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Gastroenterology (New York, N.Y. 1943)
A few rare monogenic primary immunodeficiencies (PID) 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.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.We reproduced the association of the IL10 locus with CD (P=.007), although none of the significantly associated variants modified the coding sequence of IL10. 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 PID X-linked lymphoproliferative disease type 2 (XLP2), yet none of the carriers of these variants had all the clinical features of XLP2. Identified XIAP variants S123N, R233Q and P257A were associated with an impaired activation of NOD2 signaling following MDP stimulation.In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screens for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis.