North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMD-associated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.

• MeSH
• dědičné dystrofie rohovky * MeSH
• dospělí MeSH
• lidé MeSH
• optická koherentní tomografie * MeSH
• retina metabolismus   MeSH
• rodokmen MeSH
• Xenopus laevis genetika   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

• MeSH
• deoxyribonukleasa I metabolismus   MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• nádory plic genetika   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: The TLR3/cGAS-STING-IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. METHODS: The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. RESULTS: Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11-2.53, P-value = .01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07-3.84, P-value = .03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03-2.27, P-value = .03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5-6 risk alleles compared to those with 0-2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair-wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. CONCLUSIONS: Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.

• MeSH
• dospělí MeSH
• genetická epistáze * MeSH
• genotypizační techniky MeSH
• interferony genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• karcinogeneze genetika   MeSH
• kinasa I-kappa B genetika   MeSH
• kohortové studie MeSH
• kolon diagnostické zobrazování   patologie   MeSH
• kolonoskopie MeSH
• kolorektální nádory diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nukleotidyltransferasy genetika   MeSH
• protein-serin-threoninkinasy genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• rektum diagnostické zobrazování   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce genetika   MeSH
• studie případů a kontrol MeSH
• toll-like receptor 3 genetika   MeSH
• výpočetní biologie MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

Constitutive activation of interferon signaling pathways has been reported in colorectal cancer (CRC), leading to a strong CD8+ T cell response through stimulation of NLRC5 expression. Primed CD8+ T cell expansion, however, may be negatively regulated by PD-L1 expression. Additionally, aberrant PD-L1 expression enables cancer cells to escape the immune attack. Our study aimed to select potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, microRNA and transcription factor binding site prediction tools and to investigate their influence on CRC risk in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Logistic regression analysis adjusted for age and gender reported a moderate association between rectal cancer risk and two NLRC5 SNPs, rs1684575 T>G (OR: 1.60, 95% CI: 1.13-2.27, recessive model) and rs3751710 (OR: 0.70, 95% CI: 0.51-0.96, dominant model). Given that a combination of genetic variants, rather than a single polymorphism, may explain better the genetic etiology of CRC, we studied the interplay between the variants within NLRC5, PD-L1 and the previously genotyped IFNGR1 and IFNGR2 variants, to evaluate their involvement in the risk of CRC development. Overall we obtained 18 pair-wise interactions within and between the NLRC5 ad PD-L1 genes and 6 more when IFNGR variants were added. Thirteen out of the 24 interactions were below the threshold for the FDR calculated and controlled at an arbitrary level q*<0.10. Furthermore, the interaction IFNGR2 rs1059293 C>T-NLRC5 rs289747 G>A (P<0.0001) remained statistically significant even after Bonferroni correction. Our data suggest that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of CRC, providing therefore novel biological information, which could eventually improve CRC risk management but also PD-1-based immunotherapy in CRC.

• MeSH
• antigeny CD274 genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• kohortové studie MeSH
• kolorektální nádory genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: The CTLA4 (cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered also a plausible candidate for a genetic association with inflammatory bowel diseases. Previously published studies found no association of CTLA4 with Crohn's disease itself, but some indicated an association with its subphenotypes. The aim of this study was to assess the association in the Czech population, using a set of markers shown to associate with other diseases. METHODS: Six polymorphisms within the CTLA4 region were investigated in 333 patients with Crohn's disease and 482 unrelated healthy controls, all Caucasians of Czech origin. The genotypes of the SNPs were determined using the TaqMan SNP genotyping assays. Haplotypes were reconstructed using an expectation-maximization algorithm, and their association with the condition was assessed using log-linear modeling. Then, potential interactions were tested between the CTLA4 variants and other genetic factors known to confer the disease susceptibility. RESULTS: No crude associations with Crohn's disease were found for the tested CTLA4 variants under the log-additive or dominant models. However, when stratified for the genetic risk conferred by the variants in the NOD2 (the p.Leu1007fsX1008, rs5743293) or the IL23R (p.R381Q, rs11209026), a significant negative association emerged for the minor alleles of CTLA4 CT60 (rs3087243), JO31 (rs11571302), JO27-1 (rs11571297) polymorphisms. This negative association with CTLA4 was apparent only in the strata defined by presence minor alleles at the NOD2 rs5743293 (here the CTLA4 CT60 A coffered an OR = 0.43, 95%CI 0.19 - 0.95 for the presence of CT60 A), or IL23R rs11209026 (here the OR for presence of CT60 A was 0.23, 95%CI 0.07 - 0.71). We observed this effect also for the haplotype consisting of minor alleles of the three tightly linked CTLA4 markers. Furthermore, this haplotype was associated with the younger age at diagnosis (OR 1.52, 95%CI 1.09 - 2.11, p = 0.014). CONCLUSIONS: A protective effect of a CTLA4 haplotype was unmasked after stratification for the risk variants in the NOD2 and IL23R genes, and may point towards the biological relevance of the molecule in the pathogenesis of the disease.

• MeSH
• alely MeSH
• antigen CTLA-4 MeSH
• běloši genetika   MeSH
• CD antigeny MeSH
• Crohnova nemoc epidemiologie   genetika   MeSH
• cytotoxické T-lymfocyty MeSH
• genotyp MeSH
• haplotypy MeSH
• idiopatické střevní záněty genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• polymorfismus genetický MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

• MeSH
• alely * MeSH
• exprese genu MeSH
• genetická predispozice k nemoci MeSH
• genetická variace MeSH
• geny BRCA1 * MeSH
• geny BRCA2 * MeSH
• heterozygot * MeSH
• lidé MeSH
• lidské chromozomy, pár 11 MeSH
• lokus kvantitativního znaku MeSH
• mutace * MeSH
• nádorové biomarkery MeSH
• nádory prsu epidemiologie   etiologie   MeSH
• riziko MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Vga(A) protein variants confer different levels of resistance to lincosamides, streptogramin A, and pleuromutilins (LSAP) by displacing antibiotics from the ribosome. Here, we show that expression of vga(A) variants from Staphylococcus haemolyticus is regulated by cis-regulatory RNA in response to the LSAP antibiotics by the mechanism of ribosome-mediated attenuation. The specificity of induction depends on Vga(A)-mediated resistance rather than on the sequence of the riboregulator. Fine tuning between Vga(A) activity and its expression in response to the antibiotics may contribute to the selection of more potent Vga(A) variants because newly acquired mutation can be immediately phenotypically manifested.

• MeSH
• antibakteriální látky farmakologie   MeSH
• bakteriální proteiny genetika   MeSH
• linkosamidy MeSH
• makrolidy MeSH
• mnohočetná bakteriální léková rezistence * MeSH
• ribozomy genetika   MeSH
• streptogramin A * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. METHODS: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. RESULTS: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. CONCLUSIONS: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. IMPACT: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

• MeSH
• celogenomová asociační studie * MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory * etiologie   genetika   MeSH
• lidé MeSH
• pití alkoholu škodlivé účinky   epidemiologie   genetika   MeSH
• respirační komplex IV genetika   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

Most common genetic risk variants associated with neuropsychiatric disease are noncoding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type-specific open chromatin data set to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in two cell types (neurons and non-neurons) across 14 distinct brain regions of five individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein-coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provide a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database "Brain Open Chromatin Atlas (BOCA)" to facilitate interpretation.

• MeSH
• chromatin genetika   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• myši MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese genetika   MeSH
• regulační elementy transkripční genetika   MeSH
• sekvenční analýza DNA MeSH
• transposasy MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Congenital hereditary endothelial dystrophy 1 (CHED1) and posterior polymorphous corneal dystrophy 1 (PPCD1) are autosomal-dominant corneal endothelial dystrophies that have been genetically mapped to overlapping loci on the short arm of chromosome 20. We combined genetic and genomic approaches to identify the cause of disease in extensive pedigrees comprising over 100 affected individuals. After exclusion of pathogenic coding, splice-site, and copy-number variations, a parallel approach using targeted and whole-genome sequencing facilitated the identification of pathogenic variants in a conserved region of the OVOL2 proximal promoter sequence in the index families (c.-339_361dup for CHED1 and c.-370T>C for PPCD1). Direct sequencing of the OVOL2 promoter in other unrelated affected individuals identified two additional mutations within the conserved proximal promoter sequence (c.-274T>G and c.-307T>C). OVOL2 encodes ovo-like zinc finger 2, a C2H2 zinc-finger transcription factor that regulates mesenchymal-to-epithelial transition and acts as a direct transcriptional repressor of the established PPCD-associated gene ZEB1. Interestingly, we did not detect OVOL2 expression in the normal corneal endothelium. Our in vitro data demonstrate that all four mutated OVOL2 promoters exhibited more transcriptional activity than the corresponding wild-type promoter, and we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development. Our data establish CHED1 and PPCD1 as allelic conditions and show that CHED1 represents the extreme of what can be considered a disease spectrum. They also implicate transcriptional dysregulation of OVOL2 as a common cause of dominantly inherited corneal endothelial dystrophies.

• MeSH
• alely * MeSH
• dědičné dystrofie rohovky genetika   MeSH
• DNA MeSH
• lidé MeSH
• mutace * MeSH
• promotorové oblasti (genetika) * MeSH
• rodokmen MeSH
• sekvence nukleotidů MeSH
• sekvenční homologie nukleových kyselin MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH