Ming Zhao1,2, Lilli Mauer1,2, Harlan Sayles1,2, Grant W Cannon1,2, Andreas Reimold1,2, Gail S Kerr1,2, Joshua F Baker1,2, Geoffrey M Thiele1,2, Bryant R England1,2, Ted R Mikuls3,4. 1. From the Veterans Affairs (VA) Nebraska-Iowa Health Care System; Division of Rheumatology and Immunology, Department of Internal Medicine, University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA. 2. M. Zhao, MD, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC; L. Mauer, MD, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC; H. Sayles, MS, Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC, and Department of Biostatistics, College of Public Health, UNMC; G.W. Cannon, MD, VA Salt Lake City and University of Utah; A. Reimold, MD, Dallas VA and University of Texas Southwestern; G.S. Kerr, MD, Washington DC VAMC, Georgetown University and Howard University; J.F. Baker, MD, MSCE, Corporal Michael J. Crescenz VA and University of Pennsylvania; G.M. Thiele, PhD, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC; B.R. England, MD, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC; T.R. Mikuls, MD, MSPH, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC. 3. From the Veterans Affairs (VA) Nebraska-Iowa Health Care System; Division of Rheumatology and Immunology, Department of Internal Medicine, University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA. tmikuls@unmc.edu tmikuls@yahoo.com. 4. M. Zhao, MD, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC; L. Mauer, MD, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC; H. Sayles, MS, Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC, and Department of Biostatistics, College of Public Health, UNMC; G.W. Cannon, MD, VA Salt Lake City and University of Utah; A. Reimold, MD, Dallas VA and University of Texas Southwestern; G.S. Kerr, MD, Washington DC VAMC, Georgetown University and Howard University; J.F. Baker, MD, MSCE, Corporal Michael J. Crescenz VA and University of Pennsylvania; G.M. Thiele, PhD, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC; B.R. England, MD, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC; T.R. Mikuls, MD, MSPH, VA Nebraska-Iowa Healthcare System, and Division of Rheumatology and Immunology, Department of Internal Medicine, UNMC. tmikuls@unmc.edu tmikuls@yahoo.com.
Abstract
OBJECTIVE: To evaluate associations of HLA-DRB1 haplotypes and shared epitope (SE) with rheumatoid arthritis (RA) severity and all-cause mortality in RA. METHODS: Patients with RA from the Veterans Affairs Rheumatoid Arthritis (VARA) registry were followed from enrollment until death or December 31, 2013. Clinical characteristics, DNA, and serum were collected at enrollment. Radiographic damage, the presence or absence of subcutaneous nodules, disease activity measures, and functional status were assessed at enrollment and updated during followup. Sixteen HLA-DRB1 haplotypes and SE status were determined from banked DNA. Associations between HLA-DRB1 haplotypes, RA disease characteristics, and mortality were assessed in multivariable regression models. RESULTS: Within VARA, 1443 participants had genotyping and accrued 6150 patient-years of followup. Haplotypes VKA, VRA, LRA, SRA, SRE, SKR, and SEA, and SE alleles were significantly associated with seropositivity for rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP). Haplotypes VKA and SKR were associated with higher RF concentrations, while VRA, DRE, and GRQ were associated with lower RF concentrations. Haplotypes VKA, VRA, and LRA were associated with higher concentrations of anti-CCP antibody, while haplotypes SRA, SRE, LEA, SKR, and SEA were significantly associated with lower anti-CCP concentrations. Haplotype VKA (OR 1.39, 95% CI 1.08-1.80) was associated with increased frequency of radiographic damage at enrollment but none of the haplotypes were associated with the presence of subcutaneous nodules. Haplotypes SKA (HR 1.52, 95% CI 1.26-1.83) was associated with higher mortality. CONCLUSION: HLA-DRB1 haplotypes are independently and variably associated with seropositivity, autoantibody concentrations, and outcomes in RA.
OBJECTIVE: To evaluate associations of HLA-DRB1 haplotypes and shared epitope (SE) with rheumatoid arthritis (RA) severity and all-cause mortality in RA. METHODS:Patients with RA from the Veterans Affairs Rheumatoid Arthritis (VARA) registry were followed from enrollment until death or December 31, 2013. Clinical characteristics, DNA, and serum were collected at enrollment. Radiographic damage, the presence or absence of subcutaneous nodules, disease activity measures, and functional status were assessed at enrollment and updated during followup. Sixteen HLA-DRB1 haplotypes and SE status were determined from banked DNA. Associations between HLA-DRB1 haplotypes, RA disease characteristics, and mortality were assessed in multivariable regression models. RESULTS: Within VARA, 1443 participants had genotyping and accrued 6150 patient-years of followup. Haplotypes VKA, VRA, LRA, SRA, SRE, SKR, and SEA, and SE alleles were significantly associated with seropositivity for rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP). Haplotypes VKA and SKR were associated with higher RF concentrations, while VRA, DRE, and GRQ were associated with lower RF concentrations. Haplotypes VKA, VRA, and LRA were associated with higher concentrations of anti-CCP antibody, while haplotypes SRA, SRE, LEA, SKR, and SEA were significantly associated with lower anti-CCP concentrations. Haplotype VKA (OR 1.39, 95% CI 1.08-1.80) was associated with increased frequency of radiographic damage at enrollment but none of the haplotypes were associated with the presence of subcutaneous nodules. Haplotypes SKA (HR 1.52, 95% CI 1.26-1.83) was associated with higher mortality. CONCLUSION:HLA-DRB1 haplotypes are independently and variably associated with seropositivity, autoantibody concentrations, and outcomes in RA.
Authors: Benjamin J Miriovsky; Kaleb Michaud; Geoffrey M Thiele; James R O'Dell; Grant W Cannon; Gail Kerr; J Steuart Richards; Dannette Johnson; Liron Caplan; Andreas Reimold; Roderick Hooker; Ted R Mikuls Journal: Ann Rheum Dis Date: 2010-05-03 Impact factor: 19.103
Authors: Bryant R England; Harlan Sayles; Ted R Mikuls; Dannette S Johnson; Kaleb Michaud Journal: Arthritis Care Res (Hoboken) Date: 2015-05 Impact factor: 4.794
Authors: Bryant R England; Harlan Sayles; Kaleb Michaud; Liron Caplan; Lisa A Davis; Grant W Cannon; Brian C Sauer; Elizabeth B Solow; Andreas M Reimold; Gail S Kerr; Pascale Schwab; Josh F Baker; Ted R Mikuls Journal: Arthritis Care Res (Hoboken) Date: 2016-01 Impact factor: 4.794
Authors: Floris A van Gaalen; Jill van Aken; Tom W J Huizinga; Geziena M Th Schreuder; Ferdinand C Breedveld; Eric Zanelli; Walther J van Venrooij; Cornelis L Verweij; René E M Toes; René R P de Vries Journal: Arthritis Rheum Date: 2004-07
Authors: Too Chun-Lai; Leonid Padyukov; Jasbir Singh Dhaliwal; Emeli Lundström; Abqariyah Yahya; Nor Asiah Muhamad; Lars Klareskog; Lars Alfredsson; Per Tobias Larsson; Shahnaz Murad Journal: PLoS One Date: 2011-06-15 Impact factor: 3.240
Authors: Soumya Raychaudhuri; Cynthia Sandor; Eli A Stahl; Jan Freudenberg; Hye-Soon Lee; Xiaoming Jia; Lars Alfredsson; Leonid Padyukov; Lars Klareskog; Jane Worthington; Katherine A Siminovitch; Sang-Cheol Bae; Robert M Plenge; Peter K Gregersen; Paul I W de Bakker Journal: Nat Genet Date: 2012-01-29 Impact factor: 38.330
Authors: Stephanie F Ling; Sebastien Viatte; Mark Lunt; Alper M Van Sijl; Lucia Silva-Fernandez; Deborah P M Symmons; Adam Young; Alexander J Macgregor; Anne Barton Journal: Arthritis Rheumatol Date: 2016-11 Impact factor: 10.995
Authors: Seema Sharma; Darren Plant; John Bowes; Alex Macgregor; Suzanne Verstappen; Anne Barton; Sebastien Viatte Journal: Arthritis Res Ther Date: 2022-04-25 Impact factor: 5.606