The objective of this study is to perform comprehensive genetic studies on a biological and positional candidate gene for systemic erythematosus (SLE) that codes for coagulation factor II or prothrombin (F2). We will resequence the entire F2 gene in selected SLE patients and controls and then to examine the role of this sequence variation in relation to SLE and the risk of coronary heart disease (CHD) in SLE patients. Following are the specific aims:
Aim 1) resequence the entire F2 gene (21.3 kb) to identify common and rare putative functional variants in 100 SLE patients positive for both APA and CHD and 100 selected normal subjects having high titers of APA in order to create a high-density map of SNPs in the F2 gene and then to use this data in subsequent aims.
Aim 2) screen rare variants and tagSNPs of common variants in the entire case-control sample available to us (577 cases, 677 controls;80.5% U.S. white, 19.5% U.S. black) to determine their distributions. The data from the rare and common tagSNPs will be used in Aims 3 and 4 for genotype-phenotype analyses to test the hypotheses of """"""""common trait - rare variant"""""""" and """"""""common trait - common variant"""""""", respectively.
Aim 3) evaluate the relationship between F2 genetic variants and SLE risk and quantitative traits, including F2 activity, the occurrence of APA [anti-apoH, anti-cardiolipin (ACL), lupus anticoagulant (LAC), anti-oxidized phospholipids (anti-oxPL) and anti- F2] and LDL oxidation parameters [oxidized LDL (oxLDL), antibodies against oxLDL (anti-oxLDL) and LDL immune complexes], and Aim 4) examine the relationship between F2 genetic variation and the occurrence of subclinical cardiovascular disease in SLE patients and subsets of SLE patients by the presence or absence of APA and anti-oxLDL.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Jaquish, Cashell E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Public Health
United States
Zip Code
Demirci, F Yesim; Wang, Xingbin; Morris, David L et al. (2017) Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus. J Med Genet 54:381-389
Demirci, F Yesim; Wang, Xingbin; Kelly, Jennifer A et al. (2016) Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry. Arthritis Rheumatol 68:174-83
Kamboh, M Ilyas; Wang, Xingbin; Kao, Amy H et al. (2013) Genome-wide association study of antiphospholipid antibodies. Autoimmune Dis 2013:761046
Demirci, F Yesim K; Dressen, Amy S; Kammerer, Candace M et al. (2011) Functional polymorphisms of the coagulation factor II gene (F2) and susceptibility to systemic lupus erythematosus. J Rheumatol 38:652-7
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
Dasgupta, Sudeshna; Demirci, F Yesim; Dressen, Amy S et al. (2011) Association analysis of PON2 genetic variants with serum paraoxonase activity and systemic lupus erythematosus. BMC Med Genet 12:7
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