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Lupus Study Points to Ancestry-Specific Genetic Risk Factors, Treatment Targets

NEW YORK – Findings from a new genomic study suggest that some of the genetic factors that contribute to systemic lupus erythematosus (SLE) can differ between individuals with European and African ancestry, perhaps influencing the pathways that may be most amenable to drug targeting.

"Individuals of African ancestry experience the disease more severely and with an increased co-morbidity burden compared to European ancestry populations," first and corresponding author Katherine Owen, a researcher affiliated with Wake Forest School of Medicine and AMPEL BioSolutions in Virginia, and her co-authors wrote in the American Journal of Human Genetics on Wednesday.

"We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between [African America] and [European American] population is partially conferred by genomic influences on biological pathways," the authors proposed.

Starting with more than 800 risk SNPs identified in a prior SLE genome-wide association study that included individuals from different ancestry groups, Owen and her colleagues incorporated gene-coding sequence, expression quantitative trait locus, and other regulatory and functional clues to narrow in on SNPs associated with African American and European American SLE cases, along with the genes expected to undergo sequence or regulatory changes in the presence of these SNPs.

Their analyses highlighted more than 1,700 SLE contributors, including some that appeared to drive disease regardless of ancestry and others that seemed to have distinct influence on disease risk in individuals with African or European ancestry. With those findings and follow-up bioinformatic analyses focused on gene function, expression, regulation, and connectivity, they not only explored pathways contributing to SLE within and across populations, but also the potential treatment targets that floated up from these pathways.

"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," the researchers said.

In particular, the team saw an over-representation of SLE contributors in genes and pathways related to innate immune function and myeloid immune cell activity in individuals with predominantly European ancestry. On the other hand, alterations related to B cell activity, endoplasmic reticulum stress, and metabolic dysfunction turned up more frequently in African American individuals with SLE.

On the treatment side, meanwhile, the investigators proposed potential drug candidates stemming from the ancestry-specific pathways linked to SLE in the study, as well as the pathways affecting T cell activity and other processes that appeared to impact SLE risk across populations.

In the European ancestry group, for example, they pointed to the possibility of treatments targeting leukocyte or lymphocyte immune cell activity, while genetic and regulatory features found in the SLE cases in African Americans hinted that it may be possible to target B cells or pathways contributing to proteasomal activity.

"[O]ur study demonstrates that multilevel analysis is capable of defining gene regulatory pathways which not only reflect differences in [European American] and [African American] populations but also represents candidate pathways that may be the target of ancestry-specific therapies," the authors wrote. "Indeed, the ancestral SNP-associated predicted genes and gene expression profiles outlined here illustrate fundamental differences in lupus molecular pathways between ancestries and indicate that unique sets of drugs may be particularly effective at treating lupus within each ancestral group."

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