As a follow up to our previous genetic studies both in childhood-onset and adult-onset SLE, our goal is to identify major genetic risk factors in novel genes and characterize the causal mutations and the mechanisms of disease involvement of these new genes. For the purpose of these studies we have assembled an unparalleled study population of 6,500 adult-onsets and 1,100 childhood-onset cases of SLE and a large multidisciplinary collaborative team of investigators. Based on Bayesian methodology, we developed a gene selection tool to increase the power of genetic association studies, and we devised a novel microarray platform to discover susceptibility genes contributing to SLE. We tested our model in a cohort of childhood-onset SLE families and replicated the results in a second much larger childhood-onset SLE cohort and a very large cohort of adult onset SLE. We propose to identify the causal variants in the following new genes:
F AIM, IRAK1, KLRG1, TNFSF4, TLR8 and SELP by fine mapping, re-sequencing and re-evaluation of the new SNPs identified through sequencing in case-control association studies in four different ethnicities in both childhood-onset and adult-onset cohorts. Based on the variants and causal haplotype blocks found, we will conduct hypothesis-based analyses in clinical sub-phenotypes of SLE. Finally we will conduct functional studies toward understanding the mechanisms through which the genetic variants discovered and characterized in sub-phenotypes of SLE may be involved in the causation or perpetuation of SLE. We anticipate that these studies will identify novel gene variants, especially those that are common to several ethnic groups and to both childhood- and adult-onset SLE. Results of these association studies will lead to the molecular characterization of their effects on the gene products and an understanding of the role of these genes in the pathogenesis of SLE. Knowledge gained from these studies will reveal new paradigms and open promising new directions in the understanding and ultimately the treatment of this devastating disorder.
SLE or lupus is a devastating human disease affecting mainly females and is responsible for significant morbidity and suffering to hundreds of thousands of patients within USA. The disease is caused by interacting genetic and environmental factors. The discovery and characterization of the genetic factors which are the goals of this study are crucial for the understanding of the pathology of the disease and will result in novel targets and therapies for this devastating condition.
|Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :|
|Jacob, Chaim O; Yu, Ning; Yoo, Dae-Goon et al. (2017) Haploinsufficiency of NADPH Oxidase Subunit Neutrophil Cytosolic Factor 2 Is Sufficient to Accelerate Full-Blown Lupus in NZM 2328 Mice. Arthritis Rheumatol 69:1647-1660|
|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|
|Zhao, Jian; Giles, Brendan M; Taylor, Rhonda L et al. (2016) Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. Ann Rheum Dis 75:242-52|
|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|
|Armstrong, Don L; Eisenstein, Miriam; Zidovetzki, Raphael et al. (2015) Systemic lupus erythematosus-associated neutrophil cytosolic factor 2 mutation affects the structure of NADPH oxidase complex. J Biol Chem 290:12595-602|
|Martins, M; Williams, A H; Comeau, M et al. (2015) Genetic association of CD247 (CD3?) with SLE in a large-scale multiethnic study. Genes Immun 16:142-50|
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