Krabben A, Wilson A G, de Rooy D P C, Zhernakova A, Brouwer E, Lindqvist E, Saxne T, Stoeken G, van Nies J A B, Knevel R, Huizinga T W J, Toes R, Gregersen P K, van der Helm-van Mil A H M
Leiden University Medical Center, Leiden, The Netherlands.
Arthritis Rheum. 2013 Dec;65(12):3051-7. doi: 10.1002/art.38141.
The progression of joint destruction in rheumatoid arthritis (RA) is determined by genetic factors. Changes in IL4 and IL4R genes have been associated with RA severity, but this finding has not been replicated. This study was undertaken to investigate the association between IL4- and IL4R-tagging single-nucleotide polymorphisms (SNPs) and the progression rate of joint damage in RA in a multicohort candidate gene study.
IL4- and IL4R-tagging SNPs (n = 8 and 39, respectively) were genotyped in 600 RA patients for whom 2,846 sets of radiographs of the hands and feet were obtained during 7 years of followup. Subsequently, SNPs significantly associated with the progression of joint damage were genotyped and studied in relation to 3,415 radiographs of 1,953 RA patients; these included data sets from Groningen (The Netherlands), Lund (Sweden), Sheffield (UK), the North American Rheumatoid Arthritis Consortium (US), Wichita (US), and the National Data Bank (US). The relative increase in progression rate per year in the presence of a genotype was determined in each cohort. An inverse variance weighting meta-analysis was performed on the 6 data sets that together formed the replication phase.
In the discovery phase, none of the IL4 SNPs and 7 of the IL4R SNPs were significantly associated with the joint damage progression rate. In the replication phase, 2 SNPs in the IL4R gene were significantly associated with the joint damage progression rate (rs1805011 [P = 0.02] and rs1119132 [P = 0.001]).
Genetic variants in IL4R were identified, and their association with the progression rate of joint damage in RA was independently replicated.
类风湿关节炎（RA）关节破坏的进展由遗传因素决定。白细胞介素4（IL4）和IL4受体（IL4R）基因的变化与RA严重程度相关，但这一发现尚未得到重复验证。本多队列候选基因研究旨在调查IL4和IL4R标签单核苷酸多态性（SNP）与RA关节损伤进展率之间的关联。
对600例RA患者的IL4和IL4R标签SNP（分别为8个和39个）进行基因分型，这些患者在7年随访期间共获得2846套手和足的X线片。随后，对与关节损伤进展显著相关的SNP进行基因分型，并针对1953例RA患者的3415张X线片进行研究；这些数据集来自格罗宁根（荷兰）、隆德（瑞典）、谢菲尔德（英国）、北美类风湿关节炎联盟（美国）、威奇托（美国）和国家数据库（美国）。在每个队列中确定存在某种基因型时每年进展率的相对增加。对共同构成复制阶段的6个数据集进行逆方差加权荟萃分析。
在发现阶段，IL4的SNP均与关节损伤进展率无显著关联，而IL4R的SNP中有7个与关节损伤进展率显著相关。在复制阶段，IL4R基因中的2个SNP与关节损伤进展率显著相关（rs1805011 [P = 0.02]和rs1119132 [P = 0.001]）。
已鉴定出IL4R中的遗传变异，并且它们与RA关节损伤进展率的关联得到了独立重复验证。
