribute to cancer susceptibility and disease progression. Previous studies have suggested that miR-101 may play important roles in the development of cancer by regulating key tumor-associated genes. However, the role of single nucleotide polymorphisms (SNPs) of miR-101 in breast cancer susceptibility remains unclear. In this study, we genotyped 11 SNPs of the miR-101 genes (including miR-101-1 and miR-101-2) in a case-control study of 1064 breast cancer cases and 1073 cancer-free controls. The results revealed that rs462480 and rs1053872 in the flank regions of pre-miR-101-2 were significantly associated with increased risk of breast cancer (rs462480 AC/CC vs AA: adjusted OR = 1.182, 95% CI: 1.030–1.357, P = 0.017; rs1053872 CG/GG vs CC: adjusted OR = 1.179, 95% CI: 1.040–1.337, P = 0.010). However, the remaining 9 SNPs were not significantly associated with risk of breast cancer. Additionally, combined analysis of the two high-risk SNPs revealed that subjects carrying the variant genotypes of rs462480 and rs1053872 had increased risk of breast cancer in a dose-response manner (Ptrend = 0.002). Compared with individuals with “0–1” risk allele, those carrying “2–4” risk alleles had 1.29-fold risk of breast cancer. In conclusion, these findings suggested that the SNPs rs462480 and rs1053872 residing in miR-101-2 gene may have a solid impact on genetic susceptibility to breast cancer, which may improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Genetic variants at 5p15 have been associated with multiple cancers risk, suggesting pleiotropic effect on cancer. We hypothesized that genetic variants at 5p15 are important in the development of gastric cancer. To test this hypothesis, we evaluated the associations of genetic variants at 5p15 with gastric cancer based on our existing genome-wide association study (GWAS) data set of gastric cancer (1006 cases and 2273 controls), and replicated two promising loci in an independent case–control study with 1681 gastric cancer cases and 1705 controls in a Chinese population. We found that rs10052016 was consistently associated with gastric cancer risk in GWAS discovery stage (odds ratio [OR] = 0.69, 95% confidence interval [95% CI] = 0.55–0.87) and replication stage (OR = 0.80, 95% CI = 0.68–0.94). After combining these two studies, we found that the G allele of rs10052016 (at 132 kb upstream of TERT) was significantly associated with a decreased risk of gastric cancer (OR = 0.76, 95% CI = 0.67–0.87, P = 5.35 × 10–5). Moreover, the protective allele of rs10052016-G was also significantly associated with late onset of gastric cancer (P = 0.013). In summary, these findings indicate that genetic variants at 5p15 may contribute to gastric cancer susceptibility and may further advance our understanding of 5p15 locus in cancer development. [ABSTRACT FROM PUBLISHER]

STUDY QUESTION What are the genetic causes for the predisposition of certain Y chromosome haplogroups (Y-hgs) to spermatogenic impairment? SUMMARY ANSWER The AZFc(azoospermia factor c)/DAZ (deleted in azoospermia) duplications might underlie the susceptibility of Y-hg K* to spermatogenic impairment. WHAT IS KNOWN ALREADY The roles of Y chromosomal genetic background in spermatogenesis are controversial and vary among human populations. Individuals in predisposed Y-hgs may carry some genetic factors, which might be a potential genetic modifier for the Y-hg-specific susceptibility to spermatogenic impairment. STUDY DESIGN, SIZE, DURATION A total of 2444 individuals with azoospermia or oligozoospermia and 2456 healthy controls were recruited to this study from March 2004 and January 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a two-stage association study to investigate the risk and/or protective Y-hgs for spermatogenic impairment. In addition, the genetic causes for the predisposition of certain Y-hg to spermatogenic impairment were investigated. Deletion typing and DAZ gene copy number quantification were performed for individuals in predisposed Y-hgs. MAIN RESULTS AND THE ROLE OF CHANCE Y-hgs K* and O3e* showed significantly different distribution between cases and controls consistently in two-stage studies. Combined analyses identified significant predisposition to non-obstructive azoospermia in Y-hg K* [odds ratio (OR) 8.58; 95% confidence interval (CI) 3.31–22.28; P = 1.40 × 10−5], but a protecting effect in Y-hg O3e* (OR 0.64; 95% CI 0.53–0.78; P = 4.20 × 10−5). Based on the dynamic nature of the Y chromosome, we hypothesized that Y-hgs K* and O3e* may be accompanied by modifying genetic factors for their predisposing or protecting effects in spermatogenesis. Accordingly, we quantified the multi-copy DAZ gene, which has variable copy numbers between individuals and plays an important role in spermatogenesis. In combined analysis, we found that the over-dosage of DAZ was significantly more frequent in Y-hg K* than in O3e* (OR 4.79; 95% CI 1.67–13.70; P = 6 × 10−3). LIMITATIONS, REASONS FOR CAUTION Owing to the inconsistency of genetic background, it remains to be determined whether the results derived from Han Chinese populations are applicable to other ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study can advance the etiology of spermatogenic impairment, and also shed new light on Y chromosome evolution in human populations. Y-hg-specific genetic factors of modifying spermatogenic phenotypes deserve further investigation in larger and diverse populations. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by grants from National 973 Program (2009|CB941703, 2011CB944304 and 2012CB944600), National Natural Science Foundation of China (30930079, 81100461 and 31000552), Jiangsu Natural Science Foundation (BK2011774), Research Fund for the Doctoral Program of Higher Education of China (RFDP) (20113234120001), University Natural Science Research Project in Jiangsu Province (11KJB330001) and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). There were no competing interests. [ABSTRACT FROM PUBLISHER]

Cell cycle regulation, apoptosis, oxidative stress and inflammation response play critical roles in the development of smoking-induced lung cancer. However, it is still not well known whether their genetic variants are associated with lung cancer susceptibility. In this study, we performed imputation-based association analyses to investigate the influence of common genetic variants in these pathways and their interactions with smoking on lung cancer susceptibility. We first selected 24 042 unvalidated genetic variants in 798 genes from the imputed dataset of the previous lung cancer genome-wide association study in 2331 cases and 3077 controls, and then conducted additional two-stage validations in 4133 cases and 4522 controls. We found a genome-wide significant (P < 5.0 × 10–8) association for rs2282987 in CDK6 at 7q21.2 [odds ratio (OR) = 1.18, combined Padd = 2.27 × 10–9] and a consistent association for rs2706748 in SH3RF1 at 4q32.3 (OR = 1.17, combined Padd = 5.10 × 10–6). Interaction analyses showed that rs2282987 and rs2706748 interacted with both smoking status (Pinteraction were 1.04 × 10–2 and 3.03 × 10–2, respectively) and smoking history (Pinteraction were 1.21 × 10–2 and 5.21 × 10–2, respectively) to contribute to lung cancer susceptibility in subjects aged 51–60 years. These results further underscore the contribution of genetic variants involved in pathways of cell cycle regulation and apoptosis to lung cancer susceptibility, and highlight gene–environment interactions in lung cancer etiology, especially in subjects aged 51–60 years. [ABSTRACT FROM AUTHOR]

Congenital heart malformation (CHM) is the most common form of congenital human birth anomaly and is the leading cause of infant mortality. Although some causative genes have been identified, little progress has been made in identifying genes in which low-penetrance susceptibility variants occur in the majority of sporadic CHM cases. To identify common genetic variants associated with sporadic non-syndromic CHM in Han Chinese populations, we performed a multistage genome-wide association study (GWAS) in a total of 4,225 CHM cases and 5,112 non-CHM controls. The GWAS stage included 945 cases and 1,246 controls and was followed by 2-stage validation with 2,160 cases and 3,866 controls. The combined analyses identified significant associations (P < 5.0 × 10−8) at 1p12 (rs2474937 near TBX15; odds ratio (OR) = 1.40; P = 8.44 × 10−10) and 4q31.1 (rs1531070 in MAML3; OR = 1.40; P = 4.99 × 10−12). These results extend current knowledge of genetic contributions to CHM in Han Chinese populations. [ABSTRACT FROM AUTHOR]

Background: A recent genome-wide association study (GWAS) has identified three new breast cancer susceptibility loci at 12p11, 12q24 and 21q21 in populations of European descent. However, because of the genetic heterogeneity, it is largely unknown for the role of these loci in the breast cancer susceptibility in the populations of non-European descent. Methodology/Principal Findings: Here, we genotyped three variants (rs10771399 at 12p11, rs1292011 at 12q24 and rs2823093 at 21q21) in an independent case–control study with a total of 1792 breast cancer cases and 1867 cancer-free controls in a Chinese population. We found that rs10771399 and rs1292011 were significantly associated with risk of breast cancer with per-allele odds ratios (ORs) of 0.85 (95% confidence interval (CI): 0.76–0.96; P = 0.010) and 0.84 (95% CI: 0.76–0.95; P = 4.50×10−3), respectively, which was consistent with those reported in populations of European descent. Similar effects were observed between ER/PR positive and negative breast cancer for both loci. However, we did not found significant association between rs2823093 and breast cancer risk (OR = 0.97, 95%CI = 0.76–1.24; P  = 0.795). Conclusions/Significance: Our results indicate that genetic variants at 12p11 and 12q24 may also play an important role in breast cancer development in Chinese women. [ABSTRACT FROM AUTHOR]

Germline mutations in genes that cause hereditary syndromes are highly predisposed to familial pancreatic cancer. However, genetic susceptibility to sporadic pancreatic cancer is largely uncovered. We conducted a two-stage association study on pancreatic cancer that included 981 cases and 1991 controls in the first stage followed by a second stage (2603 cases and 2877 controls). Using an approach based on candidate genes whose roles in pancreatic cancer have been well known, we identified two new susceptibility loci. rs11571836 located in the BRCA2 3′-untranslated region was significantly associated with lower expression of BRCA2 transcript and increased pancreatic cancer risk [odds ratio = 1.30, 95% confidence interval = 1.14–1.47, P = 7.64 × 10–5] in a recessive manner. rs12939944 located in the MAP2K4 intron was associated with decreased risk (odds ratio = 0.82, 95% confidence interval = 0.74–0.91, P = 0.0001) in a dominant manner. Our results demonstrate for the first time that common variants in BRCA2 and MAP2K4 are susceptibility to sporadic pancreatic cancer. [ABSTRACT FROM AUTHOR]

We conducted a genome-wide association study (GWAS) and a genome-wide gene-environment interaction analysis of esophageal squamous-cell carcinoma (ESCC) in 2,031 affected individuals (cases) and 2,044 controls with independent validation in 8,092 cases and 8,620 controls. We identified nine new ESCC susceptibility loci, of which seven, at chromosomes 4q23, 16q12.1, 17q21, 22q12, 3q27, 17p13 and 18p11, had a significant marginal effect (P = 1.78 × 10?39 to P = 2.49 × 10?11) and two of which, at 2q22 and 13q33, had a significant association only in the gene-alcohol drinking interaction (gene-environment interaction P (PG × E) = 4.39 × 10?11 and PG × E = 4.80 × 10?8, respectively). Variants at the 4q23 locus, which includes the ADH cluster, each had a significant interaction with alcohol drinking in their association with ESCC risk (PG × E = 2.54 × 10?7 to PG × E = 3.23 × 10?2). We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles. Our results underscore the direct genetic contribution to ESCC risk, as well as the genetic contribution to ESCC through interaction with alcohol consumption. [ABSTRACT FROM AUTHOR]

Abstract: MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF), play a pivotal role in the activties of tumor cells. A germline missense variant in exon 2 of the MET gene, N375S (rs33917957 A>G), may alter the binding affinity of MET for HGF and thus modify the risk of tumorigenesis. In this study, we performed a case-control study to assess the association between N375S and gastric cancer risk in 1,681 gastric cancer cases and 1,858 cancer-free controls. Logistic regression analysis was applied to estimate crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between genotypes and gastric cancer risk. We found that MET N375S variant genotypes (NS/SS) were associated with a significantly decreased risk of gastric cancer (OR = 0.78, 95% CI = 0.63-0.96, P = 0.021) compared with the wildtype homozygote (NN). The finding indicates that this germline variant in MET may decrease gastric cancer susceptibility in Han Chinese. [Copyright &y& Elsevier]

To find additional susceptibility loci for lung cancer, we tested promising associations from our previous genome-wide association study (GWAS) of lung cancer in the Chinese population in an extended validation sample size of 7,436 individuals with lung cancer (cases) and 7,483 controls. We found genome-wide significant (P < 5.0 × 10?8) evidence for three additional lung cancer susceptibility loci at 10p14 (rs1663689, close to GATA3, P = 2.84 × 10?10), 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60 × 10?9) and 20q13.2 (rs4809957 in CYP24A1, P = 1.20 × 10?8). We also found consistent associations for rs247008 at 5q31.1 (IL3-CSF2-P4HA2, P = 7.68 × 10?8) and rs9439519 at 1p36.32 (AJAP1-NPHP4, P = 3.65 × 10?6). Four of these loci showed evidence for interactions with smoking dose (P = 1.72 × 10?10, P = 5.07 × 10?3, P = 6.77 × 10?3 and P = 4.49 × 10?2 for rs2895680, rs4809957, rs247008 and rs9439519, respectively). These results advance our understanding of lung cancer susceptibility and highlight potential pathways that integrate genetic variants and smoking in the development of lung cancer. [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]

Pancreatic cancer has the lowest survival rate among human cancers, and there are no effective markers for its screening and early diagnosis. To identify genetic susceptibility markers for this cancer, we carried out a genome-wide association study on 981 individuals with pancreatic cancer (cases) and 1,991 cancer-free controls of Chinese descent using 666,141 autosomal SNPs. Promising associations were replicated in an additional 2,603 pancreatic cancer cases and 2,877 controls recruited from 25 hospitals in 16 provinces or cities in China. We identified five new susceptibility loci at chromosomes 21q21.3, 5p13.1, 21q22.3, 22q13.32 and 10q26.11 (P = 2.24 × 10?13 to P = 4.18 × 10?10) in addition to 13q22.1 previously reported in populations of European ancestry. These results advance our understanding of the development of pancreatic cancer and highlight potential targets for the prevention or treatment of this cancer. [ABSTRACT FROM AUTHOR]

Two recent genome-wide association studies reported significant associations of genetic variants at 1q22, 10q23 and 20p13 with gastric cancer (GC) risk in Chinese populations. However, these findings have not been confirmed in other independent studies. Here, we performed an independent case–control study in a Chinese population by genotyping three loci (rs4072037A>G at 1q22, rs2274223A>G at 10q23 and rs13042395C>T at 20p13) in 1681 GC cases and 1858 controls. We found that rs4072037 at 1q22 and rs2274223 at 10q23 were significantly associated with risk of GC with per allele odds ratio (OR) of 0.72 [95% confidence interval (CI): 0.63–0.81; P = 2.98 × 10−7] and 1.42 (95% CI: 1.27–1.58; P = 9.68 × 10−10), respectively. The association was more prominent for rs2274223 in female (OR = 1.86, 95% CI: 1.49–2.32) and gastric cardia adenocarcinoma (GCA) (OR = 1.71, 95% CI: 1.49–1.95). Furthermore, we combined the two single-nucleotide polymorphisms to evaluate the joint effect and found that the GC risk significantly increased with the number of risk allele increasing with a trend P value of 6.66 × 10−16, and individuals with four risk alleles had a 3.28-fold (95% CI: 1.75–6.13) risk of GC compared with those having no risk alleles. However, no significant association was detected between rs13042395 at 20p13 and GC risk (OR = 1.04, 95% CI: 0.94–1.15; P = 0.452). In conclusion, our results indicate that genetic variants at 1q22 and 10q23 but not 20p13 may serve as candidate markers for GC susceptibility in the Chinese population. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Inflammation induced by H.pylori colonization in the stomach is related to the development of gastric cancer and the genetic variations of the genes involved in the immune responses modify the host response to the infection. The aim of this study was to evaluate whether polymorphisms in the toll-like receptor 4 (TLR4) gene, a key regulator of both innate and adaptive immunity, were related to the susceptibility to gastric cancer in a Chinese population. Methods: Two variations in the 5′-flanking region of TLR4 (rs1927914 T > C and rs10759932 T > C) were genotyped by using the PCR-restriction fragment length polymorphism (RFLP) assay in a case-control study of 1,053 incident gastric cancer cases and 1,100 cancer-free controls in a Chinese population. Results: Individuals carrying the C allele of rs10759932 had a significantly reduced risk of gastric cancer (adjusted OR = 0.81; 95%CI = 0.67-0.96), compared with the wild-type homozygote (TT), and the protective effect was not significantly different among subgroups stratified by age, sex, smoking, drinking and H.pylori infection status (P for heterogeneity > 0.05). No significant association was observed between rs1927914 and gastric cancer risk in this study population. Conclusion: The T to C allele substitution of rs10759932 may play a protective role in gastric carcinogenesis in a Chinese population. Large studies with different ethnic populations are warranted to confirm these findings. [Copyright &y& Elsevier]

Abstract Chromosome 4q12 and 17q12 have been identified as two regions associated with susceptibility to cervical cancer in a genome-wide association study. To identify potential causal variants within these two regions, we conducted a case-control study including 1486 patients with cervical cancer and 1536 age-matched (±5 years) healthy controls. Based on RegulomeDB database, 12 potentially functional variants were selected and then genotyped by using Sequenom MassARRAY. Univariate and multivariate logistic regression models were used to evaluate the associations. We found that the G allele of rs8076131 and the A allele of rs12150079 in 17q12 region were significantly associated with increased risk of cervical cancer (adjusted OR = 1.15, 95% CI = 1.02–1.30, P = 0.02 for rs8076131; adjusted OR = 1.19, 95% CI = 1.03–1.36, P = 0.02 for rs12150079). Individuals with 3–4 risk alleles of these two variants had 24% higher odds of cervical cancer than those without the risk alleles (OR = 1.24, 95% CI = 1.07–1.44, P < 0.01). The stratified analysis showed that the associations of rs8076131 and rs12150079 with cervical cancer risk were statistically significant in subgroups of older menarche age (>16 years), more parities (≥2), nonsmokers, and having no family cancer history, but the test results for subgroup heterogeneity were not significant. The current study provides the evidence that rs8076131 and rs12150079 in 17q12 region may contribute to cervical cancer susceptibility in the Han Chinese population. Highlights • A case-control study was conducted to identify potential causal variants within GWAS-identified regions for cervical cancer. • Based on RegulomeDB, twelve putative variants were selected and genotyped. • Rs8076131 and rs12150079 within 17q12 may contribute to cervical cancer susceptibility. [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]

Background Alternative splicing is an important biological step during mRNA processing. Misregulation of alternative splicing can produce aberrant protein isoforms, thus contributing to cancer. We hypothesized that variants in 5 critical splicing factor-associated genes might play an important role in carcinogenesis of lung cancer. Materials and methods A case-control study including 1,341 non-small cell lung cancer (NSCLC) cases and 1,982 cancer-free controls were conducted to evaluate the associations of 16 tagging/functional polymorphisms in 5 splicing factor-associated genes with lung cancer risk. Results We found altogether 8 SNPs were associated with lung cancer risk with adjustment of age, gender, and smoking status after multiple corrections (FDR). Among these, six SNPs were related with SRSF7 (rs10197412, OR(95%CI) = 1.23(1.06–1.43), P for FDR = 0.018; rs12621103, OR(95%CI) = 1.25(1.08–1.46), P for FDR = 0.016; rs13024811, OR(95%CI) = 1.25(1.07–1.46), P for FDR = 0.016; rs2037875, OR(95%CI) = 1.23(1.06–1.42), P for FDR = 0.018; rs3134628, OR(95%CI) = 1.25(1.07–1.45), P for FDR = 0.016 and rs6715866, OR(95%CI) = 1.23(1.07–1.43), P for FDR = 0.016); one SNP was near PTBP2 (rs12566237: OR(95%CI) = 1.16(1.05–1.28), P for FDR = 0.016) and one SNP in HNRNPQ (rs16876385: OR(95%CI) = 1.17(1.04–1.32), P for FDR = 0.022). Conclusions Our findings indicated that genetic variants in these splicing-associated genes might modify individual susceptibility to lung cancer in Chinese population. Further large-scale well-formed population studies and functional researches are warranted to confirm our findings. [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]

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]

Objective: To investigate the associations between genetically cis-regulated gene expression levels and nonobstructive azoospermia (NOA) susceptibility.Design: Transcriptome-wide association study (TWAS).Setting: Medical university.Interventions: None.Main Outcome Measure(s): The cis-hg2 values for each gene were estimated with GCTA software. The effect sizes of cis-single-nucleotide polymorphisms (SNPs) on gene expression were measured using GEMMA software. Gene expression levels were entered into our existing NOA GWAS cohort using GEMMA software. The TWAS P-values were calculated using logistic regression models.Result(s): Expression levels of 1,296 cis-heritable genes were entered into our existing NOA GWAS data. The TWAS results identified two novel genes as statistically significantly associated with NOA susceptibility: PILRA and ZNF676. In addition, 6p21.32, previously reported in NOA GWAS, was further validated to be a susceptible region to NOA risk.Conclusion(s): Analysis with TWAS provides fruitful targets for follow-up functional studies. [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]