van der Linden Michael P M, Feitsma Anouk L, le Cessie Saskia, Kern Marlena, Olsson Lina M, Raychaudhuri Soumya, Begovich Ann B, Chang Monica, Catanese Joseph J, Kurreeman Fina A S, van Nies Jessica, van der Heijde Désirée M, Gregersen Peter K, Huizinga Tom W J, Toes René E M, van der Helm-Van Mil Annette H M
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Arthritis Rheum. 2009 Aug;60(8):2242-7. doi: 10.1002/art.24721.
The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction.
RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n=563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti-citrullinated protein antibody (ACPA)-positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study.
The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P=0.003 and P=0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P=0.021).
A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non-HLA-related genetic severity factors that has been replicated.
类风湿关节炎（RA）患者关节破坏的严重程度在个体间差异很大，且受遗传因素影响。全基因组关联研究极大地推动了RA易感性遗传学领域的发展，但RA严重程度的风险位点仍未明确界定。最近一项全基因组关联研究的荟萃分析确定了自身抗体阳性RA易感性的6个遗传区域：CD40、KIF5A/PIP4K2C、CDK6、CCL21、PRKCQ和MMEL1/TNFRSF14。本研究的目的是调查这些新描述的遗传区域是否与关节破坏率相关。
对莱顿早期关节炎诊所招募的RA患者（n = 563）进行研究。每年使用Sharp/van der Heijde方法对X线片进行评分（中位随访5年；最大随访9年）。使用线性混合模型比较基因型组之间的关节破坏率，并对年龄、性别和治疗策略进行校正。来自北美类风湿关节炎联盟（NARAC）的393例有X线片数据的抗瓜氨酸化蛋白抗体（ACPA）阳性RA患者用于重复研究。
两个单核苷酸多态性rs4810485（CD40）和rs42041（CDK6）的TT和CC/CG基因型分别与ACPA阳性RA患者较高的关节破坏率相关（分别为P = 0.003和P = 0.012），经Bonferroni多重检验校正后，rs4810485具有显著性。CD40次要等位基因与X线进展率的关联在NARAC队列中得到重复（P = 0.021）。
CD40基因座的多态性与ACPA阳性RA患者关节破坏率相关。我们的研究结果提供了首批得到重复验证的非HLA相关遗传严重程度因素之一。
