Background and purpose

Head injury has been linked to Parkinson's disease (PD) in some but not all studies. Differences in the genetic and environmental susceptibility to PD between populations might be one explanation. The joint effects of head injuries and SNCA genetic variants were investigated.

Methods

From 2001 to 2012, 561 incident idiopathic PD cases and 721 population controls from central California were enrolled. Subjects reported on head injuries throughout their lifetime and were assessed for genetic variability in the SNCA 5' region (D4S3481; Rep1) and 3' untranslated region (rs356165). In unconditional logistic regression models adjusted for confounders, interactions between head injuries and genetic risk variants were investigated.

Results

Parkinson's disease risk in individuals with head injury who are carriers of at least one 263 bp allele in D4S3481 or rs356165 variants was 3-4.5-fold higher compared with non-carriers without head injuries. However, tests for interaction between head injury and SNCA D4S3481or rs356165 were not statistically significant.

Conclusions

Our study finds some evidence that head injury and D4S3481 or rs356165 variants jointly increase the risk of PD but little evidence of interaction.

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.