RESUMO
Optimal management of lower respiratory tract infection relies on distinguishing infectious from noninfectious etiologies and identifying the microbiologic cause if applicable. This process is complicated by overlapping clinical symptoms and the colonizing lung microbiota. In a recent issue of the JCI, Mick, Tsitsiklis, and colleagues apply RNA-Seq to tracheal aspirates from critically ill children and demonstrate how integration of the host response with microbial identification results in a harmonious and accurate diagnostic classifier. Though promising, there are numerous barriers to realizing a combined host and pathogen diagnostic.
Assuntos
Doenças Transmissíveis , Microbiota , Infecções Respiratórias , Criança , Humanos , Doenças Transmissíveis/diagnóstico , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologia , Pulmão , Sequenciamento do ExomaRESUMO
We performed a multitiered, case-control association study of psoriasis in three independent sample sets of white North American individuals (1,446 cases and 1,432 controls) with 25,215 genecentric single-nucleotide polymorphisms (SNPs) and found a highly significant association with an IL12B 3'-untranslated-region SNP (rs3212227), confirming the results of a small Japanese study. This SNP was significant in all three sample sets (odds ratio [OR](common) 0.64, combined P [Pcomb]=7.85x10(-10)). A Monte Carlo simulation to address multiple testing suggests that this association is not a type I error. The coding regions of IL12B were resequenced in 96 individuals with psoriasis, and 30 additional IL12B-region SNPs were genotyped. Haplotypes were estimated, and genotype-conditioned analyses identified a second risk allele (rs6887695) located approximately 60 kb upstream of the IL12B coding region that exhibited association with psoriasis after adjustment for rs3212227. Together, these two SNPs mark a common IL12B risk haplotype (OR(common) 1.40, Pcomb=8.11x10(-9)) and a less frequent protective haplotype (OR(common) 0.58, Pcomb=5.65x10(-12)), which were statistically significant in all three studies. Since IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines (IL12A and IL23A) and their receptors (IL12RB1, IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (OR(common) 1.44, Pcomb=3.13x10(-6)). Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes have an increased risk of disease (OR(common) 1.66, Pcomb=1.33x10(-8)). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to patients with psoriasis is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.
Assuntos
Predisposição Genética para Doença , Subunidade p40 da Interleucina-12/genética , Psoríase/genética , Receptores de Interleucina/genética , Adolescente , Adulto , Teorema de Bayes , Estudos de Casos e Controles , Criança , Feminino , Genética Populacional , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-12/genéticaRESUMO
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.
