Molecular pathways identified from single nucleotide polymorphisms demonstrate mechanistic differences in systemic lupus erythematosus patients of Asian and European ancestry.
Molecular pathways identified from single nucleotide polymorphisms demonstrate mechanistic differences in systemic lupus erythematosus patients of Asian and European ancestry.
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DOI：
10.1038/s41598-023-32569-6
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发表时间：
2023-04-01
影响因子：
4.6
通讯作者：
Lipsky, Peter E.
中科院分区：
文献类型：
--
作者：
Owen, Katherine A.;Bell, Kristy A.;Price, Andrew;Bachali, Prathyusha;Ainsworth, Hannah;Marion, Miranda C.;Howard, Timothy D.;Langefeld, Carl D.;Shen, Nan;Yazdany, Jinoos;Dall'era, Maria;Grammer, Amrie C.;Lipsky, Peter E.
系统性红斑狼疮 (SLE) 是一种多器官自身免疫性疾病，具有显着的遗传因素。与欧洲血统 (EA) 个体相比，亚洲血统 (AsA) 个体经历更严重的 SLE，包括肾脏受累和组织损伤增加。然而，AsA 人群严重程度升高的机制仍不清楚。在这里，我们利用了基于使用免疫芯片基因分型阵列检测到的 EA 和 AsA SLE 患者中所有非 HLA SNP 关联的可用基因表达数据和基因型数据。我们鉴定了 2778 个血统特异性和 327 个跨血统 SLE 风险多态性。使用基于预测的生物途径的连接图谱和基因特征来检查遗传关联，并用于询问基因表达数据集。 AsA 患者的 SLE 相关通路包括氧化应激升高、代谢改变和线粒体功能障碍，而 EA 患者的 SLE 相关通路包括与胞质核酸传感和信号传导增强相关的强干扰素反应（I 型和 II 型）。对源自 AsA 队列中全基因组关联数据的独立数据集进行了询问并确定了相似的分子途径。最后，AsA SLE 患者的基因表达数据证实了 SNP 关联预测的分子途径。识别由 SLE 遗传风险预测的与祖先相关的分子途径可能有助于理清影响 AsA 和 EA 患有 SLE 个体的临床严重程度的人群差异。
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including increased renal involvement and tissue damage. However, the mechanisms underlying elevated severity in the AsA population remain unclear. Here, we utilized available gene expression data and genotype data based on all non-HLA SNP associations in EA and AsA SLE patients detected using the Immunochip genotyping array. We identified 2778 ancestry-specific and 327 trans-ancestry SLE-risk polymorphisms. Genetic associations were examined using connectivity mapping and gene signatures based on predicted biological pathways and were used to interrogate gene expression datasets. SLE-associated pathways in AsA patients included elevated oxidative stress, altered metabolism and mitochondrial dysfunction, whereas SLE-associated pathways in EA patients included a robust interferon response (type I and II) related to enhanced cytosolic nucleic acid sensing and signaling. An independent dataset derived from summary genome-wide association data in an AsA cohort was interrogated and identified similar molecular pathways. Finally, gene expression data from AsA SLE patients corroborated the molecular pathways predicted by SNP associations. Identifying ancestry-related molecular pathways predicted by genetic SLE risk may help to disentangle the population differences in clinical severity that impact AsA and EA individuals with SLE.
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影响因子：
64.5
作者：
Caielli S;Cardenas J;de Jesus AA;Baisch J;Walters L;Blanck JP;Balasubramanian P;Stagnar C;Ohouo M;Hong S;Nassi L;Stewart K;Fuller J;Gu J;Banchereau JF;Wright T;Goldbach-Mansky R;Pascual V
通讯作者：
Pascual V
影响因子：
--
作者：
Lai, Zhi-Wei;Hanczko, Robert;Bonilla, Eduardo;Caza, Tiffany N.;Clair, Brandon;Bartos, Adam;Miklossy, Gabriella;Jimah, John;Doherty, Edward;Tily, Hajra;Francis, Lisa;Garcia, Ricardo;Dawood, Maha;Yu, Jianghong;Ramos, Irene;Coman, Ioana;Faraone, Stephen V.;Phillips, Paul E.;Perl, Andras
通讯作者：
Perl, Andras
影响因子：
8
作者：
Catalina, Michelle D.;Bachali, Prathyusha;Lipsky, Peter E.
通讯作者：
Lipsky, Peter E.
影响因子：
30.8
作者：
Bentham J;Morris DL;Graham DSC;Pinder CL;Tombleson P;Behrens TW;Martín J;Fairfax BP;Knight JC;Chen L;Replogle J;Syvänen AC;Rönnblom L;Graham RR;Wither JE;Rioux JD;Alarcón-Riquelme ME;Vyse TJ
通讯作者：
Vyse TJ
影响因子：
14.3
作者：
Kain, Jessica;Owen, Katherine A.;Marion, Miranda C.;Langefeld, Carl D.;Grammer, Amrie C.;Lipsky, Peter E.
通讯作者：
Lipsky, Peter E.