Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease

Remmers, Elaine F.; Coşan, Fulya; Kirino, Yohei; Ombrello, Michael J.; Abacı, Neslihan; Satorius, Colleen; Le, Julie; Yang, Barbara; Korman, Benjamin; Çakıris, Aris; Aglar, Oznur; Emrence, Zeliha; Azaklı, Hülya; Ustek, Duran; Tuğal-Tutkun, İlknur; Akman‐Demir, Gülşen; Chen, Weiwei; Amos, Christopher I.; Dizon, Michael B.; Köse, Afet Akdağ; Azizlerli, Gülsevim; Erer, Burak; Brand, Stephan; Kaklamani, Virginia; Kaklamanis, Phaedon; Ben-Chétrit, Eldad; Stanford, Miles; Fortune, Farida; Ghabra, Marwen; Ollier, William; Cho, Young-Hun; Bang, Dongsik; O’Shea, John; Wallace, Graham R.; Gadina, Massimo; Kastner, Daniel L.; Gül, Ahmet

doi:10.1038/ng.625

Cited by 595 publications

(468 citation statements)

References 24 publications

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“…This has already generated tangible benefits, and in BD a recent genome-wide association study (GWAS) has not only confirmed the association with know HLA-B*51 but identified further associations within MHC class I and also an association at IL-10 and IL23R-IL12RB2 loci. 96,97 This is concordant with other smaller candidate single nucleotide polymorphism (SNP) analysis studies that show in sympathetic ophthalmia an association with IL-10-1082 SNP and three haplotype-tagging SNPs(htSNPs) in the IL10 gene, rs6703630, rs2222202, and rs3024490, are significantly associated with susceptibility to non-infectious uveitis, whereas a LTA þ 252AA/ TNFhtSNP2GG haplotype (rs909253 and rs361525) is protective. 98,99 Whether this will predict the outcome on an individual basis is unknown, 100 but it highlights how further GWAS and, more importantly, genomics, RNA sequencing, and transcriptomics, will shape our future approach by identifying new genes, potential biomarkers, and new targets for therapy.…”

Section: How Do We Harness Our Approaches?supporting

confidence: 76%

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Lee

Dick

2011

Eye

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The blockbuster drug paradigm is under increasing scrutiny across the biopharmaceutical industry. Intraocular inflammation poses particular challenges to this, given the heterogeneity of conditions in the uveitis spectrum, and the increasing acknowledgement of individual patient and disease variance in underlying immune responses. This need has triggered a drive towards personalised and stratified medicine, supported and enabled as a result of continued development of both experimental models and molecular biological techniques and improved clinical classification. As such we have the ability now to systematically appraise at a genomic, transcriptomic, and proteomic level individual immunophenotype, and the promise that in the eye this can be augmented by in vivo immune imaging to identify individual immunopathology. With such advances all running in parallel, we are entering an era of experimental medicine that will facilitate early diagnosis, generate biomarkers for accurate prognostication, and enable the development of individualised and targeted therapies, which can progress rapidly into clinical practice.

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Section: How Do We Harness Our Approaches?supporting

confidence: 76%

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Lee

Dick

2011

Eye

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“…By comparison, B*52/MICA*009 was found in 25% of controls (8). Recently genome-wide association studies (GWASs) in different patient populations showed specific genes linked to BD in different ethnic groups; however, all the studies identified the HLA-B loci as the strongest association (9)(10)(11). However, in a recent study, deep sequencing of the HLA region identified an SNP, rs116799036, close to MICA that gave the strongest association and was independent of HLA-B*51 (12).…”

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confidence: 99%

HLA-B51* the primary risk in Behçet disease

Wallace

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Genetic factors are involved in the pathogenesis of the disease. In addition to the human leukocyte antigen gene encoding B*51 (HLA-B*51), genome-wide association studies (GWAS) have identified common variants in regions encompassing the major histocompatibility complex class I genes, IL10, and IL23R-IL12RB2 associated with BD in both the Turkish and Japanese populations (2,3). Moreover, a GWAS with imputed genotypes identified the C-C chemokine receptor 1 gene (CCR1), STAT4, a region encompassing five genes encoding the killer cell lectin-like receptor family members, K1, C1, C2, C3, and C4 in the natural killer gene complex (KLRK1, KLRC1, KLRC2, KLRC3, and KLRC4), and the endoplasmic reticulum aminopeptidase gene (ERAP1) associated with BD (4).…”

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confidence: 99%

Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease

Kirino

Zhou

Ishigatsubo³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behçet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS ( IL10, IL23R , CCR1 , STAT4 , KLRK1 , KLRC1, KLRC2, KLRC3, KLRC4 , and ERAP1 ) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4 ) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R ( P = 6.9 × 10 −5 ), and one gene involved in innate immunity, TLR4 ( P = 8.0 × 10 −4 ), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied ( P = 0.0063–0.045). Furthermore, carriage of the familial Mediterranean fever gene ( MEFV ) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 × 10 −12 ). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.

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Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease

Cited by 595 publications

References 24 publications

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

HLA-B51* the primary risk in Behçet disease

Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease

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Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease

Cited by 595 publications

References 24 publications

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

HLA-B*51 the primary risk in Behçet disease

Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease

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HLA-B51* the primary risk in Behçet disease