Identification of IL18RAP/IL18R1 and IL12B as Leprosy Risk Genes Demonstrates Shared Pathogenesis between Inflammation and Infectious Diseases

Liu, Hong; Irwanto, Astrid; Tian, Haijun; Fu, Xi’an; Yu, Yang; Yu, Gongqi; Low, Hui-Qi; Chu, Tongsheng; Li, Yang; Shi, Benqing; Chen, Mingfei; Sun, Yonghu; Yuan, Cunzhong; Lü, Nan; You, Jiabao; Bao, Fangfang; Li, Jinghui; Liu, Jian; Liu, Huaxu; Liu, Dianchang; Yu, Xiaofei; Zhang, Lin; Yang, Qing; Wang, Na; Niu, Guiye; Ma, Shanshan; Zhou, Yan; Wang, Chuan; Chen, Shumin; Zhang, Xuejun; Li, Jianjun; Zhang, Furen

doi:10.1016/j.ajhg.2012.09.010

Cited by 81 publications

(73 citation statements)

References 39 publications

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“…In contrast, the function of CCDC122-LACC1 locus is yet unknown. Remarkably, our data add up to the accumulating body of evidence indicating a common association fingerprint across leprosy, Crohn's and Parkinson's disease (Orlova et al 2011): variants of leprosy susceptibility genes PARK2, TNFSF15, NOD2, LACC1, LRRK2, IL23R, IL18RAP/IL18R1 and IL12B have been described also associated with Crohn's, Parkinson's and inflammatory bowel disease (Liu et al 2012;Trabzuni et al 2013;Zhang et al 2009Zhang et al , 2011. It is possible to speculate that a better understanding of the genotype-phenotype regulatory switches controlled by these associated SNPs can help develop novel diagnostic and therapeutic approaches for infectious, inflammatory and neurodegenerative diseases.…”

Section: Discussionsupporting

confidence: 63%

NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians

et al. 2014

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Leprosy is a complex disease with phenotypes strongly influenced by genetic variation. A Chinese genome-wide association study (GWAS) depicted novel genes and pathways associated with leprosy susceptibility, only partially replicated by independent studies in different ethnicities. Here, we describe the results of a validation and replication study of the Chinese GWAS in Brazilians, using a stepwise strategy that involved two family-based and three independent case-control samples, resulting in 3,614 individuals enrolled. First, we genotyped a family-based sample for 36 tag single-nucleotide polymorphisms (SNPs) of five genes located in four different candidate loci: CCDC122-LACC1, NOD2, TNFSF15 and RIPK2. Association between leprosy and tag SNPs at NOD2 (rs8057431) and CCDC122-LACC1 (rs4942254) was then replicated in three additional, independent samples (combined OR(AA) = 0.49, P = 1.39e-06; OR(CC) = 0.72, P = 0.003, respectively). These results clearly implicate the NOD2 pathway in the regulation of leprosy susceptibility across diverse populations.

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Section: Discussionsupporting

confidence: 63%

NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians

et al. 2014

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“…For SNPs within previously reported loci 3,4,9,10 , we selected all of the reported genomewide and suggestive associations by choosing either the reported SNP or a proxy SNP in perfect LD (r 2 and D′ ≥ 0.99; refs. 3,4,9,10) with the reported SNP. We also selected SNPs from a number of known loci showing independent association (P value after conditional analysis on the reported association of <5 × 10 −4 ).…”

Section: Phasing and Imputationmentioning

confidence: 99%

“…The molecular nature of genetic susceptibility to leprosy has been intensively investigated by candidate gene studies 3,4 , genomewide linkage analyses [5][6][7][8] and GWAS [9][10][11] , which have identified 11 suscepti bility loci. Most of the implicated susceptibility genes encode proteins involved in immunity, whereas one locus (RAB32 at 6q24.3) suggests a role for autophagocytosis in leprosy pathogenesis.…”

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confidence: 99%

Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy

Liu¹,

et al. 2015

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Genome-wide association studies (GWAS) have led to the discovery of several susceptibility loci for leprosy with robust evidence, providing biological insight into the role of host genetic factors in mycobacterial infection. However, the identified loci only partially explain disease heritability, and additional genetic risk factors remain to be discovered. We performed a 3-stage GWAS of leprosy in the Chinese population using 8,313 cases and 16,017 controls. Besides confirming all previously published loci, we discovered six new susceptibility loci, and further gene prioritization analysis of these loci implicated BATF3, CCDC88B and CIITA-SOCS1 as new susceptibility genes for leprosy. A systematic evaluation of pleiotropic effects demonstrated a high tendency for leprosy susceptibility loci to show association with autoimmunity and inflammatory diseases. Further analysis suggests that molecular sensing of infection might have a similar pathogenic role across these diseases, whereas immune responses have discordant roles in infectious and inflammatory diseases.

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“…IL18RAP region polymorphisms are associated with multiple immune-mediated diseases, including IBD(15), atopic dermatitis(16), leprosy(17), celiac disease(18) and Type I diabetes(19). IL-18RAP interactions with IL-18R1 mediate signal transduction initiated by IL-18(20).…”

Section: Introductionmentioning

confidence: 99%

The IL18RAP Region Disease Polymorphism Decreases IL-18RAP/IL-18R1/IL-1R1 Expression and Signaling through Innate Receptor–Initiated Pathways

Hedl

Zheng

Abraham

2014

The Journal of Immunology

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Fine-tuning of cytokine-inducing pathways is essential for immune homeostasis. Consistently, a dysregulated increase or decrease in pattern recognition receptors (PRR)-induced signaling and cytokine secretion can lead to inflammatory bowel disease (IBD). Multiple gene loci are associated with IBD, but their functional effects are largely unknown. One such region in chromosome 2q12 (rs917997), also associated with other immune-mediated diseases, encompasses IL18RAP. We found that human monocyte-derived macrophages (MDM) from rs917997 AA risk carriers secrete significantly less cytokines than G carriers upon stimulation of multiple PRRs including NOD2. We identified that IL-18 signaling through IL-18RAP was critical in amplifying PRR-induced cytokine secretion in MDM. IL-18RAP responded to NOD2-initiated early, caspase-1-dependent autocrine IL-18, which dramatically enhanced MAPK, NF-κB, PI3K and calcium signaling. Reconstituting MAPK activation was sufficient to rescue decreased cytokines in NOD2-stimulated IL-18RAP-deficient MDM. Relative to GG carriers, MDM from rs917997 AA carriers had decreased expression of cell surface IL-18RAP protein, as well as of IL-18R1 and IL-1R1, genes also located in the IL18RAP region. Accordingly, these risk-carrier MDM show diminished PRR-, IL-18-, and IL-1-induced MAPK and NF-κB signaling. Taken together, our results demonstrate clear functional consequences of the rs917997 risk-polymorphism; this polymorphism leads to a loss-of-function through decreased IL-18RAP, IL-18R1 and IL-1R1 protein expression, which impairs autocrine IL-18 and IL-1 signaling, thereby leading to decreased cytokine secretion in MDM upon stimulation of a broad range of PRR.

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Identification of IL18RAP/IL18R1 and IL12B as Leprosy Risk Genes Demonstrates Shared Pathogenesis between Inflammation and Infectious Diseases

Cited by 81 publications

References 39 publications

NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians

NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians

Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy

The IL18RAP Region Disease Polymorphism Decreases IL-18RAP/IL-18R1/IL-1R1 Expression and Signaling through Innate Receptor–Initiated Pathways

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