美国类风湿关节炎退伍军人中的 HLA-DRB1 单倍型、共享表位与疾病结局。

HLA-DRB1 Haplotypes, Shared Epitope, and Disease Outcomes in US Veterans with Rheumatoid Arthritis.

机构信息

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.

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.

出版信息

J Rheumatol. 2019 Jul;46(7):685-693. doi: 10.3899/jrheum.180724. Epub 2019 Mar 1.

DOI:10.3899/jrheum.180724

PMID:30824656

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7249261/

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.

摘要

目的

评估 HLA-DRB1 单倍型和共享表位 (SE) 与类风湿关节炎 (RA) 严重程度和 RA 全因死亡率的相关性。

方法

退伍军人事务部类风湿关节炎 (VARA) 登记处的 RA 患者从入组开始随访，直至死亡或 2013 年 12 月 31 日。入组时收集临床特征、DNA 和血清，入组时和随访期间评估放射学损伤、是否存在皮下结节、疾病活动度指标和功能状态。从银行 DNA 中确定了 16 种 HLA-DRB1 单倍型和 SE 状态。在多变量回归模型中评估了 HLA-DRB1 单倍型与 RA 疾病特征和死亡率之间的关系。

结果

在 VARA 中，有 1443 名参与者进行了基因分型，并随访了 6150 患者年。单倍型 VKA、VRA、LRA、SRA、SRE、SKR 和 SEA 以及 SE 等位基因与类风湿因子 (RF) 和/或抗环瓜氨酸肽 (抗-CCP) 的血清阳性显著相关。单倍型 VKA 和 SKR 与较高的 RF 浓度相关，而 VRA、DRE 和 GRQ 与较低的 RF 浓度相关。单倍型 VKA、VRA 和 LRA 与较高浓度的抗-CCP 抗体相关，而单倍型 SRA、SRE、LEA、SKR 和 SEA 与较低浓度的抗-CCP 抗体显著相关。单倍型 VKA（OR 1.39，95%CI 1.08-1.80）与入组时放射学损伤的频率增加相关，但没有一个单倍型与皮下结节的存在相关。单倍型 SKA（HR 1.52，95%CI 1.26-1.83）与更高的死亡率相关。