This application is to support a Midcareer Investigator Award allowing continued patient-oriented investigation into the genetic basis of rheumatoid arthritis (RA). The immediate goal is to examine how sex and HLA interact in RA heredity, while the long-term goal is to describe RA disease mechanisms in such detail that effective prevention or therapy will be possible. This award will provide career development support to protect time for this patient-oriented clinical research, develop new research skills, and do mentoring of junior investigators. The applicant will continue studies of sex influence on HLA penetrance in rheumatoid arthritis. The current studies have shown that RA is independently associated with several disease susceptibility loci in the HLA region, not just DRB1 variants but also independently with tumor necrosis factor (TNFalpha) variants. The future studies will define the functional correlates of TNF variants by identifying unrelated persons with common HLA genotypes and then examining inducible TNF production and MHC class II density in peripheral blood cells. Such results will be used to develop multivariate models to determine whether these explain sex differences in HLA penetrance. A second ongoing project, in cooperation with investigators at Case Western Reserve University, is to identify RA families suitable for genetic studies. A third project is proposed for this application. RA families will be studied to determine whether there is segregation distortion of RA-associated HLA haplotypes, that is, whether a child (either affected or not) is more likely than expected to inherit a RA-associated HLA haplotype from a mother with the HLA haplotype or a father with the HLA haplotype. Such parent-of-origin effects might represent genomic imprinting. Dr. Moxley has already demonstrated mentoring success, guiding junior investigators through design, performance, problem- solving, analysis, and publication. Virginia Commonwealth University has a rich patient population and strong programs to educate investigators in clinical research and biostatistics.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZAR1-JRL-C (M1))
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Serrate-Sztein, Susana
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Virginia Commonwealth University
Internal Medicine/Medicine
Schools of Medicine
United States
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Moxley, George; Stern, Alan G; Carlson, Patricia et al. (2004) Premenopausal sexual dimorphism in lipopolysaccharide-stimulated production and secretion of tumor necrosis factor. J Rheumatol 31:686-94
Stern, A G; Moxley, G; Sudha Rao, T P et al. (2004) Utility of digital photographs of the hand for assessing the presence of hand osteoarthritis. Osteoarthritis Cartilage 12:360-5
Stern, A G; de Carvalho, M R C; Buck, G A et al. (2003) Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta. Osteoarthritis Cartilage 11:394-402
Moxley, George; Cohen, Harley J (2002) Genetic studies, clinical heterogeneity, and disease outcome studies in rheumatoid arthritis. Rheum Dis Clin North Am 28:39-58
Moxley, George; Posthuma, Danielle; Carlson, Patricia et al. (2002) Sexual dimorphism in innate immunity. Arthritis Rheum 46:250-8