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

M. Ilyas Kamboh; Dharambir K. Sanghera; Haider Mehdi; Cara S. Nestlerode; Qi Chen; Osama Khalifa; Asma Naqvi; Susan Manzi; Clareann H. Bunker

doi:10.1046/j.1529-8817.2004.00097.x

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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

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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

M. Ilyas Kamboh, Dharambir K. Sanghera, Haider Mehdi, Cara S. Nestlerode, Qi Chen, Osama Khalifa, Asma Naqvi, Susan Manzi and Clareann H. Bunker

Annals of human genetics, Vol.68(4), pp.285-299

07/2004

DOI: 10.1046/j.1529-8817.2004.00097.x

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Abstract

Summary 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.

Antiphospholipid

Apolipoprotein H

Haplotypes

Polymorphisms

β2‐Glycoprotein I

Details

Title: Subtitle: 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
Creators: M. Ilyas Kamboh - Department of Human Genetics
Dharambir K. Sanghera - Department of Human Genetics
Haider Mehdi - Department of Human Genetics
Cara S. Nestlerode - Department of Human Genetics
Qi Chen - Department of Human Genetics
Osama Khalifa - Department of Human Genetics
Asma Naqvi - Department of Human Genetics
Susan Manzi - University of Pittsburgh
Clareann H. Bunker - Department of Epidemiology, Graduate School of Public Health
Resource Type: Journal article
Publication Details: Annals of human genetics, Vol.68(4), pp.285-299
DOI: 10.1046/j.1529-8817.2004.00097.x
ISSN: 0003-4800
eISSN: 1469-1809
Publisher: Blackwell Science Ltd
Number of pages: 15
Language: English
Date published: 07/2004
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984360057602771

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