Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility

Takeuchi, Masaki; Mizuki, Nobuhisa; Meguro, Akira; Ombrello, Michael J.; Kirino, Yohei; Satorius, Colleen; Le, Julie; Blake, Mary; Erer, Burak; Kawagoe, Tatsukata; Üstek, Duran; Tuğal-Tutkun, İlknur; Seyahi, Emire; Özyazgan, Yılmaz; Sousa, Inês; Davatchi, Fereydoun; Francisco, Vânia; Shahram, Farhad; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida; Ohno, Shigeaki; Ueda, Atsushi; Ishigatsubo, Yoshiaki; Gadina, Massimo; Oliveira, Sofia A.; Gül, Ahmet; Kastner, Daniel L.; Remmers, Elaine F.

doi:10.1038/ng.3786

Cited by 126 publications

(113 citation statements)

References 56 publications

(63 reference statements)

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“…12 The results showed that four SNPs (rs913678 in CEBPB-PTPN1, rs9316059 in LACC1, rs10094579 in RIPK2, rs224127 in ADO-EGR2) contribute to the genetic susceptibility to BD in a Chinese Han population.…”

Section: Discussionmentioning

confidence: 96%

“…The Immunochip study was performed in Turkish patients, and the findings concerning LACC1 rs9316059 was also confirmed in a Japanese cohort. 12 In the same study, the association with SNP rs2121033 in LACC1 was identified by meta-analysis in three populations (Turkish, Iranian and Japanese). These two SNPs are in strong LD with each other (r 2 =0.891, in HCB).…”

Section: Discussionmentioning

confidence: 96%

“…More significantly, the same study identified six new BD risk loci (IL1A-IL1B, IRF8, CEBPB-PTPN1, ADO-EGR2, RIPK2 and LACC1) with genome-wide significance (p<5×10 −8 ) and a number of new loci with a suggestive disease association (p<5×10 −5 ). Takeuchi et al also performed a replication study 12 and confirmed the association for some, but not all, loci in Iranian and Japanese cohorts. These findings indicated that the genetic background of BD may differ among different ethnic groups.…”

Section: Introductionmentioning

confidence: 84%

“…P het <0.05 and I 2 >0.5 were considered to be significant. Statistical power was estimated from effect size in the original Turkish data sets from the 'Takeuchi' study, 12 …”

Section: Discussionmentioning

confidence: 99%

“…12 Criteria used were as follows: we selected the lead SNPs in the potential susceptibility loci with a p value less than 5×10 −5 . In order to increase the reliability of our results, the other †Some SNPs (six in total) were excluded since they were not polymorphic in Han Chinese (rs17753641, rs17810546, rs79891766, rs116379815, rs13190001 and rs1698386).…”

Section: Snps Selectionmentioning

confidence: 99%

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Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behcet’s disease in a Chinese Han population

Hou

et al. 2018

Br J Ophthalmol

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BackgroundAn Immunochip study recently identified the association of a number of new genetic loci with Behcet’s disease (BD).ObjectiveTo confirm the association between new genetic loci reported in an Immunochip study and BD in a Han Chinese population.MethodsA two-stage association study was carried out in 1238 patients with BD and 1458 healthy controls. Twenty-two candidate single nucleotide polymorphisms (SNPs) were selected for genotyping by iPLEXGold genotyping or TaqMan SNP assays and a meta-analysis was performed for significantly associated markers.ResultsThe results showed that four SNPs (LACC1/rs9316059, CEBPB-PTPN1/rs913678, ADO-EGR2/rs224127 and RIPK2/rs10094579) were associated with BD in an allelic association test (rs9316059 T allele: pc=4.95×10−8, OR=0.687; rs913678 C allele: pc=3.01×10−4, OR=1.297; rs224127 A allele: pc=3.77×10−4, OR=1.274; rs10094579 A allele: pc=6.93×10−4, OR=1.302). For four SNPs tested by meta-analysis, the association with BD was strengthened and all exceeded genome-wide significance (rs9316059: p=2.96×10−16; rs913678: p=2.09×10−16; rs224127: p=5.28×10−13; rs10094579: p=9.21×10−11).ConclusionsOur findings confirmed the association of four loci (LACC1, CEBPB-PTPN1, ADO-EGR2 and RIPK2) in Chinese Han patients with BD.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 84%

“…P het <0.05 and I 2 >0.5 were considered to be significant. Statistical power was estimated from effect size in the original Turkish data sets from the 'Takeuchi' study, 12 …”

Section: Discussionmentioning

confidence: 99%

Section: Snps Selectionmentioning

confidence: 99%

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Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behcet’s disease in a Chinese Han population

Hou

et al. 2018

Br J Ophthalmol

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A Novel RELA Truncating Mutation in a Familial Behçet’s Disease–like Mucocutaneous Ulcerative Condition

Adeeb

Dorris

Morgan

et al. 2021

Arthritis & Rheumatology

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Objective. Monogenic Behçet's disease (BD)-like conditions are increasingly recognized and to date have been found to predominantly involve loss-of-function variants in TNFAIP3. This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD-like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls). Methods. Whole-exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v-rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA −/− mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF-κB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild-type and truncated RELA in experimental systems and patient samples. Results. A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA −/− mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild-type RELA; however, there was no difference in RELA nuclear translocation. In RelA −/− MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98-fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild-type RELA (P = 0.036). Conclusion. Our data indicate that RELA loss-of-function mutations cause BD-like autoinflammation and NMO via impaired NF-κB signaling and increased apoptosis.

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Genetic Association of a Gain‐of‐Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet’s Disease

Ortiz-Fernández

Coit

Yılmaz

et al. 2021

Arthritis & Rheumatology

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Objective Behçet’s disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet’s disease in a diverse multiethnic population. Methods A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray‐24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed. Results We identified 2 novel genetic susceptibility loci for Behçet’s disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10−9) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10−8). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide‐stimulated monocytes. In addition, our results replicated the association (P < 5 × 10−8) of 6 previously identified susceptibility loci in Behçet’s disease: IL10, IL23R, IL12A‐AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behçet’s disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10−5), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet’s disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated. Conclusion We performed the largest genetic association study in Behçet’s disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.

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Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility

Cited by 126 publications

References 56 publications

Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behcet’s disease in a Chinese Han population

Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behcet’s disease in a Chinese Han population

A Novel RELA Truncating Mutation in a Familial Behçet’s Disease–like Mucocutaneous Ulcerative Condition

Genetic Association of a Gain‐of‐Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet’s Disease

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