一项大型队列研究中人类白细胞抗原、PTPN22、CTLA4基因与类风湿关节炎自身抗体状态、诊断年龄及骨侵蚀等表型之间的关联。
Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study.
作者信息
Karlson E W, Chibnik L B, Cui J, Plenge R M, Glass R J, Maher N E, Parker A, Roubenoff R, Izmailova E, Coblyn J S, Weinblatt M E, Shadick N A
机构信息
Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
出版信息
Ann Rheum Dis. 2008 Mar;67(3):358-63. doi: 10.1136/ard.2007.071662. Epub 2007 Jul 31.
BACKGROUND
HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA).
OBJECTIVE
We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis.
METHODS
A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions.
RESULTS
In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA.
CONCLUSIONS
In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.
背景
HLA - DRB1共享表位（HLA - SE）、蛋白酪氨酸磷酸酶非受体型22（PTPN22）和细胞毒性T淋巴细胞相关蛋白4（CTLA4）等位基因与环瓜氨酸肽（CCP）及类风湿关节炎（RA）相关。
目的
我们在一个大型队列中研究了HLA - SE、PTPN22、CTLA4基因型与RA表型之间的关联，以（a）重复先前与CCP状态的关联，以及（b）确定与影像学侵蚀和诊断年龄的关联。
方法
对来自布莱根妇女医院类风湿关节炎序列研究（BRASS）的689例RA患者进行HLA - SE、PTPN22（rs2476601）和CTLA4（rs3087243）基因分型。采用多变量模型评估基因型与CCP、类风湿因子（RF）侵蚀性表型及诊断年龄之间的关联，并对年龄、性别和病程进行校正。采用新的因果路径分析来检验遗传危险因素和CCP是否处于预测侵蚀的因果路径这一假设。
结果
在多变量分析中，任何HLA - SE的存在与CCP阳性（比值比（OR）3.05，95%可信区间2.18 - 4.25）和RF阳性（OR 2.53，95%可信区间1.83 - 3.5）表型密切相关；任何PTPN22 T等位基因的存在与CCP阳性（OR 1.81，95%可信区间1.24 - 2.66）和RF阳性表型（OR 1.84，95%可信区间1.27 - 2.66）相关。CTLA4与CCP或RF表型无关。虽然HLA - SE与侵蚀性RA表型相关（OR 1.52，95%可信区间1.01 - 2.17），但在以CCP为条件进行分析后，这种相关性不再显著。PTPN22和CTLA4与侵蚀性表型无关。与不存在HLA - SE相比，任何HLA - SE的存在与诊断年龄平均早3.6年相关（41.3岁对44.9岁，p = 0.002），PTPN22与诊断年龄早4.2年相关（39.5岁对43.6岁，p = 0.002）。CTLA4基因型与RA诊断年龄无关。
结论
在这个大型临床队列中，我们重复了HLA - SE和PTPN22与CCP阳性和RF阳性表型之间的关联，但未发现CTLA4与它们的关联。我们还发现了HLA - SE、PTPN22与较早诊断年龄之间存在关联的证据。由于在无条件分析中HLA - SE与侵蚀性表型相关，但在以CCP为条件进行分析后不显著，这表明CCP处于预测侵蚀性表型的因果路径中。
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