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1.
Hum Genet ; 138(4): 375-388, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30852652

RESUMO

Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of 'transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10- 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.


Assuntos
Caderinas/genética , Loci Gênicos , Redes e Vias Metabólicas/genética , Metabolismo/genética , Transcriptoma , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
2.
J Invest Dermatol ; 139(7): 1480-1489, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30641038

RESUMO

Atopic dermatitis (AD) affects up to 20% of children and adults worldwide. To gain a deeper understanding of the pathophysiology of AD, we conducted a large-scale transcriptomic study of AD with deeply sequenced RNA-sequencing samples using long (126-bp) paired-end reads. In addition to the comparisons against previous transcriptomic studies, we conducted in-depth analysis to obtain a high-resolution view of the global architecture of the AD transcriptome and contrasted it with that of psoriasis from the same cohort. By using 147 RNA samples in total, we found striking correlation between dysregulated genes in lesional psoriasis and lesional AD skin with 81% of AD dysregulated genes being shared with psoriasis. However, we described disease-specific molecular and cellular features, with AD skin showing dominance of IL-13 pathways, but with near undetectable IL-4 expression. We also demonstrated greater disease heterogeneity and larger proportion of dysregulated long noncoding RNAs in AD, and illustrated the translational impact, including skin-type classification and drug-target prediction. This study is by far the largest study comparing the AD and psoriasis transcriptomes using RNA sequencing and demonstrating the shared inflammatory components, as well as specific discordant cytokine signatures of these two skin diseases.

4.
Nat Genet ; 50(8): 1072-1080, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30013184

RESUMO

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

7.
Artigo em Inglês | MEDLINE | ID: mdl-29679657

RESUMO

BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. OBJECTIVE: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects. METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study. RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses. CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.

8.
J Allergy Clin Immunol ; 141(5): 1668-1676.e16, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29421277

RESUMO

BACKGROUND: Genomic approaches have revealed characteristic site specificities of skin bacterial community structures. In addition, in children with atopic dermatitis (AD), characteristic shifts were described at creases and, in particular, during flares, which have been postulated to mirror disturbed skin barrier function, cutaneous inflammation, or both. OBJECTIVE: We sought to comprehensively analyze microbial configurations in patients with AD across body sites and to explore the effect of distinct abnormalities of epidermal barrier function. METHODS: The skin microbiome was determined by using bacterial 16S rRNA sequencing at 4 nonlesional body sites, as well as acute and chronic lesions of 10 patients with AD and 10 healthy control subjects matched for age, sex, and filaggrin (FLG) mutation status. Nonlesional sampling sites were characterized for skin physiology parameters, including chromatography-based lipid profiling. RESULTS: Epidermal lipid composition, in particular levels of long-chain unsaturated free fatty acids, strongly correlated with bacterial composition, in particular Propionibacteria and Corynebacteria abundance. AD displayed a distinct community structure, with increased abundance and altered composition of staphylococcal species across body sites, the strongest loss of diversity and increase in Staphylococcus aureus seen on chronic lesions, and a progressive shift from nonlesional skin to acute and chronic lesions. FLG-deficient skin showed a distinct microbiome composition resembling in part the AD-related pattern. CONCLUSION: Epidermal barrier integrity and function affect the skin microbiome composition. AD shows an altered microbial configuration across diverse body sites, which is most pronounced at sites of predilection and AD. Eczematous affection appears to be a more important determinant than body site.

9.
World J Biol Psychiatry ; 19(3): 187-199, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-27367046

RESUMO

OBJECTIVES: Patients with anorexia nervosa (AN) are ideally suited to identify differentially methylated genes in response to starvation. METHODS: We examined high-throughput DNA methylation derived from whole blood of 47 females with AN, 47 lean females without AN and 100 population-based females to compare AN with both controls. To account for different cell type compositions, we applied two reference-free methods (FastLMM-EWASher, RefFreeEWAS) and searched for consensus CpG sites identified by both methods. We used a validation sample of five monozygotic AN-discordant twin pairs. RESULTS: Fifty-one consensus sites were identified in AN vs. lean and 81 in AN vs. population-based comparisons. These sites have not been reported in AN methylation analyses, but for the latter comparison 54/81 sites showed directionally consistent differential methylation effects in the AN-discordant twins. For a single nucleotide polymorphism rs923768 in CSGALNACT1 a nearby site was nominally associated with AN. At the gene level, we confirmed hypermethylated sites at TNXB. We found support for a locus at NR1H3 in the AN vs. lean control comparison, but the methylation direction was opposite to the one previously reported. CONCLUSIONS: We confirm genes like TNXB previously described to comprise differentially methylated sites, and highlight further sites that might be specifically involved in AN starvation processes.


Assuntos
Anorexia Nervosa/genética , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA , Inanição/genética , Tenascina/genética , Magreza/genética , Adulto , Feminino , Humanos , Adulto Jovem
11.
Hum Mol Genet ; 26(21): 4301-4313, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973304

RESUMO

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.


Assuntos
Psoríase/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Exoma , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon/genética , Helicase IFIH1 Induzida por Interferon/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único/genética , Psoríase/fisiopatologia , Fatores de Risco , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Sequenciamento Completo do Exoma
12.
Nat Genet ; 49(12): 1752-1757, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083406

RESUMO

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.


Assuntos
Asma/genética , Eczema/genética , Predisposição Genética para Doença/genética , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
J Invest Dermatol ; 137(9): 1945-1954, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28595995

RESUMO

miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In this study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in the lesional skin of patients with psoriasis. The expression of miR-146a was approximately twofold higher than that of miR-146b in healthy human skin, and it was more strongly induced by stimulation of proinflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of patients with psoriasis, among which FERMT1 was verified as a direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in the miR-146a encoding gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a-/- and skin fibroblasts from miR-146a-/- and miR-146b-/- mice stimulated with psoriasis-associated cytokines as compared with wild-type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin.


Assuntos
Proliferação de Células/genética , Regulação da Expressão Gênica , Queratinócitos/metabolismo , MicroRNAs/genética , Psoríase/genética , Animais , Apoptose/genética , Estudos de Casos e Controles , Células Cultivadas , Dermatite/genética , Dermatite/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/patologia , Reação em Cadeia da Polimerase em Tempo Real/métodos
14.
J Invest Dermatol ; 137(5): 1074-1081, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28011146

RESUMO

Epidemiological studies suggested an association between atopic dermatitis (AD) and cardiovascular disease. Therefore, we investigate associations and potential underlying pathways of AD and cardiovascular disease in large cohort studies: the AOK PLUS cohort (n = 1.2 Mio), the GINIplus/LISAplus birth cohorts (n = 2,286), and the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 2,990). In addition, metabolomics in KORA F4 and established cardiovascular risk loci in genome-wide data on 10,788 AD cases and 30,047 controls were analyzed. Longitudinal analysis of patients with AD in AOK PLUS showed slightly increased risk for incident angina pectoris (adjusted risk ratio 1.17 [95% confidence interval 1.12-1.23]), hypertension (1.04 [1.02-1.06]), and peripheral arterial disease (1.15 [1.11-1.19]) but not for myocardial infarction (1.05 [0.99-1.12]) and stroke (1.02 [0.98-1.07]). In KORA F4 and GINIplus/LISAplus, AD was not associated with cardiovascular risk factors and no differences in metabolite levels were detected. There was no robust evidence for shared genetic risk variants of AD and cardiovascular disease. This study indicates only a marginally increased risk for angina pectoris, hypertension, and peripheral arterial disease and no increased risk for myocardial infarction or stroke in patients with AD. Relevant associations of AD with cardiovascular risk factors reported in US populations could not be confirmed. Likewise, patients with AD did not have increased genetic risk factors for cardiovascular disease.


Assuntos
Doenças Cardiovasculares/epidemiologia , Dermatite Atópica/complicações , Predisposição Genética para Doença , Metabolômica/métodos , Adulto , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Estudos de Coortes , Dermatite Atópica/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Fatores de Risco
15.
J Invest Dermatol ; 136(12): 2380-2386, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27448748

RESUMO

Gene-mapping studies have consistently identified a susceptibility locus for atopic dermatitis and other inflammatory diseases on chromosome band 11q13.5, with the strongest association observed for a common variant located in an intergenic region between the two annotated genes C11orf30 and LRRC32. Using a targeted resequencing approach we identified low-frequency and rare missense mutations within the LRRC32 gene encoding the protein GARP, a receptor on activated regulatory T cells that binds latent transforming growth factor-ß. Subsequent association testing in more than 2,000 atopic dermatitis patients and 2,000 control subjects showed a significant excess of these LRRC32 variants in individuals with atopic dermatitis. Structural protein modeling and bioinformatic analysis predicted a disruption of protein transport upon these variants, and overexpression assays in CD4+CD25- T cells showed a significant reduction in surface expression of the mutated protein. Consistently, flow cytometric (FACS) analyses of different T-cell subtypes obtained from atopic dermatitis patients showed a significantly reduced surface expression of GARP and a reduced conversion of CD4+CD25- T cells into regulatory T cells, along with lower expression of latency-associated protein upon stimulation in carriers of the LRRC32 A407T variant. These results link inherited disturbances of transforming growth factor-ß signaling with atopic dermatitis risk.


Assuntos
Dermatite Atópica/genética , Dermatite Atópica/patologia , Predisposição Genética para Doença , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Adulto , Estudos de Casos e Controles , Células Cultivadas , Mapeamento Cromossômico , Dermatite Atópica/tratamento farmacológico , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Dados de Sequência Molecular , Prognóstico , RNA Mensageiro/análise , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Medição de Risco , Deleção de Sequência , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
16.
PLoS One ; 11(5): e0154872, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27149374

RESUMO

In recent years, genome-wide association studies (GWAS) have identified many loci that are shared among common disorders and this has raised interest in pleiotropy. For performing appropriate analysis, several methods have been proposed, e.g. conducting a look-up in external sources or exploiting GWAS results by meta-analysis based methods. We recently proposed the Compare & Contrast Meta-Analysis (CCMA) approach where significance thresholds were obtained by simulation. Here we present analytical formulae for the density and cumulative distribution function of the CCMA test statistic under the null hypothesis of no pleiotropy and no association, which, conveniently for practical reasons, turns out to be exponentially distributed. This allows researchers to apply the CCMA method without having to rely on simulations. Finally, we show that CCMA demonstrates power to detect disease-specific, agonistic and antagonistic loci comparable to the frequently used Subset-Based Meta-Analysis approach, while better controlling the type I error rate.


Assuntos
Pleiotropia Genética , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Interpretação Estatística de Dados , Pleiotropia Genética/genética , Humanos , Modelos Estatísticos
17.
J Allergy Clin Immunol ; 137(1): 130-136, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26253344

RESUMO

BACKGROUND: Atopic dermatitis (AD) is characterized by epidermal barrier failure and immune-mediated inflammation. Evidence on AD as a potential risk factor for inflammatory comorbidities is scarce. OBJECTIVES: We sought to test the hypothesis that prevalent AD is a risk factor for incident rheumatoid arthritis (RA) and inflammatory bowel disease (IBD; Crohn disease [CD], ulcerative colitis [UC]) and is inversely related to type 1 diabetes (T1D) and to investigate established RA, IBD, and T1D susceptibility loci in AD. METHODS: This cohort study used data from German National Health Insurance beneficiaries aged 40 years or younger (n = 655,815) from 2005 through 2011. Prevalent AD in the period 2005 to 2006 was defined as primary exposure, and incident RA, IBD, and T1D in the period 2007 to 2011 were defined as primary outcomes. Risk ratios were calculated with generalized linear models. Established RA, IBD, and T1D loci were explored in high-density genotyping data from 2,425 cases with AD and 5,449 controls. RESULTS: Patients with AD (n = 49,847) were at increased risk for incident RA (risk ratio [RR], 1.72; 95% CI, 1.25-2.37) and/or IBD (CD: RR, 1.34; 95% CI, 1.11-1.61; UC: RR, 1.25; 95% CI, 1.03-1.53). After adjusting for health care utilization, there was a nominally significant inverse effect on T1D risk (RR, 0.72; 95% CI, 0.53-0.998). There was no disproportionate occurrence of known RA, CD, UC, or T1D risk alleles in AD. CONCLUSIONS: AD is a risk factor for the development of RA and IBD. This excess comorbidity cannot be attributed to major known IBD and RA genetic risk factors.


Assuntos
Artrite Reumatoide/epidemiologia , Dermatite Atópica/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Doenças Inflamatórias Intestinais/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Razão de Chances , Prevalência , Fatores de Risco , Adulto Jovem
18.
Nat Commun ; 6: 8804, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26542096

RESUMO

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.


Assuntos
Asma/genética , Dermatite Atópica/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Adolescente , Adulto , Sistemas de Transporte de Aminoácidos Neutros/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Transporte/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fator de Transcrição Ikaros/genética , Interleucina-4/genética , Cinesina/genética , Modelos Logísticos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Adulto Jovem
19.
Nat Genet ; 47(12): 1449-1456, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26482879

RESUMO

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.


Assuntos
Dermatite Atópica/etnologia , Dermatite Atópica/genética , Grupos Étnicos/genética , Loci Gênicos , Marcadores Genéticos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Dermatite Atópica/patologia , Humanos , Imunidade Inata/genética , Fatores de Risco , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
20.
Am J Respir Crit Care Med ; 192(6): 727-36, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26051272

RESUMO

RATIONALE: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. OBJECTIVES: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. METHODS: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. MEASUREMENTS AND MAIN RESULTS: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. CONCLUSIONS: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Sarcoidose/genética , Adulto , Afro-Americanos/genética , Idoso , Estudos de Casos e Controles , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoidose/etnologia , Sarcoidose/imunologia
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