Apolipoprotein H (APOH) is an essential cofactor for the binding of antiphospholipid antibodies to anionic phospholipids, suggesting that structural variations in the APOH molecule may have a significant impact on the binding of autoantibodies to their substrate; thus, determining the outcome of thrombosis. Based upon the current physiologic role of APOH and the information that the APOH gene is genetically polymorphic, the investigators hypothesize that genetically determined structural changes in the phospholipid interaction binding sites on the APOH molecule have a significant impact in determining the binding affinity of antiphospholipid autoantibodies and the occurrence of associated thrombotic events in patients with systemic lupus erythematosus (SLE). The proposed comprehensive study will establish the molecular basis of known structural and quantitative polymorphism by direct sequencing of the expressed portion of the APOH gene (Aim 1); detect new and common genetic polymorphisms in the APOH gene (Aim 2); perform in vitro expression studies and examine the binding abilities of various APOH allele products to anionic phospholipids (Aim 3); compare the quantitative plasma levels of APOH between SLE patients and controls (Aim 4); evaluate the relationship between APOH polymorphisms and quantitative plasma levels of APOH (Aim 5); determine the frequency distributions of known APOH polymorphisms in SLE patients and controls (Aim 6); and evaluate the relationship between genetically defined structural polymorphisms, and quantitative polymorphism in the APOH gene, and the occurrence of antiphospholipid antibodies in SLE patients (Aim 7). The investigators state that the proposed studies will facilitate the identification and characterization of the role of APOH genetic polymorphisms in the prediction of the antiphospholipid antibodies in SLE patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054900-04
Application #
6139182
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Serrate-Sztein, Susana
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
4
Fiscal Year
2000
Total Cost
$378,650
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Public Health
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Chung, Sharon A; Taylor, Kimberly E; Graham, Robert R et al. (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet 7:e1001323
Chen, Qi; Reis, Steven E; Kammerer, Candace et al. (2011) Association of anti-oxidized LDL and candidate genes with severity of coronary stenosis in the Women's Ischemia Syndrome Evaluation study. J Lipid Res 52:801-7
Taylor, Kimberly E; Chung, Sharon A; Graham, Robert R et al. (2011) Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS Genet 7:e1001311
Suresh, Sangita; Demirci, F Yesim; Lefterov, Iliya et al. (2010) Functional and genetic characterization of the promoter region of apolipoprotein H (beta2-glycoprotein I). FEBS J 277:951-63
Suresh, Sangita; Demirci, F Yesim K; Jacobs, Erin et al. (2009) Apolipoprotein H promoter polymorphisms in relation to lupus and lupus-related phenotypes. J Rheumatol 36:315-22
Taylor, Kimberly E; Remmers, Elaine F; Lee, Annette T et al. (2008) Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 4:e1000084
Hom, Geoffrey; Graham, Robert R; Modrek, Barmak et al. (2008) Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358:900-9
Mehdi, Haider; Naqvi, Asma; Kamboh, M Ilyas (2008) Recombinant hepatitis B surface antigen and anionic phospholipids share a binding region in the fifth domain of beta2-glycoprotein I (apolipoprotein H). Biochim Biophys Acta 1782:163-8
Shih, P Betty; Manzi, Susan; Shaw, Penny et al. (2008) Genetic variation in C-reactive protein (CRP) gene may be associated with risk of systemic lupus erythematosus and CRP concentrations. J Rheumatol 35:2171-8
Musone, Stacy L; Taylor, Kimberly E; Lu, Timothy T et al. (2008) Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet 40:1062-4

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