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.
Trait-Stratified Genome-Wide Association Study Identifies Novel and Diverse Genetic Associations with Serologic and Cytokine Phenotypes in Systemic Lupus Erythematosus.
Kariuki4, Silvia N., Franek4, Beverly S., Kumar4, Akaash A., Arrington4, Jasmine, Mikolaitis2, Racheal A., Utset4, Tammy O., Jolly2, Meenakshi
Hospital for Special Surgery, Mary Kirkland Center for Lupus Research, New York, NY
Rush University, Section of Rheumatology, Chicago, IL
University of Chicago Pritzker School of Medicine, Section of Genetic Medicine, Chicago, IL
University of Chicago Pritzker School of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, Chicago, IL
Systemic lupus erythematosus (SLE) is a highly heterogeneous disorder. SLE-associated autoantibodies and high serum interferon alpha (IFN-a) are important heritable phenotypes in SLE which are correlated with each other, and play a role in disease pathogenesis. We set out to detect genetic factors associated with autoantibody profiles and serum IFN-a in SLE.
SLE patients were stratified by extremes of phenotype in serology and serum IFN-a for a case-case genome-wide association study. Single nucleotide polymorphisms (SNPs) in seven loci were selected for follow up in a large independent cohort of 450 SLE patients and 522 controls using a multi-step screening approach based on novel metrics and expert database review. The seven loci were: LRRC20, PPM1H, LPAR1, ANKS1A, PTPRM, EFNA5, and VSIG2.
SNPs in the LRRC20, PPM1H, LPAR1, ANKS1A, and VSIG2 loci each demonstrated strong association with a particular serologic profile (all OR>2.2 and p<8×10-4). Each of these serologic profiles was associated with increased serum IFN-a. SNPs in PTPRM and LRRC20 were associated with increased serum IFN-a independent of serologic profile (p=3.2 × 10-6 and p= 5.0 × 10-3 respectively). None of the SNPs were strongly associated with SLE in case-control analysis, suggesting that the major impact of these variants will be upon subphenotypes in SLE.
This study demonstrates the power of using serologic and cytokine subphenotypes to elucidate genetic factors involved in complex autoimmune disease. The distinct associations observed emphasize the heterogeneity of molecular pathogenesis in SLE, and the need for stratification by subphenotypes in genetic studies.
To cite this abstract, please use the following information:
Kariuki, Silvia N., Franek, Beverly S., Kumar, Akaash A., Arrington, Jasmine, Mikolaitis, Racheal A., Utset, Tammy O., et al; Trait-Stratified Genome-Wide Association Study Identifies Novel and Diverse Genetic Associations with Serologic and Cytokine Phenotypes in Systemic Lupus Erythematosus. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1612