Systemic lupus erythematosus (SLE) (OMIM:152700) is a complex autoimmune disease characterized by clinical and genetic heterogeneity. 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. Finally, gene expression data from AsA SLE patients corroborated the molecular pathways predicted by SNP associations. An independent dataset derived from summary genome-wide association data in an AsA cohort was interrogated and identified similar molecular pathways. 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. Genetic associations were examined using connectivity mapping and gene signatures based on predicted biological pathways and were used to interrogate gene expression datasets. We identified 2778 ancestry-specific and 327 trans-ancestry SLE-risk polymorphisms. 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. However, the mechanisms underlying elevated severity in the AsA population remain unclear. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including increased renal involvement and tissue damage. Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component.
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