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.


A Single Risk Haplotype in the Region of UBE2L3 Is Associated with Systemic Lupus Erythematosus in Multiple Ethnic Populations.

Wang1,  Shaofeng, Adrianto1,  Indra, Wiley1,  Graham B., Kaufman2,  Kenneth M., Anaya3,  Juan-Manuel, Alarcon-Riquelme,  Marta E., on behalf of the BIOLUPUS and GENLES networ,  

Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation and Oklahoma University Health Sciences Center, Oklahoma City, OK
Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain
University of Chicago, Chicago, IL
Sanatorio Parque, Rosario, Argentina
David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA
King's College London, Guy's Hospital, London, United Kingdom
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
Univ of Texas SW Med Ctr, Dallas, TX
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation and US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Universidad del Rosario-Corporacion para Investigaciones Biologicas, Bogota, Colombia
Hanyang University Hospital for Rheumatic Diseases, Clinical Research Center for Rheumatoid Arthritis (CRCRA), Seoul, South Korea
University of Alabama at Birmingham, Birmingham, AL
Wake Forest School of Medicine, Winston-Salem, NC
Division of Rheumatologyand Immunology, Medical University of South Carolina, Charleston, SC
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA

Background/Purpose:

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies and target tissue damage. Genome-wide association (GWA) studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBcH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype.

Methods:

The IlluminaiSelect platform was employed to genotype SNPs within the UBE2L3 region in 8,922 cases and 8,077 controls, including: African-Americans (1,569 cases/1,893 controls), Asians (1,328 cases/1,348 controls), Europeans (4,248 cases/3,818 controls), Gullah (155 cases/131 controls), and Hispanics enriched for Amerindian-European admixture (1,622 cases/887 controls). Imputation was performed using IMPUTE2 and the 1000 Genomes Project reference panels. The single marker association analyses were calculated using the logistic regression function in PLINK adjusting for gender and global ancestry estimates. Haploview version 4.2 was used to generate probable haplotypes and calculate haplotypic association for all haplotypes formed by the associated markers. Eight EBV-transformed B cell lines with risk haplotype and 16 with non-risk haplotype were used to study the effect on UBE2L3 mRNA and UBcH7 protein expression. Quantitative RT-PCR and western blotting was performed to compare the mRNA and protein expression level of UBE2L3, respectively.

Results:

We identified strong associations between variants in UBE2L3 and SLE in Europeans (86 SNPs with P < 1 × 10-4), Asians (71 SNPs with P < 1 × 10-3), and modest association in African-Americans (24 SNPs with P < 0.01), and Hispanics (17 SNPs with P < 0.01). A single risk haplotype was observed in subjects of European-ancestry (P = 2.07 × 10-7), and the other associated populations. However, due to strong LD across the region we were not able to narrow the risk interval using genetic methods (r2 > 0.8). Previous studies suggested that variants in the region of UBE2L3 influence UBE2L3 transcript expression. To evaluate if the SLE risk haplotype carries variants that influence UBE2L3 transcript or UBcH7 protein levels, we used quantitative-PCR and western blotting. Our results demonstrate that individuals harboring the risk haplotype display a significant increase in both mRNA expression (P < 0.001) and UBcH7 protein expression (P = 0.001). These results suggest the variants carried on the SLE associated UBE2L3 risk haplotype influence autoimmunity by modulating UBcH7 expression.

Conclusion:

UBE2L3 is an SLE risk locus present in multiple ethnic groups. Our data demonstrate a single risk haplotype with strong linkage disequilibrium that resists further genetic refinement. The UBE2L3 risk haplotype results in increased expression of both UBE2L3 mRNA and UBcH7 protein.

To cite this abstract, please use the following information:
Wang, Shaofeng, Adrianto, Indra, Wiley, Graham B., Kaufman, Kenneth M., Anaya, Juan-Manuel, Alarcon-Riquelme, Marta E., et al; A Single Risk Haplotype in the Region of UBE2L3 Is Associated with Systemic Lupus Erythematosus in Multiple Ethnic Populations. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :636
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