Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis
Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis
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DOI：
10.1016/j.ajhg.2013.12.002
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发表时间：
2014-01-02
影响因子：
9.8
通讯作者：
Martin, Javier
中科院分区：
文献类型：
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作者：
Mayes, Maureen D.;Bossini-Castillo, Lara;Martin, Javier
在这项研究中，1，833例系统性硬化症（SSc）病例和3，466例对照者使用免疫芯片阵列进行基因分型。对人类白细胞抗原（HLA）区域的经典等位基因、氨基酸残基和SNP进行插补和检测。这些分析产生了一个由六个多态性氨基酸位置和七个SNP组成的模型，解释了该地区观察到的显著关联。此外，对几种选定的非HLA变体进行了包括4，017例SSc病例和5，935例对照的复制步骤，总共达到5，850例病例和9，401例对照的欧洲血统。根据这一策略，我们确定并验证了三个SSc风险基因座，包括3 p14的DNASE 1 L3，3q 25的SCHIP 1-IL 12 A基因座和6 q21的ATG 5，以及11 q23的TREH-DDX 6基因座的关联。先前报道的几个SSc风险基因座的关联得到了验证和进一步完善，观察到的PXK关联峰值与DNASE 1 L3相关。我们的研究增加了已知与SSc相关的遗传关联的数量，进一步深入了解了共享自身免疫风险因素的多效性效应，并强调了密集定位检测以前被忽视的易感基因座的能力。
In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.