RESUMO
Leukocyte telomere length is a highly polygenic trait that has been associated with a complex range of lifestyle factors and disease risk. McQuillan et al.'s results comparing telomere length to malaria incidence rates suggest that infections may be another important factor, possibly through permanent shortening of telomeres in hematopoietic progenitor cells.
Assuntos
Leucócitos , Malária , Telômero , Humanos , Malária/epidemiologia , Doenças Endêmicas , Encurtamento do Telômero , IncidênciaRESUMO
To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
Assuntos
Loci Gênicos , Predisposição Genética para Doença , Imunidade Inata/genética , Psoríase/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Proteína DEAD-box 58 , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/imunologia , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/imunologia , Estudo de Associação Genômica Ampla , Guanilato Ciclase/genética , Guanilato Ciclase/imunologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Psoríase/imunologia , Receptores Imunológicos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Pele/imunologia , Linfócitos T/imunologia , População Branca/genéticaRESUMO
Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
Assuntos
Esôfago de Barrett/genética , Cromossomos Humanos Par 16 , Predisposição Genética para Doença , Complexo Principal de Histocompatibilidade , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Modelos GenéticosRESUMO
Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.