Molecular pathways identified from single nucleotide polymorphisms demonstrate mechanistic differences in systemic lupus erythematosus patients of Asian and European ancestry

作者：Katherine A. Owen, Kristy Bell, Andrew Price, Prathyusha Bachali, Hannah C. Ainsworth, Miranda C. Marion, Timothy D. Howard, Carl D. Langefeld, Nan Shen, Jinoos Yazdany, Maria Dall’Era, Amrie C. Grammer, Peter E. Lipsky · 发表于：Scientific Reports · 年份：2023 · DOI：10.1038/s41598-023-32569-6 · 被引用次数：12 · 研究领域：Systemic Lupus Erythematosus Research、Atherosclerosis and Cardiovascular Diseases、Galectins and Cancer Biology

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 pop...