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
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
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DOI：
10.1136/ard.2007.071662
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发表时间：
2008-03-01
影响因子：
27.4
通讯作者：
Shadick, N. A.
中科院分区：
文献类型：
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作者：
Karlson, E. W.;Chibnik, L. B.;Shadick, N. A.
背景：HLA-DRB1 共享表位 (HLA-SE)、PTPN22 和 CTLA4 等位基因与环瓜氨酸肽 (CCP) 和类风湿性关节炎 (RA) 相关。 目的：我们在一个大型队列中检查了 HLA-SE、PTPN22、CTLA4 基因型和 RA 表型之间的关联，以 (a) 复制先前与 CCP 状态的关联，以及 (b) 确定与放射学检查的关联方法：对来自 Brigham RA 序贯研究 (BRASS) 的总共 689 名 RA 患者进行了 HLA-SE、PTPN22 (rs2476601) 和 CTLA4 (rs3087243) 基因分型。使用调整年龄、性别和病程的多变量模型评估基因型与 CCP、类风湿因子 (RF) 糜烂表型和诊断时年龄之间的关联。使用新颖的因果路径分析来检验遗传风险因素和 CCP 存在于预测糜烂的因果路径中的假设。结果：在多变量分析中，任何 HLA-SE 的存在与 CCP+（比值比 (OR) 3.05，95% CI 2.18-4.25）和 RF+（OR 2.53，95% CI 1.83-3.5）密切相关。表型；任何 PTPN22 T 等位基因的存在与 CCP+（OR 1.81，95% CI 1.24-2.66）和 RF+ 表型（OR 1.84，95% CI 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% CI 1.01-2.17），但在 CCP 调节后，这一点不再显着。 PTPN22 和 CTLA4 与糜烂表型无关。与不存在 HLA-SE 相比，任何 HLASE 的存在与诊断平均提前 3.6 年相关（41.3 岁与 44.9 岁，p=0.002），PTPN22 与诊断年龄提前 4.2 岁相关（39.5 岁与 43.6 岁，p=0.002）。 CTLA4 基因型与诊断 RA 时的年龄无关。结论：在这个大型临床队列中，我们复制了 HLA-SE 和 PTPN22 之间的关联，但没有复制 CTLA4 与 CCP+ 和 RF+ 表型的关联。我们还发现了 HLA-SE 和 PTPN22 与早期诊断年龄之间关联的证据。由于在无条件分析中 HLA-SE 与糜烂表型相关，但在 CCP 条件作用后不显着，这表明 CCP 处于预测糜烂表型的因果路径中。
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 HLASE 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.