Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Identification of a Novel Systemic Lupus Erythematosus Susceptibility Locus at 11p13 near CD44 in a Multi-Ethnic Study.

Lessard3,  Christopher J., Adrianto1,  Indra, Kelly1,  Jennifer A., Kaufman1,  Kenneth M., Network2,  Marta E. Alarcon-Riquelme for the BIOLUPUS, Anaya4,  Juan-Manuel, Bae10,  Sang-Cheol

Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
Division of Medicine, Imperial College of London, London, UK
Division of Rheumatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA
Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas (CSIC), Granada, Spain
Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco
Sanatorio Parque, Rosario, Argentina
Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago
US Department of Veterans Affairs Medical Center, Department of Medicine, University of Oklahoma Health Sciences Center, and Cincinnati Children's Hospital Medical Center
Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation and Center for Genomics and Oncological Research (GENyO), Granada, Spain
Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation and Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogota, Columbia
Clinical Pharmacology, Oklahoma Medical Research Foundation
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
Department of Medicine, University of Southern California, Los Angeles, CA

Background:

SLE is a chronic, heterogeneous autoimmune disorder characterized by inflammation, loss of tolerance to self-antigens and dysregulated interferon responses. In this study, we sought to replicate a putative association at 11p13 from a genome-wide association (GWA) study not yet exceeding the stringent threshold for genome-wide significance (typically P<5×10-8).

Methods:

Genotyping was performed using Illumina iSelect technology. Stringent quality control measures were applied for Hardy-Weinberg proportions, proportion of missing genotypes and missingness between cases and controls. After quality control filtering, 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African-American (AA) descent and 1265 cases and 1260 controls of Asian origin were included in the replication analysis. Logistic regression was implemented using PLINK under dominant, recessive and additive genetic models. Covariates for gender and population admixture were included. Stouffer's weighted Ztrend scores were calculated for a meta-analysis between the GWA and replication results.

Results:

Our GWA scan identified two SNPs in strong linkage disequilibrium (LD, r2=0.94) located ~74kb telomeric to CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, P=0.004, OR=0.78, 95%CI=0.690–0.9334; rs387619, P=0.003, OR=0.78, 95%CI=0.675–0.9141). We observed independent replication at both rs2732552 (P=9.03×10-8, OR=0.83, 95%CI =0.77–0.88) and rs387619 (P=7.7×10-7, OR=0.83, 95%CI=0.77–0.90) in the European samples with a Pmeta=1.82×10-9 for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (P=5×10-3, OR=0.81, 95%CI=0.70–0.94 and P=4.3×10-4, OR=0.80, 95%CI=0.70–0.91, respectively). The Asian SLE cases were associated with rs387619 (P=0.001, OR=0.8 95%CI=0.70–0.91), but not the AA SLE cases, consistent with differences in the haplotype patterns between racial groups. The meta-analysis at rs2732552 for all 4 ethnic groups produced Pmeta=3.00×10–13.

Conclusion:

We have established genetic association with SLE to a haplotype near CD44. Imputation and trans-ethnic mapping focus the effect on a ~14kb haplotype in a region of strong regulatory potential that may influence expression of the centromeric gene CD44. This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory and oncologic phenotypes. Further functional studies of this complex locus will be required to determine the precise variant(s) influencing SLE risk and to characterize the contribution to disease.

To cite this abstract, please use the following information:
Lessard, Christopher J., Adrianto, Indra, Kelly, Jennifer A., Kaufman, Kenneth M., Network, Marta E. Alarcon-Riquelme for the BIOLUPUS, Anaya, Juan-Manuel, et al; Identification of a Novel Systemic Lupus Erythematosus Susceptibility Locus at 11p13 near CD44 in a Multi-Ethnic Study. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2147
DOI: 10.1002/art.29911

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