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1401 A Genome Wide Association Scan of SLE genetic risk in a cohort of African-American persons
  1. Isaac TW Harley1,2,3,
  2. Celi Sun1,
  3. Adrienne H Williams4,
  4. Julie T Ziegler4,
  5. Mary E Comeau4,
  6. Miranda C Marion4,
  7. Stuart B Glenn5,
  8. Adam Adler5,
  9. Summer G Frank-Pearce6,
  10. Nan Shen7,
  11. Jennifer A Kelly8,
  12. Bahram Namjou-Khales9,10,
  13. Michelle Petri11,
  14. Marta Alarcon-Riquelme12,13,
  15. W Joseph McCune14,
  16. Patrick Gaffney8,
  17. Kathy Sivils15,
  18. Jane E Salmon16,
  19. Michael H Weisman17,
  20. Jeffrey C Edberg18,
  21. Elizabeth E Brown19,20,
  22. Tammy Utset21,
  23. Lindsey A Criswell22,
  24. Chaim O Jacob23,
  25. Betty Tsao24,
  26. Timothy J Vyse25,
  27. Judith A James5,26,27,
  28. Gary S Gilkeson24,
  29. Diane L Kamen24,
  30. Courtney Montgomery8,28,
  31. Joan T Merrill5,28,
  32. Swapan K Nath5,
  33. Viktoryia Laurynenka9,
  34. Iouri Chepelev29,
  35. Valerie Harris-Lewis5,30,31,
  36. R Hal Scofield5,30,31,
  37. Robert P Kimberly18,
  38. Carl D Langefeld4,
  39. John B Harley29 and
  40. Kenneth M Kaufman9,10,29
  1. 1Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
  2. 2Human Immunology and Immunotherapy Initiative (HI3), Department of Immunology, University of Colorado School of Medicine, Aurora, CO, USA
  3. 3Rocky Mountain Regional Veteran’s Administration Medical Center (VAMC), Medicine Service, Rheumatology Section, Aurora, CO, USA
  4. 4Center for Public Health Genomics and the Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
  5. 5Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
  6. 6Department of Biostatistics and Epidemiology, Hudson College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
  7. 7Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, P.R. China
  8. 8Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
  9. 9Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
  10. 10Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
  11. 11Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
  12. 12Unit of Chronic Inflammatory Diseases, Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17167, Sweden
  13. 13Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucia, Parque Tecnológico de la Salud, Granada 18016, Spain
  14. 14Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
  15. 15Translational Science Division of The Janssen Pharmaceutical Companies of Johnson and Johnson. Spring House, Pennsylvania, 19002, USA
  16. 16Hospital for Special Surgery, New York, NY 10021, USA
  17. 17Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
  18. 18Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
  19. 19Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
  20. 20Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
  21. 21University of Chicago Pritzker School of Medicine, Chicago, IL, USA
  22. 22National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD 20892, USA
  23. 23Keck School of Medicine of USC, Los Angeles, CA, USA
  24. 24Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
  25. 25Divisions of Genetics/Molecular Medicine and Immunology, King’s College London, Guy’s Hospital, London SE1 9RT, UK
  26. 26Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
  27. 27Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
  28. 28Clinical Pharmacology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
  29. 29US Department of Veterans Affairs Medical Center, Cincinnati, Ohio 45229, USA
  30. 30University of Oklahoma Health Sciences Center, Oklahoma City
  31. 31US Department of Veterans Affairs Medical Center, Oklahoma City


Systemic lupus erythematosus (SLE) is the prototypical multi-system autoimmune disease with diverse clinical features in persons with disease. SLE is also unified by characteristic autoimmunity directed against nucleic acid or nucleoprotein complexes. SLE is both more prevalent and typically exhibits a more severe clinical course in persons with African-American ancestry than in persons with European ancestry. The reasons for this discrepancy remain incompletely understood. GWAS studies of SLE in cohorts of individuals with Amerindian, East Asian and European ancestry have identified > 180 risk loci for SLE across the genome. These loci act in several pathways: clearance of autoantigens, innate immune response to nucleic acids, and lymphocyte activation. Despite these advances in understanding the genetic basis of SLE, a genome-wide association scan (GWAS) of SLE in a cohort of individuals with African-American ancestry has not yet been reported. Here, we report preliminary results of GWAS in 1494 SLE cases and 6076 matched controls with African-American ancestry. Illumina Infinium Omni 1, Omni 1S, Omni 2.5 and OmniExpress platforms were used for genotyping. Genotypes were imputed using the TOPMed reference panel at NHLBI. By defining the contribution common genetic variants to disease risk across the genome, our study represents a step towards understanding the genetic basis of SLE and the increased prevalence and severity of SLE in African ancestry populations. To fully define the relative contribution of environment and genetics to the discrepant SLE severity and prevalence observed in African-American populations, future studies will be necessary. These studies should focus both on comprehensive understanding of the environmental influences and comprehensive assessment of genome- wide genetic variation (i.e. whole-genome sequencing) that impact SLE risk and disease severity.

Our results confirm genome-wide significant (P < 5E-8) association with loci ascertained in other populations (STAT4-STAT1, TNIP1, MIR146A, HLA-C4A-C4B, IRF5, BLK, PLAT-IKBKB, RELA-RNASEH2C-OVOL1, ITGAM, and IRF8) and identify several novel genome-wide significant risk loci that are newly described in our study (ENSA, IKBKB/Chr8: Centromere and PCMTD1-ST18). Further, we compared associated variants in our study with those from three large SLE GWAS studies in cohorts of individuals with European, East Asian and Amerindian ancestry. This comparison of SLE risk loci revealed pervasive sharing of SLE genetic risk across ancestral groups. For 70% of the risk loci, the lead marker exhibited nominal association (P < 0.05) with SLE in our GWAS of SLE in African- American persons. Importantly, the association of all such variants cohered with the reported direction in other ancestries.

Overall, our findings are consistent with a polygenic contribution to SLE in African-American individuals that is largely shared across populations. We also find association with a rare variant (MAF < 1%) of large effect (OR = 3.91) near a locus previously identified via ImmunoChip (Illumina), PLAT-IKBKB. The lead variant at this locus is non-polymorphic in populations with ancestry outside of Africa. This association explains the increased risk of SLE in ~4% of cases in our cohort. On the one hand, our GWAS of SLE in persons African-American ancestry provides insights that reinforce the conclusions concerning the known risk loci from other ancestries. On the other hand, this mechanism uniquely raises SLE risk in a small proportion of African ancestry individuals with SLE. Together our findings reveal both uniformity and diversity of genetic risk factors impacting SLE development across populations.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: .

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