Our goal is to identify major genetic risk factors for the development of systemic lupus erythematosus (SLE) that are common to multiple ethnic groups. During the last decade, more than 10 whole genome linkage scans have mapped many SLE susceptibility loci. Evidence for linkage to SLE at 1q23-25 and 1q31-32 have been identified and confirmed by our group and other investigators using multiplex families of Caucasian, African- American, Mexican-American, or other ethnic origins. We hypothesize that 1q contains SLE susceptibility genes shared by more than one ethnic group. To this end, we have evidence for association of SLE susceptibility with four positional candidate genes (PBX1 and OX40L in 1q23-25, and CFH/CFHR3/CFHR1 and CR2 in 1q31-32) in two or more ethnic groups, including association of copy number variants (CNVs) of CFH/CFHR3/CFHR1 with SLE. An anonymous 1q25.1 locus has recently been identified as one of the 4 novel associations with SLE in whole genome association (WGA) and replication studies of Caucasian cases and controls conducted by the SLE Genetic consortium (SLEGEN) using 317,000 SNPs. Because of the high cost of WGA for replicating in independent Caucasian samples and for extending WGA to each of the non- Caucasian ethnic groups, we propose to conduct a targeted genome association study using both high-density SNPs and CNVs covering the two 1q intervals (1q23-25 plus 1q31-32) that have strong linkage and association evidence in multiple ethnic groups. In addition, we plan to assess novel genes identified in WGA studies in SLE and other autoimmune diseases for association with SLE in our independent samples. Samples available for this study are from >15,000 subjects including Caucasian, Asian, and African-American cohorts. We anticipate that these experiments will identify major genetic effects located in chromosome 1q as well as novel gene variants associated with SLE that are common to several ethnic groups. Results of these association studies will lead to localization of causal gene variants (SNPs and/or CNVs), and characterization of their effects on the gene products. Knowledge gained from these studies may reveal new paradigms for the pathogenesis of the disease, and may provide new therapeutic targets for disease management. Common risk variants to several, but not all, autoimmune diseases will help elucidate both shared and unique pathways underlying these complex disorders. 7.

Public Health Relevance

This study aims to identify major genetic risk factors, located on the long arm of chromosome 1, that increase risk for systemic lupus erythematosus (SLE). If we identify a particular genetic factor that is shared by more than one ethnic group, it is likely to play an important role in the pathogenesis of lupus. The identification of novel genes common to multiple ethnic groups will yield new insights into the mechanisms underlying the disease, which may lead to the development of specific targets for therapeutic interventions.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Wang, Yan Z
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Feng, Xuebing; Che, Nan; Liu, Yan et al. (2014) Restored immunosuppressive effect of mesenchymal stem cells on B cells after olfactory 1/early B cell factor-associated zinc-finger protein down-regulation in patients with systemic lupus erythematosus. Arthritis Rheumatol 66:3413-23
Freedman, Barry I; Langefeld, Carl D; Andringa, Kelly K et al. (2014) End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol 66:390-6
Armstrong, D L; Zidovetzki, R; Alarcón-Riquelme, M E et al. (2014) GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun 15:347-54
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
Deng, Yun; Tsao, Betty P (2014) Advances in lupus genetics and epigenetics. Curr Opin Rheumatol 26:482-92
Kaiser, Rachel; Taylor, Kimberly E; Deng, Yun et al. (2013) Brief Report: Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians. Arthritis Rheum 65:211-5
Ramos, Paula S; Oates, James C; Kamen, Diane L et al. (2013) Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry. J Rheumatol 40:842-9
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2013) MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet 9:e1003336
Kaufman, Kenneth M; Zhao, Jian; Kelly, Jennifer A et al. (2013) Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. Ann Rheum Dis 72:437-44
Sakurai, Daisuke; Zhao, Jian; Deng, Yun et al. (2013) Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression. PLoS Genet 9:e1003870

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