RESUMO
BACKGROUND & AIMS: Previously identified clinical risk factors such as sex, alcohol consumption, and age at infection do not accurately predict which patients with chronic hepatitis C (CHC) will develop advanced fibrosis (bridging fibrosis and cirrhosis). The aim of this study was to identify genetic polymorphisms that can predict the risk of advanced fibrosis in patients with CHC. METHODS: A total of 916 subjects with CHC was enrolled from 2 centers. A gene-centric disease association study of 24,832 putative functional, single nucleotide polymorphisms (SNPs) was performed. Of the 1609 SNPs that were significantly associated (P
Assuntos
Predisposição Genética para Doença , Hepatite C Crônica/genética , Hepatite C Crônica/patologia , Cirrose Hepática/genética , Polimorfismo Genético , Proteínas Quinases/genética , RNA Helicases/genética , Adolescente , Adulto , Idoso , Alelos , RNA Helicases DEAD-box , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Haplótipos , Heterozigoto , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Probabilidade , Prognóstico , Estudos Prospectivos , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting approximately 1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P=6.6 x 10(-4); replication-study allelic P=5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.