The incidence, prevalence, and often the severity of lupus in ethnic minorities is substantially higher than in European-Americans. Current evidence also indicates that these populations may have different risk alleles. Despite existing SNP databases and haplotype resources, our group and others have demonstrated the importance and value of re-sequencing in the identification of new variants that may contribute to disease susceptibility or severity. To facilitate the identification of novel SNPs and new haplotypic variants among populations of different ancestries, the Sequencing Core of this Program Project will re-sequence high priority candidate gene/genetic regions identified through the Genome Wide Association Studies (GWASs) and the first large replication study outlined in this Program Project. We anticipate a strategy in two phases in synergy with Projects 1-4. First, in Phase I to inform the first replication and early fine mapping studies, a focused subset of top candidate genes will be re-sequenced using standard 3730 series technology in a moderate through-put capacity. This stage will focus on coding and regulatory regions and splice junctions, anticipafing ~10 kb per gene in 150 SLE affecteds among African-American, Ameridian admixed Hispanics, and Asians. Second, in Phase II and based on results of both the GWAS and the first large replication study, the 50 strongest candidate genes/gene regions will be re-sequenced from ~150 SLE patients drawn from Projects 2, 3, and 4 based on disease status and SNP genotypes at selected SLE susceptibility loci. Genomic regions of interest will be enriched via hybridization and elufion from NimbleGen custom slide arrays and sequenced using the lllumina GS II genome analyzer using the Paired-End methodology. Sequence data will be organized in a database cataloguing genefic variations at SLE suscepfibility loci available to SLEGEN investigators as an essential resource for invesfigafions of the functional variations that predispose to SLE. Data will be deposited in dbSNP and GenBank for public access in keeping with the NIH data sharing recommendafions.

Public Health Relevance

The Sequencing Core of the Genomics of Lupus Program Project will facilitate the identification of new genetic variants in several racial groups which will expand our understanding of the genetic architecture of lupus, as a prototype autoimmune disease, and which will create a catalogue of suscepfibility loci that will be publicly available to all investigators for genotype-phenotype studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083194-02
Application #
8133963
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$1
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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 :
Hanscombe, Ken B; Morris, David L; Noble, Janelle A et al. (2018) Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. Hum Mol Genet 27:3813-3824
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
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
Lessard, Christopher J; Sajuthi, Satria; Zhao, Jian et al. (2016) Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans. Arthritis Rheumatol 68:1197-1209
Lu, Rufei; Munroe, Melissa E; Guthridge, Joel M et al. (2016) Dysregulation of innate and adaptive serum mediators precedes systemic lupus erythematosus classification and improves prognostic accuracy of autoantibodies. J Autoimmun 74:182-193
Munroe, Melissa E; Lu, Rufei; Zhao, Yan D et al. (2016) Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis 75:2014-2021
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
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 68:1290-1300

Showing the most recent 10 out of 81 publications