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Gastroenterology ; 154(8): 2165-2177, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29501442

RESUMO

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.


Assuntos
Doença de Crohn/genética , Síndromes de Imunodeficiência/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bélgica , Células Cultivadas , Criança , Pré-Escolar , Doença de Crohn/sangue , Doença de Crohn/imunologia , Feminino , Imunofluorescência , França , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/imunologia , Interleucina-10/genética , Masculino , Pessoa de Meia-Idade , Monócitos , Mutação de Sentido Incorreto , Proteína Adaptadora de Sinalização NOD2/metabolismo , Cultura Primária de Células , Análise de Sequência de DNA , Transdução de Sinais/genética , Adulto Jovem
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