Do Genetic Susceptibility Variants Associate with Disease Severity in Early Active Rheumatoid Arthritis?
Do Genetic Susceptibility Variants Associate with Disease Severity in Early Active Rheumatoid Arthritis?
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DOI：
10.3899/jrheum.141211
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Lewis CM
中科院分区：
文献类型：
--
作者：
Scott IC;Rijsdijk F;Walker J;Quist J;Spain SL;Tan R;Steer S;Okada Y;Raychaudhuri S;Cope AP;Lewis CM
遗传变异影响类风湿性关节炎（RA）的发展和严重程度。最近的研究扩大了RA易感性变异的数量。我们在早期活动性RA患者的临床试验队列中测试了这些与疾病严重程度相关的假设。我们评估了524例RA患者，这些患者参加了早期RA联合抗风湿药物（CARDERA）试验。我们使用线性混合效应和潜在生长曲线模型，检测了经验证的易感性变体- 69个单核苷酸多态性（SNP）、15个HLA-DRB 1等位基因和6个HLA分子位置的氨基酸多态性-在2年内与Larsen评分、28关节疾病活动评分和健康评估问卷（HAQ）评分进展的相关性。HLA变异与关节破坏有关。*04：01 SNP（rs660895，p = 0.0003）、*04：01等位基因（p = 0.0002）和HLA-DRβ1氨基酸13位组氨酸（p = 0.0005）和11位缬氨酸（p = 0.0012）与放射学进展显著相关。这种关联仅在抗瓜氨酸蛋白抗体（ACPA）阳性患者中显着，这表明虽然它们的作用不是由ACPA介导的，但它们仅预测ACPA阳性RA的关节损伤。非HLA变异与放射学损害无关（单独评估和累积加权遗传风险评分）。两个SNP -rs 11889341（STAT 4，p = 0.0001）和rs653178（SH 2B 3-PTPN 11，p = 0.0004）-与6-24个月的HAQ评分相关。HLA易感性变异在确定早期活动性ACPA阳性RA的放射学进展中起重要作用。需要在大规模人群中进行全基因组和全HLA分析，以更好地描述RA放射性进展的遗传结构。
Genetic variants affect both the development and severity of rheumatoid arthritis (RA). Recent studies have expanded the number of RA susceptibility variants. We tested the hypothesis that these associated with disease severity in a clinical trial cohort of patients with early, active RA. We evaluated 524 patients with RA enrolled in the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trials. We tested validated susceptibility variants — 69 single-nucleotide polymorphisms (SNP), 15 HLA-DRB1 alleles, and amino acid polymorphisms in 6 HLA molecule positions — for their associations with progression in Larsen scoring, 28-joint Disease Activity Scores, and Health Assessment Questionnaire (HAQ) scores over 2 years using linear mixed-effects and latent growth curve models. HLA variants were associated with joint destruction. The *04:01 SNP (rs660895, p = 0.0003), *04:01 allele (p = 0.0002), and HLA-DRβ1 amino acids histidine at position 13 (p = 0.0005) and valine at position 11 (p = 0.0012) significantly associated with radiological progression. This association was only significant in anticitrullinated protein antibody (ACPA)-positive patients, suggesting that while their effects were not mediated by ACPA, they only predicted joint damage in ACPA-positive RA. Non-HLA variants did not associate with radiograph damage (assessed individually and cumulatively as a weighted genetic risk score). Two SNP — rs11889341 (STAT4, p = 0.0001) and rs653178 (SH2B3-PTPN11, p = 0.0004) — associated with HAQ scores over 6–24 months. HLA susceptibility variants play an important role in determining radiological progression in early, active ACPA-positive RA. Genome-wide and HLA-wide analyses across large populations are required to better characterize the genetic architecture of radiological progression in RA.
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影响因子：
27.4
作者：
Karlson EW;Chibnik LB;Kraft P;Cui J;Keenan BT;Ding B;Raychaudhuri S;Klareskog L;Alfredsson L;Plenge RM
通讯作者：
Plenge RM
影响因子：
3.7
作者：
Jia X;Zha T;Wu B;Zhang Y;Chen W;Wang X;Yu H;He G
通讯作者：
He G
DOI：
10.1111/j.1463-1326.2008.00997.x
发表时间：
2009-02
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Brown WM;Pierce J;Hilner JE;Perdue LH;Lohman K;Li L;Venkatesh RB;Hunt S;Mychaleckyj JC;Deloukas P;Type 1 Diabetes Genetics Consortium
通讯作者：
Type 1 Diabetes Genetics Consortium
影响因子：
9.8
作者：
Han, Buhm;Diogo, Dorothee;Raychaudhuri, Soumya
通讯作者：
Raychaudhuri, Soumya
影响因子：
--
作者：
Goekoop-Ruiterman, YPM;de Vries-Bouwstra, JK;Dijkmans, C
通讯作者：
Dijkmans, C