Single Nucleotide Polymorphisms in the Coding Region of the Apolipoprotein H (β2‐Glycoprotein I) Gene and their Correlation with the Protein Polymorphism, Anti‐β2Glycoprotein I Antibodies and Cardiolipin Binding: Description of Novel Haplotypes and Their Evolution

Apolipoprotein H (APOH), also known as β2‐glycoprotein I, is a major autoantigen for the production of antiphospholipid antibodies (APA) in autoimmune diseases. APA is also recognized by a cryptic epitope generated following the interaction of APOH with anionic phospholipids (PL). The prevalence of APA in the general U.S. white population is about 10%, but it ranges from 30–70% in patients with lupus and antiphospholipid syndrome. Since the structural characterization of APOH from different mammalian species is important to identify the evolutionary conserved regions that may be critical for its function, we have previously determined the chimpanzee APOH gene structure and the prevalence of APA. There are only two amino acid differences between the chimpanzee and human wild type APOH proteins. Chimpanzees have an unusually high prevalence (64%) of APA. There is a common protein polymorphism in the human APOH gene, with the occurrence of four alleles APOH*1, APOH*2, APOH*3 and APOH*4, the latter being present only in blacks. Based on its differential reactivity with an APOH monoclonal antibody, the APOH*3 allele is further divided into APOH*3W (present only in whites) and APOH*3B (present only in blacks). In this study we have screened a large African population (n = 755) to determine the prevalence of APA and the molecular basis of the protein polymorphism. Almost 50% of the Africans were found to be positive for APA. The APOH*3B allele was found to be identical to the chimpanzee's wild type APOH. Novel two‐site or three‐site haplotypes, encoded in the third domain of APOH, explained the molecular basis of the APOH*3B, APOH*3W and APOH*4 alleles. Based on the comparison of the human and chimpanzee APOH DNA sequences, we suggest that the APOH*3W and APOH*4 alleles arose on the ancestral APOH*3B haplotype after the split of human races. We also found that these haplotypes are associated with the occurrence of APA. Recombinant APOH haplotypes, expressed in COS‐1 cells, showed that these mutations also affect the binding of APOH to anionic PL.

[1]  D. Alarcón-Segovia,et al.  Valine/valine genotype at position 247 of the beta2-glycoprotein I gene in Mexican patients with primary antiphospholipid syndrome: association with anti-beta2-glycoprotein I antibodies. , 2003, Arthritis and rheumatism.

[2]  A. Tobar,et al.  Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. , 2002, The Journal of clinical investigation.

[3]  M. Kamboh,et al.  A highly sensitive and nonradioactive mutation detection method based on vertical gradient temperature single‐strand conformation polymorphism , 2001, Electrophoresis.

[4]  D. Sanghera,et al.  Chimpanzee apolipoprotein H (β2-glycoprotein I): report on the gene structure, a common polymorphism, and a high prevalence of antiphospholipid antibodies , 2001, Human Genetics.

[5]  A. Gharavi,et al.  New developments in viral peptides and APL induction. , 2000, Journal of autoimmunity.

[6]  R. Hamman,et al.  DNA sequence variation in human apolipoprotein C4 gene and its effect on plasma lipid profile. , 2000, Atherosclerosis.

[7]  A. Naqvi,et al.  A hydrophobic sequence at position 313-316 (Leu-Ala-Phe-Trp) in the fifth domain of apolipoprotein H (beta2-glycoprotein I) is crucial for cardiolipin binding. , 2000, European journal of biochemistry.

[8]  L. Kuller,et al.  Genetic variation in apolipoprotein H (β2-glycoprotein I) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus , 1999, Lupus.

[9]  G. Hughes,et al.  Correlation between β2-glycoprotein I valine/leucine247 polymorphism and anti-β2-glycoprotein I antibodies in patients with primary antiphospholipid syndrome , 1999 .

[10]  P. Gregersen,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. , 1999, Arthritis and rheumatism.

[11]  H. Chaimovich,et al.  Induction of antiphospholipid antibodies by immunization with synthetic viral and bacterial peptides , 1999, Lupus.

[12]  R. Hamman,et al.  Genetic variation in the apolipoprotein H (β2-glycoprotein I) gene affects plasma apolipoprotein H concentrations , 1999, Human Genetics.

[13]  R. Hamman,et al.  Molecular basis of the apolipoprotein H (β2-glycoprotein I) protein polymorphism , 1997, Human Genetics.

[14]  D. Sanghera,et al.  Identification of structural mutations in the fifth domain of apolipoprotein H (beta 2-glycoprotein I) which affect phospholipid binding. , 1997, Human molecular genetics.

[15]  A Sali,et al.  Site-directed mutagenesis of recombinant human beta 2-glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity. , 1996, Journal of immunology.

[16]  J. Hunt,et al.  The fifth domain of beta 2-glycoprotein I contains a phospholipid binding site (Cys281-Cys288) and a region recognized by anticardiolipin antibodies. , 1994, Journal of immunology.

[17]  Robert B Sim,et al.  Human β2-glycoprotein I: molecular analysis of DNA and amino acid polymorphism , 1993, Human Genetics.

[18]  M. Peeples,et al.  Characterization and Acute-Phase Modulation of Canine Apolipoprotein H (β2-Glycoprotein 1) , 1993 .

[19]  S. Krilis,et al.  Identification of a region of beta 2-glycoprotein I critical for lipid binding and anti-cardiolipin antibody cofactor activity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  I. Campbell,et al.  Activity, disulphate mapping and structural modelling of the fifth domain of human β2‐glycoprotein I , 1992 .

[21]  Y. Matsuda,et al.  Molecular cloning of mouse beta 2-glycoprotein I and mapping of the gene to chromosome 11. , 1992, Genomics.

[22]  R. Ferrell,et al.  Apolipoprotein H (beta-2-glycoprotein I) polymorphism in Asians. , 1992, Human biology.

[23]  E. Bendixen,et al.  Complete primary structure of bovine beta 2-glycoprotein I: localization of the disulfide bridges. , 1992, Biochemistry.

[24]  M. Peeples,et al.  Nucleotide sequence and expression of the human gene encoding apolipoprotein H (β2-glycoprotein I) , 1991 .

[25]  S. Santoro,et al.  Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. , 1990, Annals of internal medicine.

[26]  I. Wool,et al.  The primary structure of rat 2 -glycoprotein I , 1989 .

[27]  R. Ferrell,et al.  Genetic studies of human apolipoproteins. IV. Structural heterogeneity of apolipoprotein H (beta 2-glycoprotein I). , 1988, American journal of human genetics.

[28]  M. Kamboh,et al.  Heterogeneity of the apolipoprotein H*3 allele and its role in affecting the binding of apolipoprotein H (β2-glycoprotein I) to anionic phospholipids , 2004, Human Genetics.

[29]  C. Bunker,et al.  Genetic association of five apolipoprotein polymorphisms with serum lipoprotein‐lipid levels in African blacks , 1999, Genetic epidemiology.

[30]  M. Peeples,et al.  Characterization and acute phase modulation of canine apolipoprotein H (beta 2-glycoprotein I). , 1993, Biochemical and biophysical research communications.

[31]  I. Campbell,et al.  Activity, disulphide mapping and structural modelling of the fifth domain of human beta 2-glycoprotein I. , 1992, FEBS letters.