Genetic and genomic studies of PADI4 in rheumatoid arthritis
Genetic and genomic studies of PADI4 in rheumatoid arthritis
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DOI：
10.1093/rheumatology/keh614
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发表时间：
2005-07-01
期刊：
影响因子：
5.5
通讯作者：
Brown, MA
中科院分区：
文献类型：
--
作者：
Harney, SMJ;Meisel, C;Brown, MA
目标.先前在日本描述了类风湿性关节炎（RA）与PADI 4（肽基精氨酸脱亚胺酶）的强遗传关联，尽管这在英国的后续研究中未得到证实。因此，我们进行了进一步的研究PADI 4和RA在英国白人之间的遗传关联，并研究了PADI 4在RA患者外周血中的表达。使用聚合酶链反应（PCR）-限制性片段长度多态性对111例RA病例和对照组的7种单核苷酸多态性（SNP）进行基因分型。然后在439例RA患者和428例对照的更大组中检验第一个数据集（P = 0.03）中与RA显著相关的标志物（PADI 4_100，rs#2240339）的相关性。采用实时荧光定量PCR检测13例RA患者和11例健康对照者外周血单个核细胞中PADI 4的转录水平。在最初的病例对照研究中，单个SNP与RA弱相关（P = 0.03），单个SNP（PADI 4_100）和该SNP与相邻SNP的双标记单倍型（PADI 4_104）与RA显著相关（分别为P = 0.02和P = 0.03）。在第二个样本集中，PADI 4_100与RA无关。PADI 4在病例组中的表达是对照组的4倍（P = 0.004），但表达水平与炎症标志物的水平无关。PADI 4在RA患者的血液中显著过表达，但PADI 4内的遗传变异不是白种人RA的主要风险因素。
Objectives. Strong genetic association of rheumatoid arthritis (RA) with PADI4 (peptidyl arginine deiminase) has previously been described in Japanese, although this was not confirmed in a subsequent study in the UK. We therefore undertook a further study of genetic association between PADI4 and RA in UK Caucasians and also studied expression of PADI4 in the peripheral blood of patients with RA.Methods. Seven single-nucleotide polymorphisms (SNP) were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism in 111 RA cases and controls. A marker significantly associated with RA (PADI4_100, rs#2240339) in this first data set (P = 0.03) was then tested for association in a larger group of 439 RA patients and 428 controls. PADI4 transcription was also assessed by real-time quantitative PCR using RNA extracted from peripheral blood mononuclear cells from 13 RA patients and 11 healthy controls.Results. A single SNP was weakly associated with RA (P = 0.03) in the initial case-control study, a single SNP (PADI4_100) and a two marker haplotype of that SNP and the neighbouring SNP (PADI4_104) were significantly associated with RA (P = 0.02 and P = 0.03 respectively). PADI4_100 was not associated with RA in a second sample set. PADI4 expression was four times greater in cases than controls (P = 0.004), but expression levels did not correlate with the levels of markers of inflammation.Conclusion. PADI4 is significantly overexpressed in the blood of RA patients but genetic variation within PADI4 is not a major risk factor for RA in Caucasians.