Uncovering Genetic Variation in Systemic Lupus Erythematosus Risk Variants in Indigenous Peruvians

Objective: Systemic lupus erythematosus (SLE) results in worse clinical outcomes among individuals of Amerindian descent. The genetic basis for this is uncertain, and there is a significant lack of genetic research focused on Amerindian ancestry populations. This study aims to compare the frequencies of SLE risk variants and polygenic risk scores between Indigenous Peruvians and global populations with diverse ancestral backgrounds. Methods: We studied 670 individuals from the Peruvian Genome Project, 2,068 individuals from the 1000 Genomes Project Phase 3 release, and 47 patients with SLE from Lima, Peru. Ancestry was inferred using admixture and RFMix. Data were imputed with the TOPMed Imputation server and annotated to hg38. We compared the frequencies of 199 SLE-associated risk variants among study participants. We also calculated SLE genetic risk scores and fixation index (FST) statistics. Results: All 199 SLE risk single-nucleotide polymorphisms had highly significant differences in frequencies across Peruvian and other continental populations (P values <0.001). Indigenous Peruvian patients have higher polygenic risk for SLE compared to European, African, South Asian, and East Asian patients. FST analysis of SLE risk variants revealed the largest FST between Peruvian patients and African patients (mean FST 0.12), and the smallest between Peruvian patients and East Asian patients (mean FST 0.09). Conclusion: SLE-associated variants are common among Indigenous Peruvian patients, with varying frequencies across subpopulations. This underscores the need for ongoing genetic studies in Indigenous populations, potentially explaining SLE heterogeneity.