Gandjbakhch Frédérique, Fajardy Isabelle, Ferré Benjamin, Dubucquoi Sylvain, Flipo René-Marc, Roger Nadine, Solau-Gervais Elisabeth
Department of Rheumatology, Lille University Hospital, Lille, France.
J Rheumatol. 2009 May;36(5):881-6. doi: 10.3899/jrheum.080398. Epub 2009 Mar 30.
A functional haplotype of peptidyl arginine deiminase 4 (PADI4) was associated with susceptibility to rheumatoid arthritis (RA) in Asian populations, but the results are contradictory in Europeans. We investigated (1) the association of 2 single-nucleotide polymorphisms (SNP) located in exon 2 of PADI4 with RA in another Caucasian population; and (2) the association between PADI4 and anti-citrullinated protein (anti-CCP) antibodies.
DNA samples were obtained from 405 French RA patients and 275 controls. All RA patients met the revised criteria of the American College of Rheumatology. PADI4_89 163(G-->A) and PADI4_90 245(T-->C) SNP were genotyped using a PCR-RFLP method confirmed by direct sequencing. All patients and controls were genotyped for HLA-DRB1. The presence of anti-CCP antibodies was tested in 243 RA patients using an ELISA technique.
We focused on PADI4_89 163(G-->A) and PADI4_90 245(T-->C) SNP that distinguished 2 main haplotypes: AC haplotype (PADI4_89A PADI4_90C) and GT haplotype (PADI4_89G PADI4_90T), described, respectively, as "nonsusceptible" and "susceptible." A positive association between RA and presence of the GT haplotype was found in the heterozygous state (p = 0.002) and the homozygous state (RA patients 22%, controls 13%; p = 0.005). A correlation was observed between the presence but not the level of anti-CCP antibodies and the GT heterozygous (p = 0.03) and homozygous (p = 0.05) haplotypes. No correlation was found between the HLA-DRB1 shared epitope and any of the PADI4 haplotypes.
Our findings confirm those of Japanese, Korean, and Canadian studies and suggest that PADI4 may be a new susceptibility gene independent of HLA-DRB1 for RA in Caucasian populations.
肽基精氨酸脱亚氨酶4（PADI4）的一种功能性单倍型与亚洲人群类风湿关节炎（RA）易感性相关，但在欧洲人群中结果相互矛盾。我们研究了（1）位于PADI4第2外显子的2个单核苷酸多态性（SNP）与另一白种人群RA的关联；以及（2）PADI4与抗瓜氨酸化蛋白（抗CCP）抗体之间的关联。
从405例法国RA患者和275例对照中获取DNA样本。所有RA患者均符合美国风湿病学会修订标准。采用经直接测序确认的PCR-RFLP方法对PADI4_89 163（G→A）和PADI4_90 245（T→C）SNP进行基因分型。对所有患者和对照进行HLA-DRB1基因分型。采用ELISA技术检测243例RA患者抗CCP抗体的存在情况。
我们关注区分2种主要单倍型的PADI4_89 163（G→A）和PADI4_90 245（T→C）SNP：AC单倍型（PADI4_89A PADI4_90C）和GT单倍型（PADI4_89G PADI4_90T），分别被描述为“非易感”和“易感”。在杂合状态（p = 0.002）和纯合状态（RA患者22%，对照13%；p = 0.005）下发现RA与GT单倍型的存在呈正相关。观察到抗CCP抗体的存在而非水平与GT杂合（p = 0.03）和纯合（p = 0.05）单倍型之间存在相关性。未发现HLA-DRB1共享表位与任何PADI4单倍型之间存在相关性。
我们的研究结果证实了日本、韩国和加拿大的研究结果，并表明PADI4可能是白种人群中独立于HLA-DRB1的RA新易感基因。
