Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson’s disease: an observational and case–control study

Abstract

Background/Objectives The common non-coding single nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson’s disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD. Methods For immunophenotyping, blood cells from 81 subjects were analyzed by qRT-PCR and flow cytometry. A case-control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD. Results Homozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (OR = 2.48, p = 0.007), thereby identifying a novel gene-environment interaction that promotes risk for PD via alterations in immune responses. Conclusions In sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression.

LRRK2 levels in immune cells are increased in Parkinson’s disease

“…45 . Briefly, PBMCs were isolated from whole blood using density centrifugation with Ficoll-Paque (GE Healthcare, Uppsala, Sweden).…”

Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits

“…Recognition of an important role of neuroinflammation in human PD and in the α-syn PFF model has been growing. 66,[87][88][89][90][91][92][93][94][95] In addition, previous results demonstrated that dieldrin exposure exacerbates MPTP-induced increases in expression of glial fibrillary acidic protein (GFAP) levels in the striatum, suggesting that dieldrin exposure leads to a greater neuroinflammatory response to a second insult. While we were unable to test expression of neuroinflammatory genes after the application of PFFs, we did identify dieldrin-induced changes in the expression of neuroinflammatory genes.…”

Genetic risk factors in Parkinson’s disease

“…Additionally, there are several hits at the HLA (human leukocyte antigen) locus (Chang et al 2017; Nalls et al 2014) which encodes the major histocompatibility complex class II (MHC-II). Although the association between PD and the HLA region is complex, it has been suggested that the hits at HLA-DRB6 and HLA-DQA1 could implicate regulation of antigen presentation as a potential mechanism by which the immune response links environmental factors to genetic susceptibility in conferring risk for PD (Kannarkat et al 2015). Indeed, Sulzer et al have recently reported that α -synuclein-derived fragments act as antigenic epitopes displayed by HLA receptors, where both helper and cytotoxic T-cell responses are present in a high percentage of patients when tested (Sulzer et al 2017).…”