Analysis of Trans-Ancestral SLE Risk Loci Identifies Unique Biologic Networks and Drug Targets in African and European Ancestries

• Published in: American journal of human genetics Vol. 107; no. 5; pp. 864 - 881
• Main Authors: Owen, Katherine A., Price, Andrew, Ainsworth, Hannah, Aidukaitis, Bryce N., Bachali, Prathyusha, Catalina, Michelle D., Dittman, James M., Howard, Timothy D., Kingsmore, Kathryn M., Labonte, Adam C., Marion, Miranda C., Robl, Robert D., Zimmerman, Kip D., Langefeld, Carl D., Grammer, Amrie C., Lipsky, Peter E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.11.2020; Elsevier
• Subjects: ancesty; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Black People; Bortezomib - therapeutic use; DNA, Intergenic - genetics; DNA, Intergenic - immunology; drug repurposing; Enhancer Elements, Genetic; Gene Expression; Gene Ontology; Gene Regulatory Networks; Genetic Predisposition to Disease; genetics; Genome, Human; Genome-Wide Association Study; GWAS; Heterocyclic Compounds - therapeutic use; Humans; Immunochip; Interferons - genetics; Interferons - immunology; Isoquinolines - therapeutic use; Lactams; lupus; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - ethnology; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Molecular Sequence Annotation; pathway analysis; Polymorphism, Single Nucleotide; Protein Array Analysis; Quantitative Trait Loci; Quantitative Trait, Heritable; SLE; White People; drug repurposing; genetics; GWAS; Immunochip; pathway analysis; SLE; ancesty; lupus
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2020.09.007

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of African ancestry (AA) experience the disease more severely and with an increased co-morbidity burden compared to European ancestry (EA) populations. We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between AA and EA populations is partially conferred by genomic influences on biological pathways. To address this, we applied a comprehensive approach to identify all genes predicted from SNP-associated risk loci detected with the Immunochip. By combining genes predicted via eQTL analysis, as well as those predicted from base-pair changes in intergenic enhancer sites, coding-region variants, and SNP-gene proximity, we were able to identify 1,731 potential ancestry-specific and trans-ancestry genetic drivers of SLE. Gene associations were linked to upstream and downstream regulators using connectivity mapping, and predicted biological pathways were mined for candidate drug targets. Examination of trans-ancestral pathways reflect the well-defined role for interferons in SLE and revealed pathways associated with tissue repair and remodeling. EA-dominant genetic drivers were more often associated with innate immune and myeloid cell function pathways, whereas AA-dominant pathways mirror clinical findings in AA subjects, suggesting disease progression is driven by aberrant B cell activity accompanied by ER stress and metabolic dysfunction. Finally, potential ancestry-specific and non-specific drug candidates were identified. The integration of all SLE SNP-predicted genes into functional pathways revealed critical molecular pathways representative of each population, underscoring the influence of ancestry on disease mechanism and also providing key insight for therapeutic selection.