The common noncoding 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.
The aim of this study was to determine the effect of this SNP on the MHC-II locus and its synergy with pesticide exposure.
For immunophenotyping, blood cells from 81 subjects were analyzed by quantitative reverse transcription-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.
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 (odds ratio=2.48, P=0.007), thereby identifying a novel gene–environment interaction that promotes risk for PD via alterations in immune responses.
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.