[en] 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.
Xavier, R.J., Podolsky, D.K., Unravelling the pathogenesis of inflammatory bowel disease. Nature 448 (2007), 427–434.
Abraham, C., Cho, J.H., Inflammatory bowel disease. N Engl J Med 361 (2009), 2066–2078.
Jostins, L., Ripke, S., Weersma, R.K., et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491 (2012), 119–124.
Liu, J.Z., van Sommeren, S., Huang, H., et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 47 (2015), 979–986.
Huang, H., Fang, M., Jostins, L., et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547 (2017), 173–178.
Uhlig, H.H., Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 62 (2013), 1795–1805.
Uhlig, H.H., Schwerd, T., Koletzko, S., et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147 (2014), 990–1007 e3.
Bodmer, W., Bonilla, C., Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40 (2008), 695–701.
Momozawa, Y., Mni, M., Nakamura, K., et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat Genet 43 (2011), 43–47.
Nejentsev, S., Walker, N., Riches, D., et al. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324 (2009), 387–389.
Winkelstein, J.A., Marino, M.C., Johnston, R.B. Jr., et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79 (2000), 155–169.
Marks, D.J., Miyagi, K., Rahman, F.Z., et al. Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn's disease. Am J Gastroenterol 104 (2009), 117–124.
Dieckgraefe, B.K., Korzenik, J.R., Husain, A., et al. Association of glycogen storage disease 1b and Crohn disease: results of a North American survey. Eur J Pediatr 161:Suppl 1 (2002), S88–S92.
Ishii, E., Matui, T., Iida, M., et al. Chediak-Higashi syndrome with intestinal complication. Report of a case. J Clin Gastroenterol 9 (1987), 556–558.
Kaplan, J., De Domenico, I., Ward, D.M., Chediak-Higashi syndrome. Curr Opin Hematol 15 (2008), 22–29.
Grucela, A.L., Patel, P., Goldstein, E., et al. Granulomatous enterocolitis associated with Hermansky-Pudlak syndrome. Am J Gastroenterol 101 (2006), 2090–2095.
D'Agata, I.D., Paradis, K., Chad, Z., et al. Leucocyte adhesion deficiency presenting as a chronic ileocolitis. Gut 39 (1996), 605–608.
Lamport, R.D., Katz, S., Eskreis, D., Crohn's disease associated with cyclic neutropenia. Am J Gastroenterol 87 (1992), 1638–1642.
Cannioto, Z., Berti, I., Martelossi, S., et al. IBD and IBD mimicking enterocolitis in children younger than 2 years of age. Eur J Pediatr 168 (2009), 149–155.
Gambineri, E., Torgerson, T.R., Ochs, H.D., Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 15 (2003), 430–435.
Kotlarz, D., Beier, R., Murugan, D., et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143 (2012), 347–355.
Pachlopnik Schmid, J., Canioni, D., Moshous, D., et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 117 (2011), 1522–1529.
Worthey, E.A., Mayer, A.N., Syverson, G.D., et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 13 (2011), 255–262.
Franke, A., McGovern, D.P., Barrett, J.C., et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42 (2010), 1118–1125.
Glocker, E.O., Kotlarz, D., Boztug, K., et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361 (2009), 2033–2045.
Glocker, E.O., Frede, N., Perro, M., et al. Infant colitis—it's in the genes. Lancet, 376, 2010, 1272.
Engelhardt, K.R., Shah, N., Faizura-Yeop, I., et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol 131 (2013), 825–830.
Begue, B., Verdier, J., Rieux-Laucat, F., et al. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol 106 (2011), 1544–1555.
Mao, H., Yang, W., Lee, P.P., et al. Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn's disease. Genes Immun 13 (2012), 437–442.
Moran, C.J., Walters, T.D., Guo, C.H., et al. IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis 19 (2013), 115–123.
Shouval, D.S., Biswas, A., Goettel, J.A., et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 40 (2014), 706–719.
Rioux, J.D., Xavier, R.J., Taylor, K.D., et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39 (2007), 596–604.
Roberts, R.L., Hollis-Moffatt, J.E., Gearry, R.B., et al. Confirmation of association of IRGM and NCF4 with ileal Crohn's disease in a population-based cohort. Genes Immun 9 (2008), 561–565.
Eglinton, T.W., Roberts, R., Pearson, J., et al. Clinical and genetic risk factors for perianal Crohn's disease in a population-based cohort. Am J Gastroenterol 107 (2012), 589–596.
Oh, S.H., Baek, J., Kim, K.M., et al. Is whole exome sequencing clinically practical in the management of pediatric Crohn's disease?. Gut Liver 9 (2015), 767–775.
Dhillon, S.S., Fattouh, R., Elkadri, A., et al. Variants in nicotinamide adenine dinucleotide phosphate oxidase complex components determine susceptibility to very early onset inflammatory bowel disease. Gastroenterology 147 (2014), 680–689 e2.
Aguilar, C., Lenoir, C., Lambert, N., et al. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy Clin Immunol 134 (2014), 1131–1141 e9.
Kelsen, J.R., Dawany, N., Martinez, A., et al. A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report. BMC Gastroenterol, 15, 2015, 160.
Girardelli, M., Arrigo, S., Barabino, A., et al. The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency. BMC Pediatr, 15, 2015, 208.
Zeissig, Y., Petersen, B.S., Milutinovic, S., et al. XIAP variants in male Crohn's disease. Gut 64 (2015), 66–76.
Howie, B.N., Donnelly, P., Marchini, J., A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet, 5, 2009, e1000529.
Purcell, S., Neale, B., Todd-Brown, K., et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 (2007), 559–575.
de Bakker, P.I., Ferreira, M.A., Jia, X., et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet 17 (2008), R122–R128.
Van der Auwera, G.A., Carneiro, M.O., Hartl, C., et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics, 43, 2013 11.10.1–33.
Kumar, P., Henikoff, S., Ng, P.C., Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4 (2009), 1073–1081.
Adzhubei, I., Jordan, D.M., Sunyaev, S.R., Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet, 2013 Chapter 7:Unit7 20.
Ammann, S., Elling, R., Gyrd-Hansen, M., et al. A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency. Clin Exp Immunol 176 (2014), 394–400.
El Kasmi, K.C., Smith, A.M., Williams, L., et al. Cutting edge: A transcriptional repressor and corepressor induced by the STAT3-regulated anti-inflammatory signaling pathway. J Immunol 179 (2007), 7215–7219.
Boyle, A.P., Hong, E.L., Hariharan, M., et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 22 (2012), 1790–1797.
Grundberg, E., Small, K.S., Hedman, A.K., et al. Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet 44 (2012), 1084–1089.
Westra, H.J., Peters, M.J., Esko, T., et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45 (2013), 1238–1243.
Fairfax, B.P., Humburg, P., Makino, S., et al. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science, 343, 2014, 1246949.
Eckelman, B.P., Salvesen, G.S., Scott, F.L., Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 7 (2006), 988–994.
Galban, S., Duckett, C.S., XIAP as a ubiquitin ligase in cellular signaling. Cell Death Differ 17 (2010), 54–60.
Krieg, A., Correa, R.G., Garrison, J.B., et al. XIAP mediates NOD signaling via interaction with RIP2. Proc Natl Acad Sci U S A 106 (2009), 14524–14529.
Pedersen, J., LaCasse, E.C., Seidelin, J.B., et al. Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation. Trends Mol Med 20 (2014), 652–665.
Karczewski, K.J., Weisburd, B., Thomas, B., et al. The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res 45 (2017), D840–D845.
Yang, X., Miyawaki, T., Kanegane, H., SAP and XIAP deficiency in hemophagocytic lymphohistiocytosis. Pediatr Int 54 (2012), 447–454.
Rigaud, S., Fondaneche, M.C., Lambert, N., et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444 (2006), 110–114.
Latour, S., Aguilar, C., XIAP deficiency syndrome in humans. Semin Cell Dev Biol 39 (2015), 115–123.
Aguilar, C., Latour, S., X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome. J Clin Immunol 35 (2015), 331–338.
Speckmann, C., Lehmberg, K., Albert, M.H., et al. X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clin Immunol 149 (2013), 133–141.
Muise, A.M., Xu, W., Guo, C.H., et al. NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut 61 (2012), 1028–1035.
Levine, A., Griffiths, A., Markowitz, J., et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 17 (2011), 1314–1321.
