Valine/Leucine247 polymorphism of β2-glycoprotein I in patients with antiphospholipid syndrome: lack of association with anti-β2-glycoprotein I antibodies

Abstract

In antiphospholipid syndrome (APS) the presence of anti-β₂-glycoprotein I (β₂GPI) antibodies is strongly associated with thromboembolic complications. It has been suggested that the common β₂GPI Valine/Leucine²⁴⁷ (Val/Leu²⁴⁷)polymorphism could be found more commonly in APS and might influence the generation of anti-β₂GPI antibodies. Therefore we studied β₂GPI Val/Leu²⁴⁷single-nucleotide polymorphism (SNP) by PCR in 338 patients with various autoimmune diseases (46 with secondary and 84 with primary APS) and 147 sex and age-matched healthy controls. In all patients lupus anticoagulant, anticardiolipin and anti-β₂GPI antibodies (both IgG and IgM) were also determined. All patients and controls were Caucasians. Frequencies of the SNP genotypes in patients did not depart from genetic equilibrum and did not differ from those found in controls. There was also no association between the presence of β₂GPI Val/Leu²⁴⁷genotypes and the presence or absence of lupus anticoagulant, anticardiolipin antibodies, anti-β₂GPI antibodies or clinical APS symptoms in all patients studied. In conclusion, among the exclusively Caucasian, Polish population of autoimmune patients β₂GPI Val/Leu²⁴⁷SNP has the same distribution as in healthy subjects and does not influence the production of anti-β₂GPI antibodies.

Keywords

antiphospholipid antibodies APS autoimmune diseases β2-glycoprotein I genetics

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References

Wilson WA , Gharavi AE , Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome . Arthritis Rheum 1999; 42: 1309-1311 .

Galli M , Comfurius P , Maassen C et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to plasma protein cofactor . Lancet 1990; 335: 1544-1547 .

McNeil HP , Simpson RJ , Chesterman CN , Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β2-Glycoprotein I (apolipoprotein H) . Proc Natl Acad Sci USA 1990; 87: 4120-4124 .

Matsuura E , Igarashi Y , Fujimoto M , Ichikawa K , Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease . Lancet 1990; 336: 177-178 .

Okkels H , Rasmussen TE , Sanghera DK , Kamboh MI , Kristensen T. Structure of the human β2-glycoprotein I (apolipoprotein H) gene . Eur J Biochem 1999; 259: 435-440 .

Hunt J , Krillis S. The fifth domain of beta 2-glycoprotein I contains a phospholipids binding site (Cys281-Cys288) and a region recognized by anticardiolipin antibodies . J Immunol 1994; 152: 653-659 .

Giles IP , Isenberg DA , Latchman DS , Rahman A. How do antiphospholipid antibodies bind β2-glycoprotein I ? Arthritis Rheum 2003; 48: 2111-2121 .

Roubey RAS , Eisenberg RA , Harper MF , Winfield JB. Anticardiolipin autoantibodies recognize β2-Glycoprotein I in the absence of phospholipid . J Immunol 1995; 154: 954-960 .

Arnout J , Jankowski M. Antiphospholipid antibodies: prothrombotic mechanisms and laboratory diagnosis. In Arnout J , de Gaetano G , Hoylaerts M , Peerlinck K , Van Geet C , Vehaeghe R eds. Thrombosis. Fundamental and clinical aspects. Leuven University Press , 2003: 371-392.

10.

De Laat B , Derksen RH , Urbanus RT , de Groot PG. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta2-glycoprotein I cause LAC and their presence correlates strongly with thrombosis . Blood 2005; 105: 1540-1545 .

11.

Atsumi T , Tsutsumi A , Amengual O et al. Correlation between β2-glycoprotein I valine/leucine247 polymorphism and anti β2-glycoprotein I antibodies in patients with primary antiphospholipid syndrome . Rheumatology 1999; 38: 721-723 .

12.

Prieto GA , Cabral AR , Zapata-Zuñiga, Simón AJ , Villa AR , Alarcón-Segovia D , Cabiedes J. Valine/valine genotype at position 247 of the β2-glycoprotein I gene in Mexican patients with primary antiphospholipid syndrome. Association with anti-β2-glycoprotein I antibodies . Arthritis Rheum 2003; 48: 471-474 .

13.

Kuwana M , Matsuura E , Kobayashi K et al. Binding of β2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a criptic epitope that activates pathogenic autoreactive T cells . Blood 2005; 105: 1552-1557

14.

Ichikawa K , Tsutsumi A , Atsumi T et al. A chimeric antibody with the human 1 constant region as a putative standard for assays to detect IgG β2-glycoprotein I -dependent anticardiolipin and anti-β2-glycoprotein I antibodies . Arthritis Rheum 1999; 42: 2461-2470 .

15.

Edworthy SM. Clinical manifestations of systemic lupus erythematosus. In Harris ED , Budd RC , Firestein GS , Genovese MC , Sergent JS , Ruddy S , Sledge CB eds. Kelley’s Textbook of Rheumatology, 7th edn. Elsevier Saunders , 2005: 1201-1224.

16.

Exner T , Triplett DA , Taberner D , Machin SJ. Guidelines for testing and revised criteria for lupus anticoagulant . Thromb Haemost 1991; 65: 320-320 .

17.

Brandt JT , Triplett DA , Alving B , Scharrer I. Criteria for the diagnosis of lupus anticoagulant: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardization Committee of the ISTH . Thromb Haemost 1995; 74: 1185-1190 .

18.

Swadzba J , De Clerck LS , Stevens WJ et al. Anticardiolipin, anti-β2-glycoprotein I, antiphrotrombin antibodies and lupus anticoagulant in patients with systemic lupus erythematosus with a history of thrombosis . J Rheumatol 1997; 24: 1710-1715 .

19.

Camilleri RS , Mackie IJ , Humphries , Machin SJ , Cohen H. Lack of association of β2-glycoprotein I polymorphisms Val247Leu and Trp316Ser with antiphospholipid antibodies in patients with thrombosis and pregnancy complications . Br J Haematol 2003; 120: 1066-1072 .

20.

Yasuda S , Atsumi T , Matsuura E et al. Significance of Valine/Leucine247polymorphism of β2-glycoprotein I in antiphospholipid syndrome. Increased reactivity of anti-β2-glycoprotein I autoantibodies to the Valine247 β2-glycoprotein I variant . Arthritis Rheum 2005; 52: 212-218 .

21.

Kamboh MI , Sanghera DK , Mehdi H et al. Single nucleotide polymorphisms in the coding region of apolipoprotein H (β2-glycoprotein I) gene and their correlation with the protein polymorphism, anti-β2-glycoprotein I antibodies and cardiolipin binding: description of novel haplotypes and their evolution . Ann Hum Genet 2004; 68: 285-299 .

22.

von Scheven E , Elder ME. Association between β2-glycoprotein I gene polymorphisms and pediatric SLE and antiphospholipid antibodies . Lupus 2005; 14: 440-444 .

23.

Kamboh MI , Manzi S , Mehdi H et al. Genetic variation in apolipo-protein H (beta2-glycoprotein I) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus . Lupus 1999; 8: 742-750 .

24.

Mehdi H , Manzi S , Desai P et al. A functional polymorphism at the transcriptional initiation site in β2-glycoprotein I (apolipoprtoein H) associated with reduced gene expression and lower plasma levels of anti-β2-glycoprotein I . Eur J Biochem 2003; 270: 230-238 .