Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Association of Reactive Intermediate Genes with Systemic Lupus Erythematosus (SLE) Varies Across Populations with Different African Ancestries.
Ramos1, Paula S., Oates2, James C., Kamen2, Diane L., Gaffney3, Patrick M., Langefeld1, Carl D., Kelly3, Jennifer A., Kaufman3, Kenneth M.
Wake Forest School of Medicine, Winston-Salem, NC
University of Washington, Seattle, WA
King's College London, Guy's Hospital, London, United Kingdom
University of California San Francisco, San Francisco, CA
Oklahoma Medical Research Foundation, Center for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucia, Oklahoma City, OK
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
Medical University of South Carolina, Charleston, SC
Oklahoma Medical Research Foundation, Oklahoma City, OK
University of Alabama at Birmingham, Birmingham, AL
University of Chicago, Chicago, IL
Keck School of Medicine, University of Southern California, Los Angeles, CA
David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
Oklahoma Medical Research Foundation and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
University of Colorado Denver School of Medicine, Aurora, CO
Very little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry in spite of its higher prevalence, incidence, disease severity, and mortality rates in African Americans (AA). Overproduction of nitric oxide (NO) has been implicated in its pathogenesis and correlated with disease severity, making NO synthases and other reactive intermediate genes biological candidates for disease susceptibility. Here, we report a comprehensive analysis of reactive intermediate genes for their association with SLE in populations of African ancestry. One such population is the Gullah of the Sea Islands of South Carolina: a population isolate with limited and well defined ancestral diversity. Such reduced genetic heterogeneity may increase the power to detect associations in this population. In addition, their higher familial disease prevalence might reflect a stronger genetic component to the disease.
We analyzed 279 SNPs from 55 regions in 133 Gullah cases and 112 Gullah controls, as well as in other 1432 AA cases and 1575 AA controls. These and approximately 300 additional ancestry informative markers were genotyped on an Illumina custom array; principal components analysis and admixture estimates were computed and adjusted for in association analyses.
While the glutathione reductase GSR (rs2253409, P=0.0014, odds ratio (OR) [95% confidence interval (CI)]=1.26 [1.091.44]) and paraoxonase PON3 (rs17879114, P=0.0016, OR [95%CI]=0.79 [0.680.91]) were the most significant single-SNP associations in AA, in the Gullah the NADH dehydrogenase NDUFS4 (rs381575, P=0.0065, OR [95%CI]=2.10 [1.233.59]) and nitric oxide synthase NOS1 (rs561712, P=0.0072, OR [95%CI]=0.62 [0.440.88]) were the most strongly associate with SLE. When analyzed together, GSR remained the most significant effect (rs2253409, P=0.00072, OR [95%CI]=1.26 [1.101.44]). Haplotype analyses revealed a significant 3-SNP haplotype in NOS1 in AA (rs3741476-rs10774909, P=0.00029, OR=1.32), as well as in the joint cohorts together (P=0.00074, OR=1.28). Two-loci interaction analysis uncovered significant interactions between NDUFS2 (rs4656993) and the minichromosome maintenance complex component MCM5 (rs4645794) in AA (P=9.74E-05, OR [95%CI]=1.40 [1.321.48]), between the ring finger protein RNF157 (rs11099897) and the toll-like receptor TLR7 (rs5741880) in the Gullah (P=6.61E-05, OR [95%CI]=4.10 [1.5410.91]), and between PON3 (rs13226149) and TLR7 (rs1731479) in the joint cohort (P=0.0003, OR [95%CI]=1.41 [1.321.50]).
These results suggest that different variants in reactive intermediate genes in different African ancestries may be associated with SLE.
To cite this abstract, please use the following information:
Ramos, Paula S., Oates, James C., Kamen, Diane L., Gaffney, Patrick M., Langefeld, Carl D., Kelly, Jennifer A., et al; Association of Reactive Intermediate Genes with Systemic Lupus Erythematosus (SLE) Varies Across Populations with Different African Ancestries. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :641