Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Rheumatology Reports
Published in: Current Rheumatology Reports 12/2019

01-12-2019 | Antiphospholipid Syndrome | Antiphospholipid Syndrome (S Zuily, Section Editor)

Genetics of Antiphospholipid Syndrome

Authors: Lourdes Ortiz-Fernández, Amr H Sawalha

Published in: Current Rheumatology Reports | Issue 12/2019

Login to get access

Abstract

Purpose of Review

Antiphospholipid syndrome (APS) is a rare heterogenous disorder associated with the presence of antiphospholipid antibodies and can present in a wide variety of clinical manifestations including thrombosis and pregnancy complications. Although the etiology of APS remains poorly understood, there is strong support for considering APS as a complex genetic disease in which multiple genetic risk factors, in conjunction with environmental factors, affect its onset, progression, and severity. Here, we provide a comprehensive review of the current knowledge of the genetic basis of APS, which remains in its infancy.

Recent Findings

Most genetic studies to date in APS were performed in small cohorts of patients. As a result, only few genetic associations reported are convincing. Several reports suggested genetic associations with HLA class II alleles in APS, and only two genetic loci outside of the HLA region (STAT4 and C1D) reached the threshold for genome-wide level of significance (P < 5 × 10−8). In this review, we also shed light on the genetic differences among the diverse clinical subsets of APS and briefly discuss the role that DNA methylation changes might play in the pathophysiology of this disease.

Summary

The genetic basis of APS remains poorly characterized. Larger collaborative multicenter studies using well-characterized patients are needed to comprehensively understand the role of genetic susceptibility in APS.
Literature
1.
2.
Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet. 2010;376:1498–509.PubMedCrossRef
3.
Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42:1309–11.PubMedCrossRef
4.
Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.PubMedCrossRef
5.
Duarte-Garcia A, Pham MM, Crowson CS, Amin S, Moder KG, Pruthi RK, et al. The epidemiology of antiphospholipid syndrome. A Population-Based Study. Arthritis Rheum. 2019;71:1545–52.CrossRef
6.
Asherson RA, Cervera R, Piette JC, Font J, Lie JT, Burcoglu A, et al. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore). 1998;77:195–207.CrossRef
7.
8.
Bansal AS, Hogan PG, Gibbs H, Frazer IH. Familial primary antiphospholipid antibody syndrome. Arthritis Rheum. 1996;39:705–6.PubMedCrossRef
9.
Islam MA, Wong KK, Sasongko TH, Gan SH, Wong JS. Familial primary antiphospholipid syndrome: a report of co-occurrence in three Malaysian family members. Eur J Rheumatol. 2016;3:139–41.PubMedPubMedCentralCrossRef
10.
Weber M, Hayem G, DeBandt M, Palazzo E, Roux S, Kahn MF, et al. The family history of patients with primary or secondary antiphospholipid syndrome (APS). Lupus. 2000;9:258–63.PubMedCrossRef
11.
Ravindran V, Rajendran S, Elias G. Primary antiphospholipid syndrome in monozygotic twins. Lupus. 2013;22:92–4.PubMedCrossRef
12.
Cevallos R, Darnige L, Arvieux J, Veyssier P, Gruel Y. Antiphospholipid and anti-beta 2 glycoprotein I antibodies in monozygotic twin sisters. J Rheumatol. 1994;21:1970–1.PubMed
13.
Asherson RA, Doherty DG, Vergani D, Khamashta MA, Hughes GR. Major histocompatibility complex associations with primary antiphospholipid syndrome. Arthritis Rheum. 1992;35:124–5.PubMedCrossRef
14.
Camps MT, Cuadrado MJ, Ocon P, Alonso A, Gutierrez A, Guil M, et al. Association between HLA class II antigens and primary antiphospholipid syndrome from the south of Spain. Lupus. 1995;4:51–5.PubMedCrossRef
15.
Vargas-Alarcon G, Granados J, Bekker C, Alcocer-Varela J, Alarcon-Segovia D. Association of HLA-DR5 (possibly DRB1*1201) with the primary antiphospholipid syndrome in Mexican patients. Arthritis Rheum. 1995;38:1340–1.PubMedCrossRef
16.
Arnett FC, Thiagarajan P, Ahn C, Reveille JD. Associations of anti-beta2-glycoprotein I autoantibodies with HLA class II alleles in three ethnic groups. Arthritis Rheum. 1999;42:268–74.PubMedCrossRef
17.
Bertolaccini ML, Atsumi T, Caliz AR, Amengual O, Khamashta MA, Hughes GR, et al. Association of antiphosphatidylserine/prothrombin autoantibodies with HLA class II genes. Arthritis Rheum. 2000;43:683–8.PubMedCrossRef
18.
Caliz R, Atsumi T, Kondeatis E, Amengual O, Khamashta MA, Vaughan RW, et al. HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. Rheumatology (Oxford). 2001;40:31–6.CrossRef
19.
Sanchez ML, Katsumata K, Atsumi T, Romero FI, Bertolaccini ML, Funke A, et al. Association of HLA-DM polymorphism with the production of antiphospholipid antibodies. Ann Rheum Dis. 2004;63:1645–8.PubMedPubMedCentralCrossRef
20.
Freitas MV, da Silva LM, Deghaide NH, Donadi EA, Louzada-Junior P. Is HLA class II susceptibility to primary antiphospholipid syndrome different from susceptibility to secondary antiphospholipid syndrome? Lupus. 2004;13:125–31.PubMedCrossRef
21.
Al Attia HM, Santhosh A. A probe into the HLA-DR and DQ of Arab patients with primary antiphospholipid (Hughes) syndrome. Rheumatol Int. 2007;28:193–5.PubMedCrossRef
22.
• Sugiura-Ogasawara M, Omae Y, Kawashima M, Toyo-Oka L, Khor SS, Sawai H, et al. The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome. J Hum Genet. 2017;62:831–8 This is a GWAS in obstetric APS revealing a genetic association with C1D with a genome-wide level of significance. PubMedCrossRef
23.
24.
de Laat B, Derksen RH, Mackie IJ, Roest M, Schoormans S, Woodhams BJ, et al. Annexin A5 polymorphism (-1C-->T) and the presence of anti-annexin A5 antibodies in the antiphospholipid syndrome. Ann Rheum Dis. 2006;65:1468–72.PubMedPubMedCentralCrossRef
25.
• Lee YH, Choi SJ, Ji JD, Song GG. Association between the valine/leucine247 polymorphism of beta2-glycoprotein I and susceptibility to anti-phospholipid syndrome: a meta-analysis. Lupus. 2012;21:865–71 This is a meta-analysis suggesting a genetic association between variants in B2GP1 (APOH) encoding β2GPI and APS, thrombosis, and the presence of anti-β2GPI antibodies. PubMedCrossRef
26.
Yin H, Borghi MO, Delgado-Vega AM, Tincani A, Meroni PL, Alarcon-Riquelme ME. Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome. Arthritis Rheum. 2009;60:2468–71.PubMedCrossRef
27.
Jimenez S, Tassies D, Espinosa G, Garcia-Criado A, Plaza J, Monteagudo J, et al. Double heterozygosity polymorphisms for platelet glycoproteins Ia/IIa and IIb/IIIa increases arterial thrombosis and arteriosclerosis in patients with the antiphospholipid syndrome or with systemic lupus erythematosus. Ann Rheum Dis. 2008;67:835–40.PubMedCrossRef
28.
Yonal I, Hindilerden F, Hancer VS, Artim-Esen B, Daglar A, Akadam B, et al. The impact of platelet membrane glycoprotein Ib alpha and Ia/IIa polymorphisms on the risk of thrombosis in the antiphospholipid syndrome. Thromb Res. 2012;129:486–91.PubMedCrossRef
29.
Ochoa E, Iriondo M, Manzano C, Fullaondo A, Villar I, Ruiz-Irastorza G, et al. LDLR and PCSK9 are associated with the presence of antiphospholipid antibodies and the development of thrombosis in aPLA carriers. PLoS One. 2016;11:e0146990.PubMedPubMedCentralCrossRef
30.
Rodriguez-Garcia ME, Cotrina-Vinagre FJ, Bellusci M. Martinez de Aragon A, Hernandez-Sanchez L, Carnicero-Rodriguez P, Martin-Hernandez E, Martinez-Azorin F: A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome. Eur J Hum Genet. 2019.
31.
Plasin-Rodriguez MA, Rodriguez-Pinto I, Patricio P, Monteagudo J, Cervera R, Reverter JC, et al. The H1 haplotype of the endothelial protein C receptor protects against arterial thrombosis in patients with antiphospholipid syndrome. Thromb Res. 2018;169:128–34.PubMedCrossRef
32.
Ostanek L, Ostanek-Panka M, Bobrowska-Snarska D, Binczak-Kuleta A, Fischer K, Kaczmarczyk M, et al. PTPN22 1858C>T gene polymorphism in patients with SLE: association with serological and clinical results. Mol Biol Rep. 2014;41:6195–200.PubMedPubMedCentralCrossRef
33.
Castro-Marrero J, Balada E, Vilardell-Tarres M, Ordi-Ros J. The PTPN22*R620W polymorphism does not confer genetic susceptibility to antiphospholipid syndrome in the Spanish population. Int J Immunogenet. 2011;38:529–31.PubMedCrossRef
34.
Horita T, Atsumi T, Yoshida N, Nakagawa H, Kataoka H, Yasuda S, et al. STAT4 single nucleotide polymorphism, rs7574865 G/T, as a risk for antiphospholipid syndrome. Ann Rheum Dis. 2009;68:1366–7.PubMedCrossRef
35.
• Fredi M, Tincani A, Yin H, Delgado-Vega AM, Borghi MO, Meroni PL, et al. IRF5 is associated with primary antiphospholipid syndrome, but is not a major risk factor. Arthritis Rheum. 2010;62:1201–2 The report expanded on the data presented in reference #26 by increasing the sample size and reported the genetic association between STAT4 and primary APS with a genome-wide level of significance. PubMedCrossRef
36.
Pierangeli SS, Vega-Ostertag ME, Raschi E, Liu X, Romay-Penabad Z, De Micheli V, et al. Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies. Ann Rheum Dis. 2007;66:1327–33.PubMedPubMedCentralCrossRef
37.
Atsumi T, Tsutsumi A, Amengual O, Khamashta MA, Hughes GR, Miyoshi Y, et al. Correlation between beta2-glycoprotein I valine/leucine247 polymorphism and anti-beta2-glycoprotein I antibodies in patients with primary antiphospholipid syndrome. Rheumatology (Oxford). 1999;38:721–3.CrossRef
38.
Hirose N, Williams R, Alberts AR, Furie RA, Chartash EK, Jain RI, et al. A role for the polymorphism at position 247 of the beta2-glycoprotein I gene in the generation of anti-beta2-glycoprotein I antibodies in the antiphospholipid syndrome. Arthritis Rheum. 1999;42:1655–61.PubMedCrossRef
39.
Yasuda S, Atsumi T, Matsuura E, Kaihara K, Yamamoto D, Ichikawa K, et al. Significance of valine/leucine247 polymorphism of beta2-glycoprotein I in antiphospholipid syndrome: increased reactivity of anti-beta2-glycoprotein I autoantibodies to the valine247 beta2-glycoprotein I variant. Arthritis Rheum. 2005;52:212–8.PubMedCrossRef
40.
Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007;357:977–86.PubMedPubMedCentralCrossRef
41.
Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB. Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. J Immunol. 2009;182:34–8.PubMedCrossRef
42.
Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med. 2008;358:900–9.PubMedCrossRef
43.
Zhou Y, Li X, Wang G, Li X. Association of FAM167A-BLK rs2736340 Polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Immunol Investig. 2016;45:336–48.CrossRef
44.
Consortium GT: Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60.CrossRef
45.
Khattri S, Zandman-Goddard G, Peeva E. B-cell directed therapies in antiphospholipid antibody syndrome--new directions based on murine and human data. Autoimmun Rev. 2012;11:717–22.PubMedCrossRef
46.
Youinou P, Renaudineau Y. The antiphospholipid syndrome as a model for B cell-induced autoimmune diseases. Thromb Res. 2004;114:363–9.PubMedCrossRef
47.
Erkan D, Vega J, Ramon G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013;65:464–71.PubMedCrossRef
48.
49.
50.
Canaud G, Bienaime F, Tabarin F, Bataillon G, Seilhean D, Noel LH, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014;371:303–12.PubMedCrossRef
51.
Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74:1011–8.PubMedCrossRef
52.
De Angelis V, Scurati S, Raschi E, Liutkus A, Belot A, Borghi MO, et al. Pro-inflammatory genotype as a risk factor for aPL-associated thrombosis: Report of a family with multiple anti-phospholipid positive members. J Autoimmun. 2009;32:60–3.PubMedCrossRef
53.
Benhamou Y, Bellien J, Armengol G, Brakenhielm E, Adriouch S, Iacob M, et al. Role of Toll-like receptors 2 and 4 in mediating endothelial dysfunction and arterial remodeling in primary arterial antiphospholipid syndrome. Arthritis Rheum. 2014;66:3210–20.CrossRef
54.
Yavuzer U, Smith GC, Bliss T, Werner D, Jackson SP. DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D. Genes Dev. 1998;12:2188–99.PubMedPubMedCentralCrossRef
55.
Schilders G, Egberts WV, Raijmakers R, Pruijn GJ. C1D is a major autoantibody target in patients with the polymyositis-scleroderma overlap syndrome. Arthritis Rheum. 2007;56:2449–54.PubMedCrossRef
56.
Dechairo BM, Zabaneh D, Collins J, Brand O, Dawson GJ, Green AP, et al. Association of the TSHR gene with Graves’ disease: the first disease specific locus. Eur J Hum Genet. 2005;13:1223–30.PubMedCrossRef
57.
de Carvalho JF, Caleiro MT. Primary antiphospholipid syndrome and thyroid involvement. J Clin Rheumatol. 2010;16:164–7.PubMedCrossRef
58.
Bogdanova N, Horst J, Chlystun M, Croucher PJ, Nebel A, Bohring A, et al. A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss. Hum Mol Genet. 2007;16:573–8.PubMedCrossRef
59.
Grandone E, Tiscia G, Colaizzo D, Chinni E, Pisanelli D, Bafunno V, et al. Role of the M2 haplotype within the annexin A5 gene in the occurrence of pregnancy-related venous thromboembolism. Am J Obstet Gynecol. 2010;203:461 e461–5.CrossRef
60.
Hiddink L, de Laat B, Derksen RH, de Groot PG, van Heerde WL. Annexin A5 haplotypes in the antiphospholipid syndrome. Thromb Res. 2015;135:417–9.PubMedCrossRef
61.
Kamboh MI, Wang X, Kao AH, Barmada MM, Clarke A, Ramsey-Goldman R, et al. Genome-wide association study of antiphospholipid antibodies. Autoimmune Dis. 2013;2013:761046.PubMedPubMedCentral
62.
Muller-Calleja N, Rossmann H, Muller C, Wild P, Blankenberg S, Pfeiffer N, et al. Antiphospholipid antibodies in a large population-based cohort: genome-wide associations and effects on monocyte gene expression. Thromb Haemost. 2016;116:115–23.PubMedCrossRef
63.
Khong JJ, Burdon KP, Lu Y, Leonardos L, Laurie KJ, Walsh JP, et al. Association of polymorphisms in MACRO domain containing 2 with thyroid-associated orbitopathy. Invest Ophthalmol Vis Sci. 2016;57:3129–37.PubMedCrossRef
64.
Weeding E, Sawalha AH. Deoxyribonucleic acid methylation in systemic lupus erythematosus: implications for future clinical practice. Front Immunol. 2018;9:875.PubMedPubMedCentralCrossRef
65.
• Weeding E, Coit P, Yalavarthi S, Kaplan MJ, Knight JS, Sawalha AH. Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils. Clin Immunol. 2018;196:110–6 This is the first genome-wide DNA methylation study in APS neutrophils. The data reveal a distinct DNA methylome in primary APS compared to lupus patients. PubMedPubMedCentralCrossRef
66.
Patsouras MD, Karagianni P, Kogionou P, Vlachoyiannopoulos PG. Differential CpG methylation of the promoter of interleukin 8 and the first intron of tissue factor in antiphospholipid syndrome. J Autoimmun. 2019;102:159–66.PubMedCrossRef
Metadata
Title
Genetics of Antiphospholipid Syndrome
Authors
Lourdes Ortiz-Fernández
Amr H Sawalha
Publication date
01-12-2019
Publisher
Springer US
Published in
Current Rheumatology Reports / Issue 12/2019
Print ISSN: 1523-3774
Electronic ISSN: 1534-6307
DOI
https://doi.org/10.1007/s11926-019-0869-y

Other articles of this Issue 12/2019

Current Rheumatology Reports 12/2019 Go to the issue

Pediatric Rheumatology (S Ozen, Section Editor)

Advances Toward Precision Medicine in Juvenile Dermatomyositis

Scleroderma (J Varga, Section Editor)

Progress in Understanding, Diagnosing, and Managing Cardiac Complications of Systemic Sclerosis

Scleroderma (J Varga, Section Editor)

Epigenetic Control of Scleroderma: Current Knowledge and Future Perspectives

Chronic Pain (R Staud, Section Editor)

Inflammation and the Central Nervous System in Inflammatory Rheumatic Disease

Vasculitis (LR Espinoza, Section Editor)

Anti-neutrophil Cytoplasmic Antibodies (ANCA) as Disease Activity Biomarkers in a “Personalized Medicine Approach” in ANCA-Associated Vasculitis

Psoriatic Arthritis (JU Scher, Section Editor)

Strategies to Improve Outcomes in Psoriatic Arthritis
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits