Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes.
Contribution of HLA and KIR Alleles to Systemic Sclerosis Susceptibility and Immunological and Clinical Disease Subtypes.
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DOI：
10.3389/fgene.2022.913196
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发表时间：
2022
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
系统性硬化症（SSc）是一种病因不明的自身炎症性纤维化疾病。可检测到的针对多种核抗原的自身抗体的存在，以及HLA与疾病的强烈关联，提示自身免疫参与，然而内源性和外源性危险因素与SSc病理之间的联系仍不确定。我们对1465例SSc病例和13273例对照进行了两个独立和荟萃分析队列的HLA遗传分析，包括临床和自身抗体阳性疾病亚组的分层关联分析。此外，我们利用患者基因型计算了KIR位点的基因剂量，编码了I类HLA配体的成对激活和抑制淋巴细胞受体，对SSc中KIR-HLA上位相互作用进行了迄今为止最大规模的分析。我们证实了先前的II类HLA与SSc风险的关联，并报道了新的I类HLA与单倍型HLA- b *44:03-HLA-C*16:01的全基因组显著性（GWS）关联。通过直接病例比较，我们进一步报告了HLA与临床和血清学亚型疾病的统计学显著相关性，并报告了HLA- drb1 *15:01与抗拓扑异构酶（ATA）阳性疾病的新关联，该基因先前被证明与拓扑异构酶-1衍生肽结合。最后，我们确定了KIRs和HLA I类配体之间的遗传上位性，表明淋巴细胞活化的遗传调节可能进一步增加个体潜在疾病风险。综上所述，这些发现支持了未来对SSc免疫耐受中断的内源性免疫和环境刺激的功能研究。
Systemic sclerosis (SSc) is an autoinflammatory, fibrotic condition of unknown aetiology. The presence of detectable autoantibodies against diverse nuclear antigens, as well as strong HLA associations with disease, suggest autoimmune involvement, however the links between endogenous and exogenous risk factors and SSc pathology remain undetermined. We have conducted a genetic analysis of HLA inheritance in two independent and meta-analysed cohorts of 1,465 SSc cases and 13,273 controls, including stratified association analyses in clinical and autoantibody positive subgroups of disease. Additionally, we have used patient genotypes to impute gene dosages across the KIR locus, encoding paired activating and inhibitory lymphocyte receptors for Class I HLA ligands, to conduct the largest analysis of KIR-HLA epistatic interactions in SSc to date. We confirm previous Class II HLA associations with SSc risk and report a new Class I association with haplotype HLA-B*44:03-HLA-C*16:01 at genome-wide significance (GWS). We further report statistically significant HLA associations with clinical and serological subtypes of disease through direct case-case comparison, and report a new association of HLA-DRB1*15:01, previously shown to bind topoisomerase-1 derived peptides, with anti-topoisomerase (ATA) positive disease. Finally, we identify genetic epistasis between KIRs and HLA class I ligands, suggesting genetic modulation of lymphocyte activation may further contribute to an individual’s underlying disease risk. Taken together, these findings support future functional investigation into endogenous immunological and environmental stimuli for disrupted immune tolerance in SSc.
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DOI：
10.1016/j.jid.2016.11.037
发表时间：
2017-05
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Li G;Larregina AT;Domsic RT;Stolz DB;Medsger TA Jr;Lafyatis R;Fuschiotti P
通讯作者：
Fuschiotti P
影响因子：
3.4
作者：
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通讯作者：
Assassi S
影响因子：
3.7
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通讯作者：
Carcassi C
DOI：
10.1073/pnas.1906593116
发表时间：
2020-01-07
影响因子：
11.1
作者：
Gourh, Pravitt;Safran, Sarah A.;Remmers, Elaine F.
通讯作者：
Remmers, Elaine F.
影响因子：
6.5
作者：
Horikawa, M;Hasegawa, M;Sato, S
通讯作者：
Sato, S