Cell Biology and Immunology Department, Institute of Parasitology and Biomedicine López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
Department of Rheumatology, Istanbul Bilim University, Istanbul, Turkey.
Rheumatology (Oxford). 2019 Feb 1;58(2):289-298. doi: 10.1093/rheumatology/key281.
SSc is an autoimmune disease characterized by alteration of the immune response, vasculopathy and fibrosis. Most genetic studies on SSc have been performed in European-ancestry populations. The aim of this study was to analyse the genetic component of SSc in Middle Eastern patients from Iran and Turkey through a genome-wide association study.
This study analysed data from a total of 834 patients diagnosed with SSc and 1455 healthy controls from Iran and Turkey. DNA was genotyped using high-throughput genotyping platforms. The data generated were imputed using the Michigan Imputation Server, and the Haplotype Reference Consortium as a reference panel. A meta-analysis combining both case-control sets was conducted by the inverse variance method.
The highest peak of association belonged to the HLA region in both the Iranian and Turkish populations. Strong and independent associations between the classical alleles HLA-DRB111: 04 [P = 2.10 × 10-24, odds ratio (OR) = 3.14] and DPB113: 01 (P = 5.37 × 10-14, OR = 5.75) and SSc were observed in the Iranian population. HLA-DRB1*11: 04 (P = 4.90 × 10-11, OR = 2.93) was the only independent signal associated in the Turkish cohort. An omnibus test yielded HLA-DRB1 58 and HLA-DPB1 76 as relevant amino acid positions for this disease. Concerning the meta-analysis, we also identified two associations close to the genome-wide significance level outside the HLA region, corresponding to IRF5-TNPO3 rs17424921-C (P = 1.34 × 10-7, OR = 1.68) and NFKB1 rs4648133-C (P = 3.11 × 10-7, OR = 1.47).
We identified significant associations in the HLA region and suggestive associations in IRF5-TNPO3 and NFKB1 loci in Iranian and Turkish patients affected by SSc through a genome-wide association study and an extensive HLA analysis.
SSc 是一种自身免疫性疾病，其特征为免疫反应改变、血管病变和纤维化。大多数 SSc 的遗传研究都是在欧洲血统人群中进行的。本研究的目的是通过全基因组关联研究分析来自伊朗和土耳其的中东患者 SSc 的遗传成分。
本研究分析了来自伊朗和土耳其的 834 例确诊为 SSc 的患者和 1455 名健康对照者的总数据。使用高通量基因分型平台对 DNA 进行基因分型。使用密歇根基因分型服务器和单倍型参考联盟作为参考面板对生成的数据进行了 imputation。通过逆方差法对两个病例对照集进行了合并的荟萃分析。
在伊朗和土耳其人群中，关联最强的峰值都位于 HLA 区域。在伊朗人群中，经典等位基因 HLA-DRB111:04[P=2.10×10-24，比值比（OR）=3.14]和 DPB113:01（P=5.37×10-14，OR=5.75）与 SSc 之间存在强烈且独立的关联。在土耳其队列中，唯一独立的信号是 HLA-DRB1*11:04（P=4.90×10-11，OR=2.93）。整体检验得出 HLA-DRB1 58 和 HLA-DPB1 76 是该疾病相关的氨基酸位置。关于荟萃分析，我们还在 HLA 区域之外发现了两个接近全基因组显著水平的关联，对应于 IRF5-TNPO3 rs17424921-C（P=1.34×10-7，OR=1.68）和 NFKB1 rs4648133-C（P=3.11×10-7，OR=1.47）。
通过全基因组关联研究和广泛的 HLA 分析，我们在伊朗和土耳其 SSc 患者中鉴定了 HLA 区域的显著关联以及在 IRF5-TNPO3 和 NFKB1 基因座的提示性关联。
