Genetics of Behcet disease inside and outside the MHC

Meguro, Akira; Inoko, Hidetoshi; Ôta, Masao; Katsuyama, Yoshihiko; Oka, Akira; Okada, Eiichi; Yamakawa, Ryoji; Yuasa, T.; Fujioka, Toshihiko; Ohno, Shigeaki; Bahram, Seiamak; Mizuki, Nobuhisa

doi:10.1136/ard.2009.108571

Cited by 120 publications

(88 citation statements)

References 51 publications

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“…Associations between other HLA-B types and BD have been reported (8)(9)(10), as have associations between BD and both HLA-A and HLA-C alleles (2,3,(14)(15)(16)(17). In our study, we observed that HLA-B*15, -B*27, and -B*57 were independent susceptibility alleles for BD, consistent with earlier reports.…”

Section: Discussionsupporting

confidence: 82%

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Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Ombrello

Kirino

Bakker

et al. 2014

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

122

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The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Behçet disease (BD). Associations between BD and other factors within the MHC have been reported also, although strong regional linkage disequilibrium complicates their confident disentanglement from HLA-B*51. In the current study, we examined a combination of directly obtained and imputed MHC-region SNPs, directly obtained HLA-B locus types, and imputed classical HLA types with their corresponding polymorphic amino acid residues for association with BD in 1,190 cases and 1,257 controls. SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 × 10 −8 ). HLA-B*51, -A*03, -B*15, -B*27, -B*49, -B*57, and -A*26 each contributed independently to BD risk. We directly examined rs116799036, a noncoding SNP upstream of HLA-B that was recently suggested to underlie the association of HLA-B*51 with BD, but we were unable to replicate that finding in our collection. Instead, we mapped the BD association to seven MHC class I (MHC-I) amino acid residues, including anchor residues that critically define the selection and binding of peptides to MHC-I molecules, residues known to influence MHC-Ikiller immunoglobulin-like receptor interactions, and a residue located in the signal peptide of HLA-B. The locations of these variants collectively implicate MHC-I peptide binding in the pathophysiology of BD. Furthermore, several lines of evidence suggest a role for altered regulation of cellular cytotoxicity in BD pathogenesis.HLA imputation | autoinflammation | antigen presentation | killer immunoglobulin-like receptors | natural killer cells

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Section: Discussionsupporting

confidence: 82%

“…However, efforts to parse the effects of MICA and HLA-B alleles definitively have been confounded by their particularly strong LD (11)(12)(13)(14). Additionally, HLA-A has been identified as a BD susceptibility locus in numerous studies (2,3,(14)(15)(16)(17), and it has been suggested that HLA-C contributes to BD risk, as well (14).…”

mentioning

confidence: 99%

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Ombrello

Kirino

Bakker

et al. 2014

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

122

View full text Add to dashboard Cite

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“…This has recently been confirmed in a genome-wide association study (3). Recent data provide evidence for a critical role of interleukin-17, interleukin-21, and their modulating effect on Th17 and regulatory T cells (4).…”

Section: Introductionmentioning

confidence: 53%

Behçet's disease: Successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis

Adler¹,

Baumgartner²,

Villiger³

2012

Arthritis Care & Research

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Objective. To evaluate the therapeutic effect of infliximab in patients with inflammatory vascular lesions due to Behçet's disease (BD). Methods. Seven patients with clinical evidence of severe vascular BD were analyzed: 3 patients with aortic involvement, 1 with recurrent venous thrombosis of the pelvic veins, 1 with recurrent venous and arterial thromboses of the thigh, and 2 with retinal vasculitis. Infliximab was initiated with 3-5 mg/kg of body weight and infusions were repeated in intervals of 4 weeks as either first-line therapy in 3 patients or add on after failure of conventional immunosuppression in the remaining 4. Ongoing immunosuppression consists of a various combination of azathioprine (n ‫؍‬ 2), methotrexate (n ‫؍‬ 3), cyclosporine (n ‫؍‬ 3), and low-dose glucocorticoids (n ‫؍‬ 3). Results. Control of inflammation was seen 1-5 days after infliximab induction in all patients. C-reactive protein level was reduced from a mean of 89 mg/liter prior to infliximab to 9 mg/liter thereafter. Vision increased rapidly in patients with retinal vasculitis. Vascular grafts remained patent. The inflamed and dissected aortic wall healed over a period of 6 months. Infliximab could be stopped in 2 patients; intervals could be extended in 4 to a maximum of 8 weeks. Infliximab and basic immunosuppression were well tolerated; no drug-induced side effects were recorded. Conclusion. Infliximab is effective in inducing and maintaining remission of vasculitic activity in patients with BD. The rapid effect together with excellent tolerability suggests that infliximab should be considered as a first-line agent in severe vascular BD.

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“…Япония [28] Корея [29] Китай [30] Турция [31] Иордания [32] Германия [6] Франция [6] Италия [6] Россия [33] США [34] HLA B5101 в генезе ББ участвует и HLA A26 [35]. При изу-чении ассоциации антигена HLA A26 [10] в мультиэтниче-ской выборке российских больных с ББ не отмечено связи этого аллеля с заболеванием [36].…”

Section: ч а с т о т а H La B 5 1 у б о л ь н ы х с б б в р а з н ы хunclassified

Behcet's disease: demographic and genetic aspects (a literature review)

Исмаиловна

Алекберова²

2014

Modern Rheumatology Journal

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Болезнь Бехчета (ББ) -системный васкулит, неизвест-ной этиологии с мультиорганным поражением. Это заболе-вание с непредсказуемыми обострениями и ремиссиями имеет уникальную географическую распространенность [1]. Сообщения о больных с клиническими проявлениями, ко-торые сегодня относят к ББ, можно найти в работах Гиппо-крата и древних врачей Японии, Китая и арабских стран, что свидетельствует о том, что болезнь известна с давних времен [2].Заболевание носит имя турецкого ученого Хулуси Бех-чета (Behcet), который в 1937 г. опубликовал наблюдение 3 больных, которые имели триаду симптомов: язвы в рото-вой полости и на гениталиях и офтальмологические проявле-ния. Автор подчеркнул, что различные органы поражаются не одновременно, а на протяжении длительного времени [3] Arab countries, Turkey, and Israel (19.9; 25.6; and 26 years, respectively)

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Genetics of Behcet disease inside and outside the MHC

Abstract: This GWAS highlights the premier genetic susceptibility locus for BD as the major histocompatibility complex itself, wherein reside two independent loci: HLA-B and HLA-A.

Cited by 120 publications

References 51 publications

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Behçet's disease: Successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis

Behcet's disease: demographic and genetic aspects (a literature review)

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