We have found a powerful genetic association with systemic lupus erythematosus in African American families. Our data to this point show an odds ration of 9.0, chi square of 9.55 and p=0.002. At the same locus there is no genetic association with lupus in American white families who are multiplex for lupus (odds ratio = 1.8, chi square = 0.04, and p = 0.4). The genetic marker for these data, D1S117, was chosen for its proximity to the Fcgamma receptor IIIPMN gene, the product of which is the most abundant receptor for immune complexes on the surface of normal neutrophils. Uncommon deletions in this gene have been identified in two lupus patients. Preliminary genetic modelling has revealed a lod score of 2.17 at a recombination fraction of zero for a homozygous recessive effect at D1S117 in African American families. At this locus in seven white families the lod score under this model is less than -2.0 for any recombination frequency lower than 0.07. The proposed study is designed to evaluate this genetic association in African Americans families. We plan to collect additional African American pedigrees who are multiplex for systemic lupus erythematosus. Then the optimal model for the mode of inheritance will be determined by applying the maximum likelihood algorithms of analysis. By evaluating the other polymorphic loci on chromosome 1 we will localize the linkage interval. Alleles of the Fcgamma RIIIPMN gene from affected African lupus patients will be characterized, first by Southern blot, then by their single stranded conformational polymorphisms and finally be sequencing. If a gene linked to D1S117 is responsible, but not Fcgamma RIIIPMN itself, then we will apply selection cloning in a quest to identify this locus. Whether at Fcgamma RIIIPMN or not, our goal during this project is to identify the gene and its allelic differences responsible for the observed genetic association with lupus in our growing collection of African American pedigrees multiplex for lupus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042460-03
Application #
2081736
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1993-09-30
Project End
1998-05-31
Budget Start
1995-09-01
Budget End
1996-05-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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
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
Kariuki, S N; Ghodke-Puranik, Y; Dorschner, J M et al. (2015) Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus. Genes Immun 16:15-23
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, 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
Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7
Guthridge, Joel M; Lu, Rufei; Sun, Harry et al. (2014) Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet 94:586-98

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