Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans
Year: 2018
Type: article
Study design: Observational Study
Abstract: Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddy280
Authors: Ken B Hanscombe, David L Morris, Janelle A Noble, Alexander T Dilthey, Philip Tombleson, Kenneth M Kaufman, Mary Comeau, Carl D Langefeld, Marta E Alarcon-Riquelme, Patrick M Gaffney, Chaim O Jacob, Kathy L Sivils, Betty P Tsao, Graciela S Alarcon, Elizabeth E Brown, Jennifer Croker, Jeff Edberg, Gary Gilkeson, Judith A James, Diane L Kamen, Jennifer A Kelly, Joseph McCune, Joan T Merrill, Michelle Petri, Rosalind Ramsey-Goldman, John D Reveille, Jane E Salmon, Hal Scofield, Tammy Utset, Daniel J Wallace, Michael H Weisman, Robert P Kimberly, John B Harley, Cathryn M Lewis, Lindsey A Criswell, Timothy J Vyse
Institutions: King's College London, Centre for Human Genetics, University of Oxford, Cincinnati Children's Hospital Medical Center, United States Department of Veterans Affairs, University of Cincinnati, Wake Forest University Health Sciences, Wake Forest University, Karolinska Institutet, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research, Oklahoma Medical Research Foundation, University of Southern California, Medical University of South Carolina, University of Alabama at Birmingham, Center for Clinical and Translational Science, Cedars-Sinai Medical Center, A. Alfred Taubman Health Care Center, Michigan Medicine, Johns Hopkins University, Johns Hopkins Medicine, Hospital for Special Surgery, Weill Cornell Medicine, University of Oklahoma Health Sciences Center, University of Chicago, University of California, San Francisco, Russell/Engleman Rheumatology Research Center
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: U.S. Department of Defense, U.S. Department of Veterans Affairs, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, National Institute for Health and Care Research, King's College London, National Institutes of Health, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: G1067063329, G1068378815, G1139746577, G1313816191, G1428910847, G1444366456, Genetic Association in American Blacks with Lupus, G2157974190, Genomics of Lupus, G2234417830, Molecular Mechanisms and Genetics of Autoimmunity COBRE, G2938899690, G3327308444, Better Outcomes for Children: Promoting Excellence in Healthcare Genomics to Inform Policy, G3746560788, G3821373447, Functional Mechanisms of Causal Variants in Systemic Lupus Erythematosus, G3946412392, G415368022, G4297781590, G462492557, Northwestern University Clinical and Translational Science Institute (NUCATS), G5576683595, G5768299, G5906610974, Oklahoma Autoimmunity Center of Excellence Mechanisms of Disease Flare, G6819879733, G6957422189, G7027826638, G7072922876, Hopkins Lupus Cohort, MCRC for Rheumatic Diseases in African Americans, G8272278149, TNFAIP3 (A20) and Susceptibility to Systemic Lupus Erythematosus, G8801902774, G9000001851, G9000004491, G9000006082, G9000006405, G9000026923, G9000027893, G9000029701, G9000074186, G9000105038, G9000116733, G9000130911, G9000149483, G9000150122, G9000169229, G9000191628, G9000198241, G9000307771, Cincinnati Rheumatic Diseases Resource Center, Improving Health in Rheumatic Diseases (ImHeaRD), Oklahoma Rheumatic Disease Research Cores Center, RESOURCE-BASED CENTER FOR THE ADVANCEMENT OF PRECISION MEDICINE IN RHEUMATOLOGY
OpenAlex ID: W2887820187