The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18016, Spain.
Am J Hum Genet. 2014 Jan 2;94(1):47-61. doi: 10.1016/j.ajhg.2013.12.002.
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.
在这项研究中，1833 例系统性硬化症 (SSc) 病例和 3466 例对照者使用免疫芯片阵列进行了基因分型。对人类白细胞抗原 (HLA) 区域的经典等位基因、氨基酸残基和单核苷酸多态性进行了推断和测试。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，该模型解释了该区域观察到的显著关联。此外，对几个选定的非 HLA 变体进行了包含 4017 例 SSc 病例和 5935 例对照者的复制步骤，总计包含 5850 例 SSc 病例和 9401 例欧洲血统对照者。通过这种策略，我们鉴定并验证了三个 SSc 风险基因座，包括 3p14 上的 DNASE1L3、3q25 上的 SCHIP1-IL12A 基因座和 6q21 上的 ATG5，以及 11q23 上 TREH-DDX6 基因座的建议关联。几个先前报道的 SSc 风险基因座的关联得到了验证和进一步细化，在 PXK 中观察到的关联峰与 DNASE1L3 有关。我们的研究增加了已知与 SSc 相关的遗传关联数量，进一步深入了解了共享自身免疫风险因素的多效性效应，并突出了密集映射检测先前被忽视的易感基因座的能力。
