Is BRD7 associated with spermatogenesis impairment and male infertility in humans? A case-control study in a Han Chinese population.

BACKGROUND: Bromodomain-containing protein 7 (BRD7), a member of the bromodomain-containing protein family, plays important roles in chromatin modification and transcriptional regulation. A recent model of Brd7-knockout mice presented azoospermia and male infertility, implying the potential role of BRD7 in spermatogenic failure in humans. This case-control study aimed to explore the association of the BRD7 gene with spermatogenic efficiency and the risk of spermatogenic defects in humans. RESULTS: A total of six heterozygous variants were detected in the coding and splicing regions of the BRD7 gene in patients with azoospermia. For each of four rare variants predicted to potentially damage BRD7 function, we further identified these four variants in oligozoospermia and normozoospermia as well. However, no difference in the allele and genotype frequencies of rare variants were observed between cases with spermatogenic failure and controls with normozoospermia; the sperm products of variant carriers were similar to those of noncarriers. Moreover, similar distribution of the alleles, genotypes and haplotypes of seven tag single nucleotide polymorphisms (tagSNPs) was observed between the cases with azoospermia and oligozoospermia and controls with normozoospermia; associations of tagSNP-distinguished BRD7 alleles with sperm products were not identified. CONCLUSIONS: The lack of an association of BRD7-linked rare and common variants with spermatogenic failure implied a limited contribution of the BRD7 gene to spermatogenic efficiency and susceptibility to male infertility in humans.

RéSUMé: CONTEXTE: Le bromodomaine contenant la protéine 7 (BRD7), un membre de la famille du bromodomaine contenant des protéines, joue des rôles importants dans la modification de la chromatine et la régulation transcriptionnelle. Un modèle récent de souris Brd7-knockout présentait une azoospermie et une infertilité mâle, ce qui implique un rôle potentiel de BRD7 dans l'altération de la spermatogenèse chez l'homme. Cette étude cas-témoins visait à explorer l'association du gène BRD7 avec l'efficacité de la spermatogenèse et le risque d'altérations spermatogéniques chez l'homme. RéSULTATS: Un total de six variants hétérozygotes ont été détectés dans les régions de codage et d'épissage du gène BRD7 chez les patients présentant une azoospermie. Pour chacun des quatre variants rares prédits pour potentiellement endommager la fonction BRD7, nous avons en outre identifié ces quatre variants dans l'oligozoospermie et la normozoospermie. Cependant, nous n'avons observé aucune différence dans les fréquences d'allèle et de génotype des variants rares entre les cas avec altérations de la spermatogenèse et les témoins avec normozoospermie ; les produits du sperme des porteurs de variants étaient semblables à ceux des non-porteurs. Par ailleurs, on a observé une distribution semblable des allèles, des génotypes et des haplotypes de sept polymorphismes simples de nucléotide de balise (tagSNPs) entre les cas avec azoospermie ou oligozoospermie et les témoins normozoospermiques; aucune association n'a pas été identifiée entre les allèles BRD7 tagSNP-distingués et des produits du sperme. CONCLUSION: L'absence d'association des variants rares liés à BRD7 et des variants communs liés à BRD7 avec les altérations de la spermatogenèse implique une contribution limitée du gène BRD7 à l'efficacité spermatogénique et à la susceptibilité à l'infertilité masculine chez l'homme.

Grouping of genomic markers in populations with family structure.

BACKGROUND: Linkage and linkage disequilibrium (LD) between genome regions cause dependencies among genomic markers. Due to family stratification in populations with non-random mating in livestock or crop, the standard measures of population LD such as [Formula: see text] may be biased. Grouping of markers according to their interdependence needs to account for the actual population structure in order to allow proper inference in genome-based evaluations. RESULTS: Given a matrix reflecting the strength of association between markers, groups are built successively using a greedy algorithm; largest groups are built at first. As an option, a representative marker is selected for each group. We provide an implementation of the grouping approach as a new function to the R package hscovar. This package enables the calculation of the theoretical covariance between biallelic markers for half- or full-sib families and the derivation of representative markers. In case studies, we have shown that the number of groups comprising dependent markers was smaller and representative SNPs were spread more uniformly over the investigated chromosome region when the family stratification was respected compared to a population-LD approach. In a simulation study, we observed that sensitivity and specificity of a genome-based association study improved if selection of representative markers took family structure into account. CONCLUSIONS: Chromosome segments which frequently recombine in the underlying population can be identified from the matrix of pairwise dependence between markers. Representative markers can be exploited, for instance, for dimension reduction prior to a genome-based association study or the grouping structure itself can be employed in a grouped penalization approach.

The A/A Genotype of XPO1 rs4430924 Is Associated With Higher Risk of Antituberculosis Drug-Induced Hepatotoxicity in Chinese Patients.

Antituberculosis (anti-TB) drug-induced hepatotoxicity may be related to the excessive reactive oxygen species induced by hepatotoxic metabolites. Antioxidant activity involves the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The BTB domain and CNC homologue 1 (Bach1) may compete with Nrf2 for binding to transcriptional enhancers. Elimination of Bach1-mediated transcriptional repression depends on nuclear exporter exportin 1 (Xpo1). Thus, Xpo1 may indirectly affect antioxidant activity. The present study aimed to examine the role of tag single-nucleotide polymorphisms in XPO1 in Chinese anti-TB treatment patients. A 1:2 matched case-control study was conducted using 314 anti-TB drug-induced hepatotoxicity cases and 628 controls. After correcting for weight and hepatoprotectant use, conditional logistic regression analysis showed that patients carrying the AA genotype of rs4430924 in XPO1 were at higher risk of anti-TB drug-induced hepatotoxicity than those carrying the GG genotype based on the subgroup of probable cases (adjusted OR, 1.938; 95%CI, 1.035-3.628; P = .039), and marginally significant differences were also found under the recessive model (P = .048) and the additive model (P = .047). Based on this 1:2 matched case-control study, the AA genotype of rs4430924 in XPO1 may be associated with higher risk of anti-TB drug-induced hepatotoxicity in Chinese anti-TB treatment patients. Further studies in larger and more varied populations are required to validate this relationship.

Tagging SNPs in the HOTAIR gene are associated with bladder cancer risk in a Chinese population.

BACKGROUND: The HOX transcript antisense intergenic RNA (HOTAIR) is a well-known long noncoding RNA (lncRNA) that plays a critical role in biological processes in most cancers. However, the function of HOTAIR in bladder cancer remains largely unknown. In this study, we hypothesize that tag single nucleotide polymorphisms (tagSNPs) in HOTAIR are associated with bladder cancer (BCa) risk. METHODS: We performed a hospital-based case-control study of 1050 cases and 1407 controls to investigate the associations between tagSNPs and the risk of BCa in a Chinese population. RESULTS: We found that individuals with the rs874945 AG/AA genotype had a significantly increased risk of BCa compared with those carrying the GG genotype, with an odds ratio (OR) of 1.23 [95% confidence interval (CI) = 1.04-1.46, P = 0.014]. The subsequently stratified analyses showed that the increased risk was more pronounced in subgroups of older subjects (age > 60 years), never smokers and subjects without pack-years of smoking. Interactive analysis showed that there was no interaction effect between smoking status and rs874945. CONCLUSION: Our study showed that rs874945 in HOTAIR was associated with BCa risk in a Chinese population.

Low Variability and Stable Frequency of Common Haplotypes of the TP53 Gene Region in Colorectal Cancer Patients in a Slovak Population.

AIM: To test the association between common TP53 haplotypes and colorectal cancer (CRC) development. PATIENTS AND METHODS: A total of 277 CRC patients and 167 healthy volunteers were included in the study. Common TP53 haplotypes were estimated from eight single-nucleotide polymorphisms (SNPs) (rs1614984, rs77697176, rs12947788, rs1800372, rs2909430, rs1042522, rs17878362 and rs11652704). Stepwise haplotype trend regression showed the haplotype-regressor cccgaRDa as a possible predictive marker. RESULTS: The rare haplotype cccgaRDa was identified in 10 CRC cases and 3 controls. Although it is approximately twice as common in CRC (odds ratio (OR)=2.068; 95% confidence interval (CI)=0.471-9.069), the cccgaRDa haplotype frequency is low in the studied groups. Results of our study suggest that the common TP53 variability is relatively low (only 3 haplotypes occurred above 10%). CONCLUSION: The haplotype background of TP53 gene is relative stable and despite low haplotype-regressor cccgaRDa frequency it shows to be a possible predictive parameter for CRC development.

Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility.

BACKGROUND: Cancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatic analyses, The Cancer Genome Atlas (TCGA) project has identified panels of somatic mutations that contributed to the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these significantly mutated genes (SMGs) and lung cancer susceptibility. PATIENTS AND METHODS: We comprehensively evaluated 1655 tagged single nucleotide polymorphisms (SNPs) located in 127 SMGs identified by TCGA, and test their association with lung cancer risk in large-scale case-control study. Functional effect of the validated SNPs, gene mutation frequency and pathways were analyzed. RESULTS: We found 11 SNPs in 8 genes showed consistent association (P < 0.1) and 8 SNPs significantly associated with lung cancer risk (P < 0.05) in both discovery and validation phases. The most significant association was rs10412613 in PPP2R1A, with the minor G allele associated with a decreased risk of lung cancer [odds ratio = 0.91, 95% confidence interval (CI): 0.87-0.96, P = 2.3 × 10-4]. Cumulative analysis of risk score built as a weight sum of the 11 SNPs showed consistently elevated risk with increasing risk score (P for trend = 9.5 × 10-9). In stratified analyses, the association of PPP2R1A:rs10412613 and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The expression quantitative trait loci analysis indicated that rs10412613, rs10804682, rs635469 and rs6742399 genotypes significantly correlated with the expression of PPP2R1A, ATR, SETBP1 and ERBB4, respectively. From TCGA data, expression of the identified genes was significantly different in lung tumors compared with normal tissues, and the genes' highest mutation frequency was found in lung cancers. Integrative pathway analysis indicated the identified genes were mainly involved in AKT/NF-κB regulatory pathway suggesting the underlying biological processes. CONCLUSION: This study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.

Association of TagSNP in lncRNA HOTAIR with susceptibility to noise-induced hearing loss in a Chinese population.

BACKGROUND: Noise-induced hearing loss (NIHL) is a multifactorial disease, and dysregulation of oxidative stress is universally acknowledged as one crucial pathogenic factor for this disease. Recently studies have found the LncRNA HOTAIR is involved in the alteration of oxidative stress level, cell proliferation, cell cycle progression, and apoptosis. Considering the effects of lncRNA HOTAIR in cellular oxidative stress, we sought to investigate the influence of lncRNA HOTAIR variants on the risk of NIHL. METHODS: To explore the effects of HOTAIR polymorphisms on individual susceptibility to NIHL, We performed genotyping of three tagSNPs (rs874945, rs4759314 and rs7958904) in HOTAIR gene in a Chinese population which consists of 570 NIHL cases and 570 controls. The luciferase assays were further performed to investigate the regulatory function of HOTAIR tagSNPs. RESULTS: Our results revealed individuals with the G allele of HOTAIR tagSNP rs4759314 and the haplotype (rs874945, rs4759314 and rs7958904) are associated with an increased risk of NIHL in a Chinese population. Meanwhile, the rs4759314 G allele could significantly increase the expression of lncRNA HOTAIR. CONCLUSIONS: The genetic polymorphism within HOTAIR gene may play a crucial role in the occurrence and development of NIHL.

Angiotensinogen gene polymorphisms and progression of chronic kidney disease in ADPKD patients.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a multisystemic and progressive disorder characterized by cyst formation and kidney enlargement and ultimately renal failure. Reduction of CKD progression in the ADPKD by pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) using ACE inhibitors indicated the involvement of RAAS pathway in the progression of CKD. The aim of the present study is to investigate the role of angiotensinogen tag-single nucleotide polymorphisms (AGT tag-SNPs) in progression of CKD. METHODS: Twelve AGT tag-SNPs were genotyped in 102 ADPKD patients and 106 non-ADPKD subjects using FRET-based KASPar method. Genotypes and haplotypes were compared between ADPKD and controls. The effect of genotypes and hypertension on CKD progression was assessed using univariate and multivariate logistic regression. Mantel-Haenszel (M-H) stratified analysis was performed to study the interaction between CKD stages and hypertension. RESULTS: Of the twelve tag-SNPs analyzed, only rs11122578 SNP deviated Hardy-Weinberg equilibrium in controls. Significant association between two AGT polymorphisms (rs11122577 and rs4762) and ADPKD was observed. Analysis of linkage disequilibrium revealed two haplotype blocks and haplotypes are not associated with ADPKD. The univariate analysis revealed that the age, hypertension, family history of diabetes and AGT rs4762 contributed to the progression of CKD in ADPKD. The modifier effect of these factors remained even after controlling other variables in multivariate analysis. CONCLUSIONS: The results of our study suggest significant association between Thr207Met polymorphism of AGT and CKD progression and acts as an effect modifier of renal disease progression in ADPKD.

Effect of ERCC8 tagSNPs and their association with H. pylori infection, smoking, and alcohol consumption on gastric cancer and atrophic gastritis risk.

Excision repair cross-complementing group 8 (ERCC8) plays a critical role in DNA repair. Genetic polymorphisms in ERCC8 may contribute to the risk of cancer development. We selected tag single nucleotide polymorphisms (tagSNPs) in Chinese patients from the HapMap database to investigate associations with gastric cancer and its precursors. Genomic DNA was extracted from 394 controls, 394 atrophic gastritis, and 394 gastric cancer cases in northern Chinese patients, and genotypes were identified using the Sequenom MassARRAY system. We found that the ERCC8 rs158572 GG+GA genotype showed a 1.651-fold (95 % confidence interval (CI) = 1.109-2.457, P = 0.013) increased risk of gastric cancer compared with the AA genotype, especially in diffuse type. Stratified analysis comparing the common genotype revealed significantly increased gastric cancer risk in males and individuals older than 50 years with rs158572 GA/GG/GG+GA genotypes, while individuals older than 50 years with rs158916 CT/CC+CT genotypes were less susceptible to atrophic gastritis. Haplotype analysis showed that the G-T haplotype was associated with increased risk of gastric cancer. Statistically significant interactions between the two ERCC8 tagSNPs and Helicobacter pylori infection were observed for gastric cancer and atrophic gastritis risk (P < 0.05). Smokers and drinkers with ERCC8 rs158572 GG+GA genotype were more susceptible to gastric cancer compared with non-smokers and non-drinkers homozygous for AA. Our findings suggested that ERCC8 rs158572 and rs158916, alone or together with environmental factors, might be associated with gastric cancer and atrophic gastritis susceptibility. Further validation of our results in larger populations along with additional studies evaluating the underlying molecular function is required.

Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia.

BACKGROUND: Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia. METHODS: A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions. RESULTS: In the exploratory study, ten markers were in significant association with schizophrenia (P<0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia. CONCLUSION: This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausible.

Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study.

MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value = 1.7 × 10(-4) ; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value = 5.38 × 10(-3) ; OR = 0.56, 95% CI = 0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value = 5.40 × 10(-3) ; OR = 1.41, 95% CI = 1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.

Relationship between interleukin 18 polymorphisms and susceptibility to chronic hepatitis B virus infection.

AIM: To identify the relationship between the tagging single nucleotide polymorphism sites (tagSNPs) of the Interleukin-18 (IL-18) gene and genetic susceptibility to chronic hepatitis B virus infection in Chinese patients. METHODS: Five hundred and one cases of chronic hepatitis B virus (HBV) infection and 301 HBV natural clearance controls were studied. Two tagSNPs in the IL-18 gene (rs1946518A/C and rs574424C/G) were genotyped by the Multiplex Snapshot technique. The genotype and allele frequencies were calculated and analyzed. RESULTS: In the genotypes of rs1946518, the AA type was present at a higher frequency in the patients compared to those in the controls. Odds ratio (OR) of the AA genotype for the comparison with that of the AC and the CC genotype was 1.537 (95% confidence intervals (CI): 1.116-2.218, P = 0.009 < 0.025). In phenotypes, the allele C at rs1946518 was of a significantly lower frequency in the patients with chronic hepatitis B than that in the controls (P = 0.017 < 0.025). OR of the allele A for the comparison with that of the allele C was 1.279 (95% CI: 1.045-1.567). As for the rs574424 genotypes, no significant difference in this genotype distribution or in this allele frequency between the patients and the control subjects was observed. No significant difference in the haplotype frequencies between the patients with chronic hepatitis B and HBV natural clearance individuals was displayed. CONCLUSION: The data suggest that genotype AA and the allele A of the IL-18 at position rs1946518 are closely associated with the resistance to chronic hepatitis B and may be the dangerous gene. However, no statistical association was found between polymorphisms of rs574424 for IL-18 and hepatitis B.

FESD II: A Revised Functional Element SNP Database of Human Ethnicities

The Functional Element SNPs Database (FESD) categorizes functional elements in human genic regions and provides a set of single nucleotide polymorphisms (SNPs) located within each area. Users may select a set of SNPs in specific functional elements with haplotype information and obtain flanking sequences for genotyping. Our previous version of FESD has been improved in several ways. We regenerated all the data in FESD II from recently updated source data such as HapMap, UCSC GoldenPath, dbSNP, OMIM, and TRANSFAC(R). Users can obtain information about tagSNPs and simulate LD blocks for each gene from four ethnicities in the HapMap project on the fly. FESD II employs a Java/JSP web interface for better platform portability and higher speed than PHP in the previous version. As a result, FESD II provides its users with more powerful information about functional element SNPs of human ethnicities.