Association between mitochondria-related genes and systemic lupus erythematosus: Findings from Mendelian randomization study

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that damages various organs of the body. Mitochondrial dysfunction is closely related to the pathogenesis of SLE, but the genetic pathophysiological mechanism underlying this association has not been fully elucidated. The current study aims to elucidate the relationships between mitochondria-related genes and SLE via Mendelian randomization analysis. The genetic association data for SLE were obtained from the IEU OPEN GWAS, comprising 7071,163 SNPs from 5201 cases and 9066 controls of European ancestry. Known mitochondrial-related genes in humans were obtained from the MitoCarta 3.0 database. Summary-level data on the methylation, expression, and protein abundance of mitochondria-related genes were obtained from studies of the corresponding methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL), respectively. Two-sample Mendelian randomization (TSMR) and summary-data-based Mendelian randomization (SMR) analyses were then performed on the screened data to determine the relationships between the molecular characteristics of mitochondria-related genes and SLE. Integration of the positive exposures obtained with TSMR and SMR revealed common results for 12 expression loci, 23 methylation loci, and 3 plasma protein loci. Among them, the mQTL, eQTL, and pQTL of SPATA20 (cg22450693) were all positively correlated (p_HEIDI > .05, p_SMR < .05, p_TSMR < .05). In addition, the SMR results between eQTLs and SLE in exposed skin tissues verified that SPATA20 is a protective factor against SLE. However, CASP9 (cg21858823, cg14078231) and MSRA (cg12810313, cg16773768) were the only mQTL- and eQTL-positive exposures, and no SNP data for CASP9 and MSRA were found in the pQTL database. Therefore, the causal relationship between pQTLs and SLE remains unclear. The findings of this study suggest that the mitochondrial-related SPATA20 gene may be regulated by epigenetic changes to reduce the risk of SLE, thus providing a basis for the prevention and intervention of SLE.