Pathogenesis and Treatment of CNS Lupus
Pathogenesis and Treatment of CNS Lupus
Large-scale association studies have identified several variants within the Human Leucocyte Antigen (HLA) and non-HLA loci that confer susceptibility to SLE. Although most studies are underpowered to detect distinct genotype–phenotype relationships, there is some evidence for increased genetic burden in NPSLE. In a study of 665 White SLE patients and 1403 controls, the HLA-DRB1*04 genotype and STAT4 rs10181656 were associated with ischemic CVD, independently of the effects of traditional risk factors and aPL antibody status. Rare mutations in TREX1, which encodes for the major 3'–5' DNA exonuclease, have been reported in sporadic SLE cases, including NPSLE cases. In a large multiancestral study, 8372 SLE cases and 7492 controls were screened for a total of 40 common and rare single-nucleotide polymorphisms (SNPs) in TREX1. Analysis of SNPs with minor allele frequency more than 10% revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures. Interestingly, Trex1-deficient mice develop lethal autoimmunity associated with increased type I interferon levels, which is relevant to SLE pathogenesis.
Novel approaches integrating genotyping with gene expression data to identify expression quantitative trait loci (eQTL) are increasingly employed in the study of human diseases. By using a whole-genome array-based assay, Zou et al. quantified 24 526 transcripts in 773 brain samples from the cerebellum and temporal cortex of autopsied patients with Alzheimer's disease and with other brain pathologies. All autopsied patients were genotyped and expression genome-wide association study using 213 528 cis-SNPs within ± 100 kb of the tested transcripts was performed. One of the identified eQTL was IRF5 cis-SNP rs4728142 that is associated with both cerebellar IRF5 expression and risk of SLE. Whether IRF5 variants are implicated in the pathogenesis of cognitive dysfunction or other neuropsychiatric manifestations in SLE patients remains to be determined.
Genetics of CNS Lupus
Large-scale association studies have identified several variants within the Human Leucocyte Antigen (HLA) and non-HLA loci that confer susceptibility to SLE. Although most studies are underpowered to detect distinct genotype–phenotype relationships, there is some evidence for increased genetic burden in NPSLE. In a study of 665 White SLE patients and 1403 controls, the HLA-DRB1*04 genotype and STAT4 rs10181656 were associated with ischemic CVD, independently of the effects of traditional risk factors and aPL antibody status. Rare mutations in TREX1, which encodes for the major 3'–5' DNA exonuclease, have been reported in sporadic SLE cases, including NPSLE cases. In a large multiancestral study, 8372 SLE cases and 7492 controls were screened for a total of 40 common and rare single-nucleotide polymorphisms (SNPs) in TREX1. Analysis of SNPs with minor allele frequency more than 10% revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures. Interestingly, Trex1-deficient mice develop lethal autoimmunity associated with increased type I interferon levels, which is relevant to SLE pathogenesis.
Novel approaches integrating genotyping with gene expression data to identify expression quantitative trait loci (eQTL) are increasingly employed in the study of human diseases. By using a whole-genome array-based assay, Zou et al. quantified 24 526 transcripts in 773 brain samples from the cerebellum and temporal cortex of autopsied patients with Alzheimer's disease and with other brain pathologies. All autopsied patients were genotyped and expression genome-wide association study using 213 528 cis-SNPs within ± 100 kb of the tested transcripts was performed. One of the identified eQTL was IRF5 cis-SNP rs4728142 that is associated with both cerebellar IRF5 expression and risk of SLE. Whether IRF5 variants are implicated in the pathogenesis of cognitive dysfunction or other neuropsychiatric manifestations in SLE patients remains to be determined.
Source...