{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T19:52:46Z","timestamp":1793303566877,"version":"4.5.0"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T00:00:00Z","timestamp":1711324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Parkinson\u2019s 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\u2019s Progression Markers Initiative (PPMI) cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims and methods<\/jats:title><jats:p>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 <jats:italic>DRA<\/jats:italic> and the <jats:italic>DRB3\/4\/5<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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 <jats:italic>p&amp;lt;0.05<\/jats:italic> by the Fisher\u2019s 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 <jats:italic>HLA-DRA*01:01:01<\/jats:italic> and -<jats:italic>DQA1*03:01:01<\/jats:italic> protective alleles (PD v HC), the <jats:italic>-DQA1*03:03:01<\/jats:italic> risk (HC v Prodrome) or protective allele (PD v Prodrome), the <jats:italic>-DRA*01:01:02<\/jats:italic> and -<jats:italic>DRB4*01:03:02<\/jats:italic> risk alleles (SWEDD v HC), and the <jats:italic>NR_SVA_381<\/jats:italic> present genotype (PD v HC) at a 5% homozygous insertion frequency near <jats:italic>HLA-DPA1<\/jats:italic>, were significant (<jats:italic>Pc&amp;lt;0.1<\/jats:italic>) after Bonferroni corrections. The homologous <jats:italic>NR_SVA_381<\/jats:italic> insertion significantly decreased the transcription levels of <jats:italic>HLA-DPA1<\/jats:italic> and <jats:italic>HLA-DPB1<\/jats:italic> in the PPMI cohort and its presence as a homozygous genotype is a risk factor (<jats:italic>Pc=0.012<\/jats:italic>) for PD. The most frequent <jats:italic>NR_SVA_381<\/jats:italic> insertion haplotype in the PPMI cohort was <jats:italic>NR_SVA_381\/DPA1*02\/DPB1*01<\/jats:italic> (3.7%). Although <jats:italic>HLA C*07\/B*07\/DRB5*01\/DRB1*15\/DQB1*06<\/jats:italic> was the most frequent HLA 5-loci phased-haplotype (n, 76) in the PPMI cohort, the <jats:italic>NR_SVA_381<\/jats:italic> insertion was present in only six of them (8%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1349030","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T04:23:37Z","timestamp":1711340617000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson\u2019s disease"],"prefix":"10.3389","volume":"15","author":[{"given":"Jerzy K.","family":"Kulski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shiina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail L.","family":"Pfaff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulev","family":"K\u00f5ks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2021.776847","article-title":"Global trends in the incidence, prevalence, and years lived with disability of parkinson\u2019s disease in 204 countries\/territories from 1990 to 2019","volume":"9","author":"Ou","year":"2021","journal-title":"Front Public Health"},{"key":"B2","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1146\/annurev-pathol-011110-130242","article-title":"Parkinson\u2019s disease: genetics and pathogenesis","volume":"6","author":"Shulman","year":"2011","journal-title":"Annu Rev Pathol Mech Dis"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S93","DOI":"10.3233\/JPD-223228","article-title":"Age-related adaptive immune changes in parkinson\u2019s disease","volume":"12","author":"Kouli","year":"2022","journal-title":"J Parkinson\u2019s Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00809","article-title":"Tau pathology in parkinson\u2019s disease","volume":"9","author":"Zhang","year":"2018","journal-title":"Front Neurol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-020-01776-5","article-title":"Tau in the pathophysiology of parkinson\u2019s disease","volume":"71","author":"Pan","year":"2021","journal-title":"J Mol Neurosci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/gut.45.3.395","article-title":"Parkinson's disease and its management. 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