Systemic lupus erythematosus (SLE) is a severe, complex, and clinically heterogeneous autoimmune disease which affects certain populations more severely than others. African-Americans (AA) exhibit a 3-5 fold increased prevalence with more severe manifestations, and greater mortality than individuals of European ancestry. Genetic research in lupus demonstrates that the strength of many genetic associations may also vary between different ethnic populations. There is also evidence that population admixture may play a significant role in influencing the risk of lupus in AA. Our preliminary data on whole-genome admixture scan using 1032 AA cases detected a significant association of SLE risk with elevated European ancestry at 2q22-24 (LOD=6.3, p<3.3x10-8). To identify SLE susceptibility genes within this admixture signal, we performed a candidate gene analysis (284 SNPs from 28 genes) in a follow-up study using 1425 AA cases and 1771 unrelated controls. We have evidence of association (0.05>p>10-6) for 6 novel genes. We have replicated some of these associations in individuals with European (0.05>p>10-5) and Asian (0.05>p>10-3) ancestry. Additionally, some of these associated genes are already reported to be strongly associated with other autoimmune diseases (i.e., Type 1 diabetes) implicating a role of general autoimmunity genes. Taken together, we hypothesize that 2q22-24 is an important and robust SLE susceptibility region which contains multiple, independent SLE predisposing variants, and these will be detected by leveraging differences in local LD structure among ethnically diverse populations. In the current proposal we will follow-up this region with dense fine-mapping and candidate gene analyses to identify SLE susceptibility genes. We will use a large set of individuals (7000 cases and 8000 controls from African, European, Asian, and Amerindian origin) with well-characterized clinical sub-phenotypes (by ACR criteria and autoantibody profiles) from 5 ethnically diverse populations. Our proposed cohort has adequate power to detect common variants with an OR=1.2. Using multiple ethnic populations will not only allow us to detect ethnic-specific or robust association across ethnically-diverse populations, but will also allow for trans-racial mapping to pin-point true predisposing variants and its relative contribution to SLE susceptibility. Upon detecting SLE susceptibility genes we will perform a genotype-phenotype correlation with clinical (ACR) criteria and autoantibody profiles. A detailed analysis of clinical phenotypic variables and their relationship to associated variants may directly address some aspects of clinical heterogeneity of SLE. Together with our research strategies, expertise, experience, track record of our research team, and available biomaterials, resources and infrastructure, we have great potential to successfully detect SLE predisposing variants at 2q22-24 identified through admixture mapping.

Public Health Relevance

Lupus is a severe, debilitating autoimmune disease that represents a significant healthcare burden in the USA and worldwide. We have identified a genomic region in chromosome 2 that may harbor multiple independent SLE susceptibility genes. None of the previously identified lupus genes are from this genomic interval. We will identify the SLE predisposing variants by comparing the genetic variants among multiple populations from diverse ethnicities. This study will not only identify the susceptibility genes but will also shed light on the relative contribution of genes and predisposing variants to the SLE susceptibility in individuals associated with African, European, Asian, and Native-American ancestries.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Wang, Yan Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oklahoma Medical Research Foundation
Oklahoma City
United States
Zip Code
Faridi, Mohd Hafeez; Khan, Samia Q; Zhao, Wenpu et al. (2017) CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. J Clin Invest 127:1271-1283
Zhang, Yue-Miao; Zhou, Xu-Jie; Nath, Swapan K et al. (2017) Evaluation of 10 SLE susceptibility loci in Asian populations, which were initially identified in European populations. Sci Rep 7:41399
Molineros, Julio E; Yang, Wanling; Zhou, Xu-Jie et al. (2017) Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci. Hum Mol Genet 26:1205-1216
Qi, Yuan-Yuan; Zhou, Xu-Jie; Nath, Swapan K et al. (2017) A rare variant (rs933717) at FBXO31-MAP1LC3B in Chinese is associated with systemic lupus erythematosus. Arthritis Rheumatol :
Zhou, Xu-Jie; Nath, Swapan K; Qi, Yuan-Yuan et al. (2016) Novel identified associations of RGS1 and RASGRP1 variants in IgA Nephropathy. Sci Rep 6:35781
Sun, Celi; Molineros, Julio E; Looger, Loren L et al. (2016) High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet 48:323-30
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
Raj, Prithvi; Rai, Ekta; Song, Ran et al. (2016) Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. Elife 5:
Kim, Kwangwoo; Bang, So-Young; Yoo, Dae Hyun et al. (2016) Imputing Variants in HLA-DR Beta Genes Reveals That HLA-DRB1 Is Solely Associated with Rheumatoid Arthritis and Systemic Lupus Erythematosus. PLoS One 11:e0150283
Kim, Kwangwoo; Bang, So-Young; Ikari, Katsunori et al. (2016) Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis. Sci Rep 6:27563

Showing the most recent 10 out of 27 publications