Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response.
Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response.
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DOI：
10.1001/jama.2015.3435
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发表时间：
2015-04-28
期刊：
影响因子：
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通讯作者：
Barton A
中科院分区：
文献类型：
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作者：
Viatte S;Plant D;Han B;Fu B;Yarwood A;Thomson W;Symmons DP;Worthington J;Young A;Hyrich KL;Morgan AW;Wilson AG;Isaacs JD;Raychaudhuri S;Barton A
在识别自身免疫性疾病的遗传易感基因方面已经取得了进展，但还需要证据来证明它们与预后和治疗反应的关系。评估与类风湿性关节炎(RA)易感性相关的特定的人类白细胞抗原-DRB1单倍型是否也与放射学严重程度、死亡率和对肿瘤坏死因子(TNF)抑制剂药物的反应有关。诺福克关节炎登记簿(NOAR；1691名患者和2811张X光照片；招募：1989-2008年；2008年作为最终随访)被用作发现队列，早期类风湿性关节炎研究(421名患者和3758张X光照片；招募：1986-1999年；2005年作为最终随访)被用作放射结果研究的独立复制队列。死亡率研究在NOAR队列(2432名患者；招募：1990-2007年；2011年作为最终随访)和类风湿性关节炎遗传学和基因组学研究中生物制剂的治疗反应研究(1846名患者在开始使用肿瘤坏死因子抑制剂时登记；招募：2006-2010年；2011年作为最终随访)中进行。进行纵向统计建模，以随时间推移整合每个患者的多个放射学记录。所有患者都来自英国，并自称有白人血统。由第11、71和74位氨基酸定义的16种HLA-DRB1单倍型。使用Larsen评分(范围：0[无]到200[严重关节损害])和X线片上手部和脚的侵蚀、全因死亡率和治疗反应(通过基于28个关节计数和欧洲抗风湿病联盟(EULAR)反应的疾病活动评分变化来衡量的治疗反应)的放射结果。HLA-DRB1基因第11位点RA和Valine与放射损伤的相关性最强(OR，1.75[95%CI，1.51~2.05]，P=4.6E~13)。到第5年时，手足腐蚀者的比例分别为：第11位非Valine携带者占48%(150/314)，杂合子携带者占61%(130/213)，纯合子携带者占74%(43/58)。在炎症性多发性关节炎患者中，第11位的Valine也与较高的全因死亡率相关(危险比，1.16[95%CI，1.03-1.31]，P=0.01)(非携带者：1398名患者在17196人年中有319人死亡，死亡率为1.9%/年；携带者：13208人年中1116名患者中有324人死亡，死亡率为每年2.5%)，对肿瘤坏死因子抑制剂治疗有较好的EULAR反应(OR，1.14[95%CI，1.01-1.30]，P=0.04)(非携带者：78%[439/561例患者]EULAR反应中等或良好；杂合子携带者：81%[698/866]；纯合子携带者：86%[277/322])。由HLA-DRB1单倍型定义的风险等级与疾病易感性、严重程度和死亡率相关，但与肿瘤坏死因子抑制剂的治疗反应呈负相关。在RA患者中，与疾病易感性相关的HLA-DRB1基因座也与放射学严重程度、死亡率和治疗反应相关。在评估人类白细胞抗原-DRB1单倍型分析在类风湿关节炎治疗中的作用的下一步中，需要在其他队列中复制这些发现。
Advances have been made in identifying genetic susceptibility loci for autoimmune diseases, but evidence is needed regarding their association with prognosis and treatment response. To assess whether specific HLA-DRB1 haplotypes associated with rheumatoid arthritis (RA) susceptibility are also associated with radiological severity, mortality, and response to tumor necrosis factor (TNF) inhibitor drugs. The Norfolk Arthritis Register (NOAR; 1691 patients and 2811 radiographs; recruitment: 1989–2008; 2008 as final follow-up) was used as a discovery cohort and the Early Rheumatoid Arthritis Study (421 patients and 3758 radiographs; recruitment: 1986–1999; 2005 as final follow-up) as an independent replication cohort for studies of radiographic outcome. Mortality studies were performed in the NOAR cohort (2432 patients; recruitment: 1990–2007; 2011 as final follow-up) and studies of treatment response in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort (1846 patients enrolled at initiation of TNF inhibitor; recruitment: 2006–2010; 2011 as final follow-up). Longitudinal statistical modeling was performed to integrate multiple radiograph records per patient over time. All patients were from the United Kingdom and had self-reported white ancestry. Sixteen HLA-DRB1 haplotypes defined by amino acids at positions 11, 71, and 74. Radiological outcome using the Larsen score (range: 0 [none] to 200 [severe joint damage]) and erosions of the hands and feet on radiographs, all-cause mortality, and treatment response measured by change in Disease Activity Score based on 28 joint counts and European League Against Rheumatism (EULAR) response. Patients with RA and valine at position 11 of HLA-DRB1 had the strongest association with radiological damage (OR, 1.75 [95% CI, 1.51–2.05], P = 4.6E-13). By year 5, the percentages of patients with erosions of the hands and feet were 48% of noncarriers (150/314) of valine at position 11, 61% of heterozygote carriers (130/213), and 74% of homozygote carriers (43/58). Valine at position 11 also was associated with higher all-cause mortality in patients with inflammatory polyarthritis (hazard ratio, 1.16 [95% CI, 1.03–1.31], P = .01) (noncarriers: 319 deaths in 1398 patients over 17 196 person-years, mortality rate of 1.9% per year; carriers: 324 deaths in 1116 patients in 13 208 person-years, mortality rate of 2.5% per year) and with better EULAR response to TNF inhibitor therapy (OR, 1.14 [95% CI, 1.01–1.30], P = .04) (noncarriers: 78% [439/561 patients] with moderate or good EULAR response; heterozygote carriers: 81% [698/866]; and homozygote carriers: 86% [277/322]). The risk hierarchy defined by HLA-DRB1 haplotypes was correlated between disease susceptibility, severity, and mortality, but inversely correlated with TNF inhibitor treatment response. Among patients with RA, the HLA-DRB1 locus, which is associated with disease susceptibility, was also associated with radiological severity, mortality, and treatment response. Replication of these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRB1 haplotype analysis for management of RA.