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1.
Cancer Epidemiol Biomarkers Prev ; 29(2): 427-433, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31748258

RESUMO

BACKGROUND: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits. METHODS: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association meta-analyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. For single marker analyses, all genome-wide significant risk alleles for BMI and WHR were compared with summary statistics of the BE/EA meta-analyses. RESULTS: Sex-combined analyses revealed a significant genetic correlation between BMI and BE/EA (rg = 0.13, P = 2 × 10-04) and a rg of 0.12 between WHR and BE/EA (P = 1 × 10-02). Sex-specific analyses revealed a pronounced genetic correlation between BMI and EA in females (rg = 0.17, P = 1.2 × 10-03), and WHR and EA in males (rg = 0.18, P = 1.51 × 10-02). On the single marker level, significant enrichment of concordant effects was observed for BMI and BE/EA risk variants (P = 8.45 × 10-03) and WHR and BE/EA risk variants (P = 2 × 10-02). CONCLUSIONS: Our study provides evidence for sex-specific genetic correlations that might reflect specific biological mecha-nisms. The data demonstrate that shared genetic factors are particularly relevant in progression from BE to EA. IMPACT: Our study quantifies the genetic correlation between BE/EA and obesity. Further research is now warranted to elucidate these effects and to understand the shared pathophysiology.

2.
Immunity ; 51(6): 997-1011.e7, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31851905

RESUMO

Toll-like receptor (TLR) activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remains unknown. Here, we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Shortly after TLR4 activation, macrophages increased glycolysis and tricarboxylic acid (TCA) cycle volume. Metabolic tracing studies revealed that TLR signaling redirected metabolic fluxes to generate acetyl-Coenzyme A (CoA) from glucose resulting in augmented histone acetylation. Signaling through the adaptor proteins MyD88 and TRIF resulted in activation of ATP-citrate lyase, which in turn facilitated the induction of distinct LPS-inducible gene sets. We postulate that metabolic licensing of histone acetylation provides another layer of control that serves to fine-tune transcriptional responses downstream of TLR activation. Our work highlights the potential of targeting the metabolic-epigenetic axis in inflammatory settings.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Acetilcoenzima A/metabolismo , Histonas/metabolismo , Macrófagos/metabolismo , Receptor 4 Toll-Like/metabolismo , Acetilação , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Ciclo do Ácido Cítrico/fisiologia , Glicólise/fisiologia , Humanos , Lipopolissacarídeos/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Transcrição Genética/genética
3.
Mol Psychiatry ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712720

RESUMO

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

4.
United European Gastroenterol J ; 7(1): 45-51, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30788115

RESUMO

Background: Achalasia is a primary oesophageal motility disorder. Although aetiology remains mainly unknown, a genetic risk variant, rs28688207 in HLA-DQB1, showed strong achalasia association suggesting involvement of immune-mediated processes in the pathogenesis. High-resolution manometry recognises three types of achalasia. The aim of our study was to perform the first genotype-phenotype analysis investigating the frequency of rs28688207 across the high-resolution manometry subtypes. Methods: This was a cross-sectional retrospective study. Achalasia patients from tertiary centres in the Czech Republic (n = 163), Germany (n = 114), Greece (n = 70) and controls were enrolled. All subjects were genotyped for the rs28688207 insertion. The Kruskal-Wallis test was used for the genotype-phenotype analysis. Results: A total of 347 achalasia patients (type I - 89, II - 210, III - 48) were included. The overall frequency of the rs28688207 was 10.3%. The distribution of the insertion was significantly different across the high-resolution manometry subtypes (p = 0.038), being most prevalent in type I (14.6%), followed by type II (9.5%) and III (6.3%). Conclusion: The frequency of the HLA-DQB1 insertion differs among high-resolution manometry achalasia subtypes. The insertion is most prevalent in type I, suggesting that immune-mediated mechanisms triggered by the insertion may play a more prominent role in the pathogenesis of this subtype.


Assuntos
Acalasia Esofágica/diagnóstico , Acalasia Esofágica/etiologia , Heterogeneidade Genética , Genótipo , Cadeias beta de HLA-DQ/genética , Manometria , Fenótipo , Alelos , Estudos Transversais , República Tcheca , Acalasia Esofágica/epidemiologia , Geografia Médica , Alemanha , Grécia , Cadeias beta de HLA-DQ/imunologia , Humanos , Polimorfismo de Nucleotídeo Único , Vigilância da População , Prevalência
5.
PLoS One ; 14(12): e0227072, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31891614

RESUMO

Esophageal adenocarcinoma (EA) and its precancerous condition Barrett's esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10-8) and novel candidate loci (5×10-8 ≤ P ≤ 5×10-5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10-7 and rs1540, Pcombined = 4.16×10-6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Mucosa Esofágica/patologia , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica , Locos de Características Quantitativas , Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Proteínas Repressoras/genética , Trocador 3 de Sódio-Hidrogênio/genética
6.
Cancer Med ; 7(10): 5057-5065, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30191681

RESUMO

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.


Assuntos
Aciltransferases/genética , Antígenos de Neoplasias/genética , Perfilação da Expressão Gênica/métodos , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Neoplasias Gástricas/genética , Estudos de Casos e Controles , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 8/genética , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
7.
Psychiatr Genet ; 27(3): 96-102, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28272115

RESUMO

OBJECTIVES: Social anxiety disorder (SAD) is a common and heritable psychiatric disorder. However, genetic studies in SAD are rare and only a few candidate genes have been implicated so far. In the present study, we investigated whether single-nucleotide polymorphisms (SNPs) associated with other psychiatric disorders also contribute toward the development of SAD and followed up variants associated with SAD on the phenotypic level. PATIENTS AND METHODS: We genotyped a total of 24 SNPs in a German sample of 321 SAD patients and 804 controls. We carried out single-marker analyses as well as quantitative association analyses of SAD severity and harm avoidance. RESULTS: None of the variants investigated showed an association with SAD in our case-control sample after Bonferroni correction. Two SNPs reached nominal significance (rs818702, P=0.032; rs140701, P=0.048). Of these, only rs140701 showed an association in the same allelic direction as reported previously. This SNP is located within the serotonin transporter gene SLC6A4, which is the primary target of selective-serotonin reuptake inhibitors used for the treatment of depressive and anxiety disorders. The quantitative association analysis of all cases with available data on symptom severity showed four SNPs with a nominal significant association. Among these SNPs, rs10994359 showed the strongest association (P=0.001) and was located near the ANK3 gene. In addition, rs10994359 was nominally associated with harm avoidance scores (P=0.001). CONCLUSION: Our results provide further evidence for an involvement of the serotonin transporter gene SLC6A4 in the etiology of anxiety-related traits. Furthermore, our study implicates that genetic variation at the genome-wide associated bipolar disorder locus ANK3 might influence anxiety-related personality traits.


Assuntos
Transtornos de Ansiedade/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Ansiedade/genética , Ansiedade/metabolismo , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Alemanha , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
8.
Lancet Oncol ; 17(10): 1363-1373, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27527254

RESUMO

BACKGROUND: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma. METHODS: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms. FINDINGS: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10-10), MSRA (rs17749155; p=5·2 × 10-10), LINC00208 and BLK (rs10108511; p=2·1 × 10-9), KHDRBS2 (rs62423175; p=3·0 × 10-9), TPPP and CEP72 (rs9918259; p=3·2 × 10-9), TMOD1 (rs7852462; p=1·5 × 10-8), SATB2 (rs139606545; p=2·0 × 10-8), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10-8) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation. INTERPRETATION: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies. FUNDING: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Risco
9.
Eur J Gastroenterol Hepatol ; 28(6): 689-95, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26882171

RESUMO

BACKGROUND AND AIM: Although an eight-residue insertion in HLA-DQß1 has been recently identified as a genetic risk factor for idiopathic achalasia, other risk factors are still unknown. In the present study, we carried out an epidemiological survey and a genotype-phenotype (G×P) analysis to gain further insights into the etiology of achalasia. METHODS: We obtained medical data from 696 achalasia patients and 410 controls, as well as their first-degree relatives (2543 of patients and 1497 of controls). For the G×P analysis, we stratified the patients into HLA-DQß1 insertion carriers and noncarriers. RESULTS: Our data show that patients are more often affected by viral infections before achalasia onset (P<0.0001, most significantly for varicella zoster virus infections). In addition, allergic (P=0.0005) and autoimmune disorders (P=0.0007, most significantly for psoriasis and Sjögren's syndrome) represent comorbid disease conditions. First-degree relatives of patients also show higher prevalence rates of allergic disorders (P=0.0007) and psoriasis (P=0.016) compared with control relatives. Moreover, the G×P analysis reveals that achalasia is triggered by pregnancies in female HLA-DQß1 insertion carriers (P=0.031). CONCLUSION: Our data point to a role of viral infections in the development of achalasia. In addition, they provide evidence for a relationship between achalasia and allergic, as well as autoimmune, disorders. Furthermore, pregnancy seems to be a disease-triggering factor in female HLA-DQß1 insertion carriers, which points to hormonal and/or immunosuppressive factors influencing disease development.


Assuntos
Doenças Autoimunes/epidemiologia , Acalasia Esofágica/epidemiologia , Cadeias beta de HLA-DQ/genética , Hipersensibilidade/epidemiologia , Complicações na Gravidez/epidemiologia , Viroses/epidemiologia , Adulto , Alelos , Estudos de Casos e Controles , Varicela/epidemiologia , Comorbidade , Acalasia Esofágica/genética , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Família , Feminino , Genótipo , Herpes Zoster/epidemiologia , Herpesvirus Humano 3 , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Gravidez , Complicações na Gravidez/genética , Psoríase/epidemiologia , Síndrome de Sjogren/epidemiologia
10.
Cancer Med ; 5(5): 888-91, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26783083

RESUMO

Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) represent two stages within the esophagitis-metaplasia-dysplasia-adenocarcinoma sequence. Previously genetic risk factors have been identified that confer risk to BE and EAC development. However, to which extent the genetic variants confer risk to different stages of the BE/EAC sequence remains mainly unknown. In this study we analyzed three most recently identified BE variants at the genes GDF7 (rs3072), TBX5 (rs2701108), and ALDH1A2 (rs3784262) separately in BE and EAC samples in order to determine their risk effects during BE/EAC sequence. Our data show that rs3072 at GDF7 and rs2701108 at TBX5 are also associated with EAC and conclude that both loci confer disease risk also at later stages of the BE/EAC sequence. In contrast, rs3784262 at ALDH1A2 was highly significantly associated with BE, but showed no association with EAC. Our data do not provide evidence that the ALDH1A2 locus confers equal risk in early and late stages of BE/EAC sequence.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Proteínas Morfogenéticas Ósseas/genética , Neoplasias Esofágicas/genética , Fatores de Diferenciação de Crescimento/genética , Lesões Pré-Cancerosas/genética , Proteínas com Domínio T/genética , Estudos de Casos e Controles , Progressão da Doença , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
Eur J Hum Genet ; 24(8): 1228-31, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26733285

RESUMO

Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQß1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQß1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10(-04), Sweden P=7.44 × 10(-05)). Combining all five European data sets - Central Europe, Italy, Spain, Poland and Sweden - the insertion is achalasia associated with Pcombined=1.67 × 10(-35). In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.


Assuntos
Acalasia Esofágica/genética , Cadeias beta de HLA-DQ/genética , Mutagênese Insercional , Acalasia Esofágica/epidemiologia , Acalasia Esofágica/etnologia , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Taxa de Mutação , Polimorfismo Genético , Prevalência
12.
Hum Mutat ; 37(3): 257-68, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26615982

RESUMO

Immunodeficiency patients with DNA repair defects exhibit radiosensitivity and proneness to leukemia/lymphoma formation. Though progress has been made in identifying the underlying mutations, in most patients the genetic basis is unknown. Two de novo mutated candidate genes, MCM3AP encoding germinal center-associated nuclear protein (GANP) and POMP encoding proteasome maturation protein (POMP), were identified by whole-exome sequencing (WES) and confirmed by Sanger sequencing in a child with complex phenotype displaying immunodeficiency, genomic instability, skin changes, and myelodysplasia. GANP was previously described to promote B-cell maturation by nuclear targeting of activation-induced cytidine deaminase (AID) and to control AID-dependent hyperrecombination. POMP is required for 20S proteasome assembly and, thus, for efficient NF-κB signaling. Patient-derived cells were characterized by impaired homologous recombination, moderate radio- and cross-linker sensitivity associated with accumulation of damage, impaired DNA damage-induced NF-κB signaling, and reduced nuclear AID levels. Complementation by wild-type (WT)-GANP normalized DNA repair and WT-POMP rescued defective NF-κB signaling. In conclusion, we identified for the first time mutations in MCM3AP and POMP in an immunodeficiency patient. These mutations lead to cooperative effects on DNA recombination and damage signaling. Digenic/polygenic mutations may constitute a novel genetic basis in immunodeficiency patients with DNA repair defects.


Assuntos
Acetiltransferases/genética , Dano ao DNA/genética , Reparo do DNA/genética , Síndromes de Imunodeficiência/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Chaperonas Moleculares/genética , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Humanos , Mutação/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
13.
Cancer Med ; 4(11): 1700-4, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26383589

RESUMO

The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett's esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P < 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P < 10(-5) ) although not genome-wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Adenocarcinoma/epidemiologia , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Neoplasias Esofágicas/epidemiologia , Feminino , Estudos de Associação Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Adulto Jovem
14.
Nat Commun ; 5: 5236, 2014 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-25327457

RESUMO

Toll-like receptors (TLRs) play a key role in innate immunity. Apart from their function in host defense, dysregulation in TLR signalling can confer risk to autoimmune diseases, septic shock or cancer. Here we report genetic variants and transcripts that are active only during TLR signalling and contribute to interindividual differences in immune response. Comparing unstimulated versus TLR4-stimulated monocytes reveals 1,471 expression quantitative trait loci (eQTLs) that are unique to TLR4 stimulation. Among these we find functional SNPs for the expression of NEU4, CCL14, CBX3 and IRF5 on TLR4 activation. Furthermore, we show that SNPs conferring risk to primary biliary cirrhosis (PBC), inflammatory bowel disease (IBD) and celiac disease are immune response eQTLs for PDGFB and IL18R1. Thus, PDGFB and IL18R1 represent plausible candidates for studying the pathophysiology of these disorders in the context of TLR4 activation. In summary, this study presents novel insights into the genetic basis of the innate immune response and exemplifies the value of eQTL studies in the context of exogenous cell stimulation.


Assuntos
Imunidade Inata , Monócitos/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Interleucina-18/metabolismo , Receptor 4 Toll-Like/metabolismo , Adolescente , Adulto , Alelos , Autoimunidade , Doença Celíaca/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Genótipo , Heterozigoto , Homozigoto , Humanos , Doenças Inflamatórias Intestinais/genética , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Monócitos/citologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Transdução de Sinais , Adulto Jovem
15.
Nat Genet ; 46(8): 901-4, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24997987

RESUMO

Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQß1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQß1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.


Assuntos
Acalasia Esofágica/genética , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Alelos , Substituição de Aminoácidos , Estudos de Casos e Controles , Acalasia Esofágica/imunologia , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Antígenos HLA-DQ/química , Haplótipos , Humanos , Modelos Logísticos , Masculino , Modelos Moleculares , Polimorfismo de Nucleotídeo Único
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