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Journal article
Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson's disease
Frontiers in immunology, Vol.15, 1349030
2024
PMID: 38590523
Abstract
Parkinson's disease (PD) is a neurodegenerative and polygenic disorder characterised by the progressive loss of neural dopamine and onset of movement disorders. We previously described eight SINE-VNTR-Alu (SVA) retrotransposon-insertion-polymorphisms (RIPs) located and expressed within the Human Leucocyte Antigen (HLA) genomic region of chromosome 6 that modulate the differential co-expression of 71 different genes including the HLA classical class I and class II genes in a Parkinson's Progression Markers Initiative (PPMI) cohort.
In the present study, we (1) reanalysed the PPMI genomic and transcriptomic sequencing data obtained from whole blood of 1521 individuals (867 cases and 654 controls) to infer the genotypes of the transcripts expressed by eight classical HLA class I and class II genes as well as
and the
haplotypes, and (2) examined the statistical differences between three different PD subgroups (cases) and healthy controls (HC) for the HLA and SVA transcribed genotypes and inferred haplotypes.
Significant differences for 57 expressed HLA alleles (21 HLA class I and 36 HLA class II alleles) up to the three-field resolution and four of eight expressed SVA were detected at
by the Fisher's exact test within one or other of three different PD subgroups (750 individuals with PD, 57 prodromes, 60 individuals who had scans without evidence of dopamine deficits [SWEDD]), when compared against a group of 654 HCs within the PPMI cohort and when not corrected by the Bonferroni test for multiple comparisons. Fourteen of 20 significant alleles were unique to the PD-HC comparison, whereas 31 of the 57 alleles overlapped between two or more different subgroup comparisons. Only the expressed
and -
protective alleles (PD v HC), the
risk (HC v Prodrome) or protective allele (PD v Prodrome), the
and -
risk alleles (SWEDD v HC), and the
present genotype (PD v HC) at a 5% homozygous insertion frequency near
, were significant (
) after Bonferroni corrections. The homologous
insertion significantly decreased the transcription levels of
and
in the PPMI cohort and its presence as a homozygous genotype is a risk factor (
) for PD. The most frequent
insertion haplotype in the PPMI cohort was
(3.7%). Although
was the most frequent HLA 5-loci phased-haplotype (n, 76) in the PPMI cohort, the
insertion was present in only six of them (8%).
These data suggest that expressed SVA and HLA gene alleles in circulating white blood cells are coordinated differentially in the regulation of immune responses and the long-term onset and progression of PD, the mechanisms of which have yet to be elucidated.
Details
- Title
- Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson's disease
- Authors/Creators
- Jerzy K Kulski - Tokai UniversityShingo Suzuki - Tokai UniversityTakashi Shiina - Tokai UniversityAbigail L Pfaff - Perron Institute for Neurological and Translational ScienceSulev Kõks - Perron Institute for Neurological and Translational Science
- Publication Details
- Frontiers in immunology, Vol.15, 1349030
- Publisher
- Frontiers Media S.A.
- Identifiers
- 991005655370307891
- Copyright
- © 2024 Kulski et al.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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