Lorentzen Johnny C, Flornes Line, Eklöw Carina, Bäckdahl Liselotte, Ribbhammar Ulrica, Guo Jian Ping, Smolnikova Marina, Dissen Erik, Seddighzadeh Maria, Brookes Anthony J, Alfredsson Lars, Klareskog Lars, Padyukov Leonid, Fossum Sigbjörn
Department of Medicine, Rheumatology Unit, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden.
Arthritis Rheum. 2007 Aug;56(8):2620-32. doi: 10.1002/art.22813.
To identify susceptibility genes in a rat model of rheumatoid arthritis (RA) and to determine whether the corresponding human genes are associated with RA.
Genes influencing oil-induced arthritis (OIA) were position mapped by comparing the susceptibility of inbred DA rats with that of DA rats carrying alleles derived from the arthritis-resistant PVG strain in chromosomal fragments overlapping the quantitative trait locus Oia2. Sequencing of gene complementary DNA (cDNA) and analysis of gene messenger RNA (mRNA) expression were performed to attempt to clone a causal gene. Associations with human RA were evaluated by genotyping single-nucleotide polymorphisms (SNPs) in the corresponding human genes and by analyzing frequencies of alleles and haplotypes in RA patients and age-, sex-, and area-matched healthy control subjects.
Congenic DA rats were resistant to OIA when they carried PVG alleles for the antigen-presenting lectin-like receptor gene complex (APLEC), which encodes immunoregulatory C-type lectin-like receptors. Multiple differences in cDNA sequence and mRNA expression precluded cloning of a single causal gene. Five corresponding human APLEC genes were identified and targeted. The SNP rs1133104 in the dendritic cell immunoreceptor gene (DCIR), and a haplotype including that marker and 4 other SNPs in DCIR and its vicinity showed an indication of allelic association with susceptibility to RA in patients who were negative for antibodies to cyclic citrullinated peptide (anti-CCP), with respective odds ratios of 1.27 (95% confidence interval [95% CI] 1.06-1.52; uncorrected P = 0.0073) and 1.37 (95% CI 1.12-1.67; uncorrected P = 0.0019). Results of permutation testing supported this association of the haplotype with RA.
Rat APLEC is associated with susceptibility to polyarthritis, and human APLEC and DCIR may be associated with susceptibility to anti-CCP-negative RA.
在类风湿关节炎（RA）大鼠模型中鉴定易感基因，并确定相应的人类基因是否与RA相关。
通过比较近交系DA大鼠与携带来自抗关节炎PVG品系等位基因的DA大鼠在与数量性状基因座Oia2重叠的染色体片段中的易感性，对影响油诱导性关节炎（OIA）的基因进行定位。进行基因互补DNA（cDNA）测序和基因信使核糖核酸（mRNA）表达分析，试图克隆一个致病基因。通过对相应人类基因中的单核苷酸多态性（SNP）进行基因分型，以及分析RA患者和年龄、性别、地区匹配的健康对照受试者的等位基因和单倍型频率，评估与人类RA的关联。
当同源DA大鼠携带编码免疫调节C型凝集素样受体的抗原呈递凝集素样受体基因复合体（APLEC）的PVG等位基因时，对OIA具有抗性。cDNA序列和mRNA表达的多个差异使得无法克隆单个致病基因。鉴定并靶向了五个相应的人类APLEC基因。树突状细胞免疫受体基因（DCIR）中的SNP rs1133104，以及包括该标记和DCIR及其附近的其他4个SNP的单倍型，在抗环瓜氨酸肽抗体（抗CCP）阴性的患者中显示出与RA易感性的等位基因关联迹象，各自的优势比分别为1.27（95%置信区间[95%CI]1.06 - 1.52；未校正P = 0.0073）和1.37（95%CI 1.12 - 1.67；未校正P = 0.0019）。置换检验结果支持该单倍型与RA的这种关联。
大鼠APLEC与多关节炎易感性相关，人类APLEC和DCIR可能与抗CCP阴性RA的易感性相关。
