C5-TRAF1与类风湿关节炎关节损伤进展的遗传学研究。
A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis.
作者信息
van Steenbergen Hanna W, Rodríguez-Rodríguez Luis, Berglin Ewa, Zhernakova Alexandra, Knevel Rachel, Ivorra-Cortés Jose, Huizinga Tom W J, Fernández-Gutiérrez Benjamin, Gregersen Peter K, Rantapää-Dahlqvist Solbritt, van der Helm-van Mil Annette H M
出版信息
Arthritis Res Ther. 2015 Jan 8;17(1):1. doi: 10.1186/s13075-014-0514-0.
INTRODUCTION
The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.
METHODS
In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.
RESULTS
No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10(-7)); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10(-8). Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.
CONCLUSION
Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.
引言
类风湿关节炎（RA）中关节损伤进展的严重程度具有遗传性。已鉴定出多个基因变异，但这些变异共同仅解释了总遗传效应的一部分。白细胞介素-6（IL-6）、白细胞介素-10（IL-10）、C5-TRAF1和Fc受体样3（FCRL3）中的变异已被描述与影像学进展相关，但不同研究的结果并不一致。我们旨在通过评估六个独立队列来阐明这些变异与影像学进展的关联。
方法
对来自荷兰、瑞典、西班牙和北美的六个不同独立数据集中纳入的2493例RA患者的总共5895套X线片进行研究，分析其与rs1800795（IL-6）、rs1800896（IL-10）、rs2900180（C5-TRAF1）和rs7528684（FCRL3）的关系。在每个队列的总RA人群以及抗瓜氨酸化肽抗体（ACPA）阳性和ACPA阴性亚组中测试关联，随后进行荟萃分析。此外，在ACPA阴性的荷兰RA患者中对相关区域C5-TRAF1进行精细定位。
结果
在总RA人群以及按ACPA分层后，未发现rs1800795（IL-6）、rs1800896（IL-10）和rs7528684（FCRL3）存在关联。C5-TRAF1中的rs2900180与ACPA阴性人群的影像学进展相关（荟萃分析P值 = 5.85×10⁻⁷）；次要等位基因与更多的影像学进展相关。精细定位揭示了一个66Kb的相关区域；TRAF1中rs7021880的P值最低。rs7021880在荟萃分析中的P值为6.35×10⁻⁸。先前的研究表明，rs7021880所在区域与TRAF1和C5的RNA表达相关。
结论
IL-6、IL-10和FCRL3中的变异与影像学进展无关。C5-TRAF1中的rs2900180以及66Kb区域中的连锁变异与ACPA阴性RA的影像学进展相关。
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