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.

中文翻译：

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单基因原发性免疫缺陷病相关基因的分析确定了克罗恩病患者XIAP的罕见变异

背景与目标

一些罕见的单基因原发性免疫缺陷（PID）的特征是类似于克罗恩病（CD）的慢性肠道炎症。我们调查了与这些10种单基因疾病相关的23个基因是否包含增加CD风险的常见，低频或罕见变体。

方法

使用与欧洲大约17,000名患有CD或不患有CD的患者（对照）的基因型相对应的元数据，对以候选基因为中心的1 Mb位点的常见和低频变异进行了分析。通过对4750例患者进行高通量测序，评估了罕见变异的贡献，其中包括2390例CD患者中的660例早发和/或家族性病例。在SW480或HeLa细胞中从载体表达变体，并在免疫荧光，萤光素酶，免疫沉淀和免疫印迹试验中分析了其产物的功能。

结果

我们重现了白介素10基因座与CD的相关性（P  = .007），尽管没有显着相关的变体改变了白介素10的编码序列。我们发现XIAP对于患有CD的患者与对照组相比，对于罕见的编码突变具有明显的丰富性。 （P  = .02）。我们确定了4个与CD相关的先前未报道的错义变体。XIAP变异导致2型PID的X连锁淋巴增生性疾病，但这些变异的携带者均未具有2连锁X连锁淋巴增生性疾病的所有临床特征。鉴定出的XIAP变异S123N，R233Q和P257A与受损戊二酰二肽刺激后激活NOD2信号。

结论

在系统分析23个PID相关基因的变异中，我们确认了XIAP中变异与CD的关联。CD相关变体的进一步筛选和对其功能的分析可以增进我们对PID相关基因与CD发病机制之间关系的了解。