Dataset Information

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.

SUBMITTER: Kannarkat GT

PROVIDER: S-EPMC4853162 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study.

Kannarkat G T GT Cook D A DA Lee J-K JK Chang J J Chung J J Sandy E E Paul K C KC Ritz B B Bronstein J J Factor S A SA Boss J M JM Tansey M G MG

NPJ Parkinson's disease 20150422

<h4>Background/objectives</h4>The common non-coding single nucleotide polymorphism (SNP) <i>rs3129882</i> in <i>HLA-DRA</i> 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.<h4>Methods</h4>For immunophenotyping, ...[more]

PMID: 27148593

Similar Datasets

Project description:Parkinson's disease (PD) was recently found to be associated with HLA in a genome-wide association study (GWAS). Follow-up GWAS's replicated the PD-HLA association but their top hits differ. Do the different hits tag the same locus or is there more than one PD-associated variant within HLA? We show that the top GWAS hits are not correlated with each other (0.00≤r(2)≤0.15). Using our GWAS (2000 cases, 1986 controls) we conducted step-wise conditional analysis on 107 SNPs with P<10(-3) for PD-association; 103 dropped-out, four remained significant. Each SNP, when conditioned on the other three, yielded P(SNP1) = 5×10(-4), P(SNP2) = 5×10(-4), P(SNP3) = 4×10(-3) and P(SNP4) = 0.025. The four SNPs were not correlated (0.01≤r(2)≤0.20). Haplotype analysis (excluding rare SNP2) revealed increasing PD risk with increasing risk alleles from OR = 1.27, P = 5×10(-3) for one risk allele to OR = 1.65, P = 4×10(-8) for three. Using additional 843 cases and 856 controls we replicated the independent effects of SNP1 (P(conditioned-on-SNP4) = 0.04) and SNP4 (P(conditioned-on-SNP1) = 0.04); SNP2 and SNP3 could not be replicated. In pooled GWAS and replication, SNP1 had OR(conditioned-on-SNP4) = 1.23, P(conditioned-on-SNP4) = 6×10(-7); SNP4 had OR(conditioned-on-SNP1) = 1.18, P(conditioned-on-SNP1) = 3×10(-3); and the haplotype with both risk alleles had OR = 1.48, P = 2×10(-12). Genotypic OR increased with the number of risk alleles an individual possessed up to OR = 1.94, P = 2×10(-11) for individuals who were homozygous for the risk allele at both SNP1 and SNP4. SNP1 is a variant in HLA-DRA and is associated with HLA-DRA, DRB5 and DQA2 gene expression. SNP4 is correlated (r(2) = 0.95) with variants that are associated with HLA-DQA2 expression, and with the top HLA SNP from the IPDGC GWAS (r(2) = 0.60). Our findings suggest more than one PD-HLA association; either different alleles of the same gene, or separate loci.

Dataset Information

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/objectives

Methods

Results

Conclusions

Publications

Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study.

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