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

BACKGROUND: 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. AIMS: The aim of this study was to determine the effect of this SNP on the MHC-II locus and its synergy with pesticide exposure. METHODS: 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. 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 (odds ratio = 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.