Multiple genes and environmental factors likely contribute to disease susceptibility and expression in systemic lupus erythematosus (SLE). While an understanding of the genes that contribute to the pathogenesis is far from complete, significant progress has been made in identifying more than 40 susceptibility genes or loci. However, much less is known about genetic factors predisposing to good outcomes in SLE. Damage in SLE, defined by irreversible changes either as result of disease activity, therapeutic interventions or co-morbid conditions occurring after the disease diagnosis, is measured by an instrument developed by the Systemic Lupus International Collaborating Clinics as the SLICC/ACR damage index. Since male SLE patients tend to develop damage earlier in the course of the illness, it is plausible that gender differences including sex hormones, sex chromosome-linked genes and/or X chromosome inactivation (XCI) in women may play a role in disease progression in SLE. We selected the androgen receptor gene (AR) located on the X chromosome and tested whether shorter polyGLN polymorphisms (d17) conferring higher androgen transactivation activity were associated with accelerated damage in SLE. Our preliminary results of 129 men and 418 women affected with SLE showed 1) accelerated damage in men during the first 5 years of disease especially in risk for developing renal damage, and 2) significant associations of increased damage (SDI e 2) with shorter CAG repeat length of AR, higher cumulative prednisone dosage, and longer disease duration. These data suggested a heightened response to testosterone and dehydroepiandrosterone (DHEA) binding mediated by enhanced androgen transactivation activity of short CAG repeat in AR might be a prognostic marker for SLE damage in both genders. Although DHEA has previously shown beneficial in treating SLE manifestations, recent studies have yielded inconsistent results, highlighting the need for further studies. We hypothesize that one or more X-linked AR variants predispose to damage accrual in SLE, and propose to assemble a multiethnic dataset of >5,000 clinically well-characterized SLE patients containing >500 male patients to address whether 1) men with SLE are at risk for overall or renal damage, 2) AR variants help identify at risk patients of both gender for damage accrual, and 3) differential levels of AR responsive gene expression contribute to damage in SLE. Results from these studies are likely to illuminate disease mechanisms, improve risk assessment of damage accrual, and promote consideration of selective androgen receptor modulators in therapeutic interventions of SLE.

Public Health Relevance

This study aims to identify genetic biomarkers associated with organ damage in patients affected with systemic lupus erythematosus (SLE). The identification of novel biomarkers will yield new insights into biologic pathways underlying the disease process, and may guide the development of specific targets for therapeutic interventions. Given that organ damage greatly affects survival and quality of life in patients with SLE, it is importan to have validated biomarkers that are useful in identifying high-risk patients for consideration of vigorous interventions to prevent the development of end stage organ damage.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Neurological, Aging and Musculoskeletal Epidemiology Study Section (NAME)
Program Officer
Wang, Yan Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2016) Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Ann Rheum Dis 75:2007-2013
Alarcón-Riquelme, Marta E; Ziegler, Julie T; Molineros, Julio et al. (2016) Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture. Arthritis Rheumatol 68:932-43
Liu, Ke; Kurien, Biji T; Zimmerman, Sarah L et al. (2016) X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis Rheumatol 68:1290-300
Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9
Kottyan, Leah C; Zoller, Erin E; Bene, Jessica et al. (2015) The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet 24:582-96
Zhao, Jian; Wu, Hui; Langefeld, Carl D et al. (2015) Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus. Clin Immunol 161:157-62
Deng, Yun; Tsao, Betty P (2014) Advances in lupus genetics and epigenetics. Curr Opin Rheumatol 26:482-92
Dai, Chao; Deng, Yun; Quinlan, Aaron et al. (2014) Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage. Curr Opin Immunol 31:87-96
Vaughn, Samuel E; Foley, Corinne; Lu, Xiaoming et al. (2014) Lupus risk variants in the PXK locus alter B-cell receptor internalization. Front Genet 5:450