Significance of valine/leucine247 polymorphism of β2‐glycoprotein I in antiphospholipid syndrome: Increased reactivity of anti–β2‐glycoprotein I autoantibodies to the valine247 β2‐glycoprotein I variant

Yasuda, Shinsuke; Atsumi, Tatsuya; Matsuura, Eiji; Kaihara, Keiko; Yamamoto, Daisuke; Ichikawa, Kenji; Koike, Takao

doi:10.1002/art.20741

Cited by 57 publications

(52 citation statements)

References 31 publications

(35 reference statements)

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“…While the lower prevalence of aPL and the less frequent use of exogenous hormones might contribute to the lower incidence of venous thrombosis observed in our Chinese patients, other factors not addressed in this study may be responsible for this ethnic difference. These include differences in the prevalence of acquired activated protein C resistance, factor V Leiden mutation, ␤ 2 -glycoprotein I genetic mutation, and antiprothrombin antibodies, which have been reported in association with venous thromboembolism in SLE patients (43)(44)(45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Incidence and risk factors of thromboembolism in systemic lupus erythematosus: A comparison of three ethnic groups

Mok

Tang

et al. 2005

Arthritis & Rheumatism

213

173

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Objective. To compare the incidence and risk factors for thromboembolic events in systemic lupus erythematosus (SLE) patients of different ethnic backgrounds.Methods. SLE patients who were newly diagnosed or were referred within 6 months of diagnosis between 1996 and 2002 were prospectively followed up for the occurrence of thromboembolic events. Cumulative hazard and risk factors for thromboembolism were evaluated and compared among patients of different ethnic origins.Results. We studied 625 patients who fulfilled the American College of Rheumatology criteria for SLE (89% women): 258 Chinese, 140 African Americans, and 227 Caucasians. The mean ؎ SD age at SLE diagnosis was 35.7 ؎ 14 years. After a followup of 3,094 patientyears, 48 arterial events and 40 venous events occurred in 83 patients. The overall incidence of arterial and venous thromboembolism was 16/1,000 patient-years and 13/1,000 patient-years, respectively. The cumulative hazard of arterial events at 60 months after the diagnosis of SLE was 8.5%, 8.1%, and 5.1% for the Chinese, African Americans, and Caucasians, respectively. The corresponding cumulative risk of venous events was 3.7%, 6.6%, and 10.3%, respectively (P ‫؍‬ 0.008 for Chinese versus Caucasians, by log rank test). Smoking, obesity, antiphospholipid antibodies, and use of antimalarial agents and exogenous estrogens were less frequent in the Chinese patients. In Cox regression models, low levels of high-density lipoprotein (HDL) cholesterol, Chinese ethnicity, oral ulcers, and serositis predicted arterial events, whereas male sex, low levels of HDL cholesterol, antiphospholipid antibodies, non-Chinese ethnicity, obesity, renal disease, and hemolytic anemia predicted venous events.Conclusion. There are ethnic differences in the incidence of arterial and venous thromboembolism in patients with SLE that cannot be fully explained by the clinical factors studied. Further evaluation of other genetic and immunologic factors is warranted.Premature atherosclerosis is a major cause of mortality and late morbidity in patients with systemic lupus erythematosus (SLE) (1-3). In several cohort studies, it was found that atherosclerotic cardiovascular and cerebrovascular diseases are more common causes of late deaths than active SLE itself (1,(4)(5)(6). More recent studies have demonstrated that subclinical coronary heart disease and carotid plaque were present in a significantly higher proportion of SLE patients than in age-and sex-matched control subjects with similar risk factors (7,8). The etiology of accelerated atherosclerosis in SLE is multifactorial and cannot be fully explained by traditional risk factors (9).Compared with individuals without SLE, the risk of myocardial infarction in SLE patients is 2-50 times higher, and the risk of stroke is 2-10 times higher (2,9,10). The prevalence of symptomatic coronary heart disease in SLE patients has been reported to be 6-20%, The Hopkins Lupus Cohort is supported by NIH grants R01-AR-43727 and M01-RR-00052 (to the outpatient Clinical Research Center).

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Section: Discussionmentioning

confidence: 99%

Incidence and risk factors of thromboembolism in systemic lupus erythematosus: A comparison of three ethnic groups

Mok

Tang

et al. 2005

Arthritis & Rheumatism

213

173

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Section: The Etiology Of Autoantibodies Against ␤ 2 Gpimentioning

confidence: 99%

“…Model systems suggest a loss of electrostatic interaction between Glu228 in domain IV and Lys308 in domain V in the Val247 variant, which may influence the stability of the circular plasma conformation. 73 An increased tendency of ␤ 2 GPI to open up and to expose the epitope for anti-␤ 2 GPI antibodies can explain the observed risk to develop autoantibodies against ␤ 2 GPI in Val/Val carriers.Recently, evidence has been brought forward that a part of ␤ 2 GPI circulates in a reduced form with free surface-exposed thiol groups and that the percentage of reduced ␤ 2 GPI is much greater in patients with APS. 74 Binding studies have shown that the avidity of patient-derived autoantibodies is significantly greater for reduced ␤ 2 GPI than for oxidized ␤ 2 GPI.…”

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confidence: 99%

The significance of autoantibodies against β2-glycoprotein I

Groot

Urbanus

2012

Blood

127

115

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AbstractThe antiphospholipid syndrome (APS) is defined by the persistent presence of antiphospholipid antibodies in patients with a history of thrombosis and/or pregnancy morbidity, including fetal loss. APS is an autoimmune disease with a confusing name because the pathologic auto-antibodies are shown to be directed against the plasma protein β2-glycoprotein I and not against phospholipids. In fact, auto-antibodies that recognize phospholipids themselves are not associated with thrombosis but with infectious diseases. One of the intriguing questions is why autoantibodies against β2-glycoprotein I are so commonly found in both patients and the healthy. Several potential mechanisms have been suggested to explain the increased thrombotic risk in patients with these autoantibodies. In this overview, we will summarize our knowledge on the etiology of the autoantibodies, and we will discuss the evidence that identify autoantibodies against β2-glycoprotein I as the culprit of APS.

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“…22 A troca do aminoácido Leu pela Val (códon 247), no V domínio da β 2 GP1, pode ocasionar modificação estrutural na proteína, ocasionando a produção de anticorpos antiβ 2 GP1, presentes na SAF, 23 e os indivíduos que apresentam homozigose Val247Val possuem maior risco de desenvolver SAF. 24,25 Neste estudo avaliou-se o polimorfismo genéti-co, localizado no códon 247 do exon 7 do gene da β 2 GP1 em amostra populacional brasileira composta por indivíduos hansênicos e saudáveis. Houve maior prevalência do genótipo Val/Val no grupo de hansêni-cos, em relação à do grupo controle.…”

Section: Discussionunclassified

“…Todos os pacientes MB com FTE apresentaram heterozigose ou homozigose (Val/Val), corroborando estudos que atribuem FTE e SAF ao polimorfismo Val247Leu. 13,24,25 Alguns estudos têm relacionado a presença desse polimorfismo com AAF em pacientes com SAF, porém os resultados são controversos. Paloma et al [24][25][26][27] Na hanseníase MB, há descrição da presença de AAF, porém a ocorrência da associação com SAF é rara.…”

Section: Discussionunclassified

Polimorfismo Val247Leu do gene β2-glicoproteína 1 pode justificar a gênese de anticorpos antiβ2GP1 e síndrome do anticorpo antifosfolípide na hanseníase multibacilar

Brochado¹,

Nascimento²,

Louzada‐Júnior³

et al. 2009

An. Bras. Dermatol.

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FUNDAMENTOS - Anticorpos antifosfolípides (AAF), como antiβ2GP1 (β2-glicoproteína 1), são descritos na hanseníase multibacilar (MB) sem, contudo, caracterizar a síndrome do anticorpo antifosfolípide (SAF), constituída por fenômenos tromboembólicos (FTE). A mutação Val247Leu no V domínio da β2GP1 - substituição da leucina por valina - expõe epítopos crípticos com consequente formação de anticorpos antiβ2GP1. OBJETIVO: Avaliar a associação do polimorfismo Val247Leu do gene β2GP1 com títulos de anticorpos antiβ2GP1 na hanseníase. MÉTODO: O polimorfismo Val247Leu foi detectado por PCR-RFLP, e os títulos de anticorpos antiβ2GP1, por Elisa. RESULTADOS: O genótipo Val/Val estatisticamente predominou no grupo de hansênicos, em relação ao controle. Embora maiores títulos de anticorpos antiβ2GP1 IgM estivessem alocados no grupo MB com genótipos Val/Val e Val/Leu, não houve diferença estatística em relação ao genótipo Leu/Leu. Dos sete pacientes MB com FTE, quatro apresentaram heterozigose, e três Val/Val homozigose. CONCLUSÃO: A prevalência do genótipo Val/Val no grupo de hansênicos pode justificar parcialmente a presença de anticorpos antiβ2GP1 na forma MB. A heterozigose ou homozigose Val/Val nos sete pacientes com hanseníase MB e FTE corroboram a implicação de expressão fenotípica anômala da β2GPl e formação de anticorpos antiβ2GPl, com consequente FTE e SAF.

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Significance of valine/leucine²⁴⁷ polymorphism of β₂‐glycoprotein I in antiphospholipid syndrome: Increased reactivity of anti–β₂‐glycoprotein I autoantibodies to the valine²⁴⁷ β₂‐glycoprotein I variant

Abstract: Objective. To clarify the consequences of the valine/leucine polymorphism at position 247 of the ␤ 2 -glycoprotein I (␤ 2 GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti-␤ 2 GPI antibody.

Cited by 57 publications

References 31 publications

Incidence and risk factors of thromboembolism in systemic lupus erythematosus: A comparison of three ethnic groups

Incidence and risk factors of thromboembolism in systemic lupus erythematosus: A comparison of three ethnic groups

The significance of autoantibodies against β2-glycoprotein I

Polimorfismo Val247Leu do gene β2-glicoproteína 1 pode justificar a gênese de anticorpos antiβ2GP1 e síndrome do anticorpo antifosfolípide na hanseníase multibacilar

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