The candidate for this K24:Mid Career Investigator in Patient Oriented Research is an experienced and productive physician-scientist whose work has concentrated upon autoimmune rheumatic diseases, including systemic lupus erythematosus. The candidate has made important contributions to the understanding of SLE pathogenesis, including genetic. He carries out this work in the Arthritis & Immunology Program at Oklahoma Medical Research Foundation, one of the largest and most productive research units dedicated to the study of immune-mediated rheumatic illness. SLE is complicated, with a wide range of manifestations. Use of stratification of a disease population has proven very useful in other diseases (BCR1 gene, for example). We hypothesize (and the preliminary data demonstrate) that the clinical phenotypes of SLE are valuable in uncovering the genetics of SLE. Thrombocytopenia predicts severe disease and death in SLE, making the identification of related genetic risk factors especially important. We selected the 38 pedigrees that had an SLE patient with thrombocytopenia from 179 pedigrees multiplex for SLE. Linkage was established at 11p13 (Iod=5.72) in the 13 African-American pedigrees. Nephritis, serositis, europsychiatric involvement, autoimmune hemolytic anemia, anti-double stranded DNA and antiphospholipid antibody were associated with thrombocytopenia. SLE is more severe in the families with a thrombocytopenic SLE patient, whether or not thrombocytopenia in an individual patient is considered. This project will explore the genetics of the severe phenotype of SLE defined by thrombocytopenia. In particular, the PI will concentrate on the statistically powerful finding on chromosome 11p13, the strongest found to date in SLE. In the first specific aim, the genetic interval will be fine mapped with DNA microsatellite markers in order to confirm linkage and narrow the interval.
In Specific Aim 2 the PI will search for genetic association with SLE by typing at single nucleotide polymorphisms throughout the defined interval supporting linkage.
In Specific Aim 3, the genetic polymorphism(s) responsible for the linkage will be sought by sequencing genes within the now narrowly defined linkage interval. Finally, Specific Aim 4 will assemble a new cohort of families multiplex for SLE so that linkages and associations as well as particular polvmorphisms can be prospectively confirmed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24AR049743-05
Application #
7261336
Study Section
Special Emphasis Panel (ZAR1-TAS-C (J1))
Program Officer
Witter, James
Project Start
2003-07-01
Project End
2008-12-30
Budget Start
2007-07-01
Budget End
2008-12-30
Support Year
5
Fiscal Year
2007
Total Cost
$154,956
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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Aggarwal, R; Sestak, A L; D'Souza, A et al. (2010) Complete complement deficiency in a large cohort of familial systemic lupus erythematosus. Lupus 19:52-7
Kurien, Biji T; D'Souza, Anil; Scofield, R Hal (2010) Heat-solubilized curry spice curcumin inhibits antibody-antigen interaction in in vitro studies: a possible therapy to alleviate autoimmune disorders. Mol Nutr Food Res 54:1202-9
Cooney, C M; Bruner, G R; Aberle, T et al. (2009) 46,X,del(X)(q13) Turner's syndrome women with systemic lupus erythematosus in a pedigree multiplex for SLE. Genes Immun 10:478-81
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Scofield, R Hal; Bruner, Gail R; Namjou, Bahram et al. (2008) Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum 58:2511-7
Kurien, Biji T; Scofield, R Hal (2008) Autoimmunity and oxidatively modified autoantigens. Autoimmun Rev 7:567-73