Association of HLA–DRB1, DQA1 and DQB1 alleles and haplotype in Parkinson’s disease from South India

Pandi, Sasiharan; Chinniah, Rathika; Sevak, Vandit; Ravi, Padma Malini; Raju, Muthuppandi; Vellaiappan, Neethi Arasu; Balakrishnan, K.

doi:10.1016/j.neulet.2021.136296

Cited by 6 publications

(7 citation statements)

References 69 publications

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“…The statistical results for the HLA-DRB1*04 alleles in previous studies of PD suggested both susceptibility ( 36 ) and protective associations ( 34 , 35 , 37 – 39 ). Our results revealed that the HLA-DRB1*04 alleles were significant statistically at the ‘possible’ level (uncorrected Fisher’s exact test, p<0.05 ) with HLA-DRB1*04:02 and - DRB1*04:04 protective in PD and PPMI ( Table 3 ), whereas HLA- DRB1*04:01 was a possible risk allele in the Prodrome and SWEDD groups, and the PPMI cohort ( Table 5 ).…”

Section: Discussionmentioning

confidence: 76%

“…Of the 32 HLA genes, the classical HLA class I genes, HLA-A , -B and -C , and the classical HLA class II genes, HLA-DR, -DQ and -DP , are characterised by an extraordinary large number of polymorphisms, whereas the non-classical HLA class I genes, such as HLA-E, -F and -G , are differentiated by their tissue-specific expression and limited polymorphism ( 32 , 33 ). Several GWASs have shown an association between the HLA locus and the risk of PD especially involving the HLA class II gene SNPs of HLA-DQA1, -DQA2, -DQB1, -DRB1 , and -DRB5 ( 27 , 34 – 36 ).…”

Section: Introductionmentioning

confidence: 99%

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Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson’s disease

Kulski,

Suzuki,

Shiina

et al. 2024

Front. Immunol.

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IntroductionParkinson’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.Aims and methodsIn 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 DRA and the DRB3/4/5 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.ResultsSignificant 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 p<0.05 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 HLA-DRA*01:01:01 and -DQA1*03:01:01 protective alleles (PD v HC), the -DQA1*03:03:01 risk (HC v Prodrome) or protective allele (PD v Prodrome), the -DRA*01:01:02 and -DRB4*01:03:02 risk alleles (SWEDD v HC), and the NR_SVA_381 present genotype (PD v HC) at a 5% homozygous insertion frequency near HLA-DPA1, were significant (Pc<0.1) after Bonferroni corrections. The homologous NR_SVA_381 insertion significantly decreased the transcription levels of HLA-DPA1 and HLA-DPB1 in the PPMI cohort and its presence as a homozygous genotype is a risk factor (Pc=0.012) for PD. The most frequent NR_SVA_381 insertion haplotype in the PPMI cohort was NR_SVA_381/DPA1*02/DPB1*01 (3.7%). Although HLA C*07/B*07/DRB5*01/DRB1*15/DQB1*06 was the most frequent HLA 5-loci phased-haplotype (n, 76) in the PPMI cohort, the NR_SVA_381 insertion was present in only six of them (8%).ConclusionsThese 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.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson’s disease

Kulski,

Suzuki,

Shiina

et al. 2024

Front. Immunol.

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“…The contribution of MHC II to PD pathology is inferred by studies demonstrating that MHC null mice are resistant to dopaminergic degeneration under conditions of ␣-syn overexpression [23]. Confirming these observations, genetic association with PD in the HLA region has been found, including HLA-DRA, HLA-DQA2, HLA-DQB1, HLA-DRB1, and HLA-DRB5 [24][25][26][27]. Importantly, a set of peptides derived from ␣-syn have been found to act as antigenic epitopes to further drive CD4+ and CD8+ cell responses in PD patients [28], thus linking preclinical studies and GWAS studies across the HLA regions.…”

Section: Introductionmentioning

confidence: 83%

Inflammatory Animal Models of Parkinson’s Disease

García-Revilla

Herrera

Pablos

et al. 2022

JPD

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Accumulating evidence suggests that microglia and peripheral immune cells may play determinant roles in the pathogenesis of Parkinson’s disease (PD). Consequently, there is a need to take advantage of immune-related models of PD to study the potential contribution of microglia and peripheral immune cells to the degeneration of the nigrostriatal system and help develop potential therapies for PD. In this review, we have summarised the main PD immune models. From a historical perspective, we highlight first the main features of intranigral injections of different pro-inflammogens, including lipopolysaccharide (LPS), thrombin, neuromelanin, etc. The use of adenoviral vectors to promote microglia-specific overexpression of different molecules in the ventral mesencephalon, including α-synuclein, IL-1β, and TNF, are also presented and briefly discussed. Finally, we summarise different models associated with peripheral inflammation whose contribution to the pathogenesis of neurodegenerative diseases is now an outstanding question. Illustrative examples included systemic LPS administration and dextran sulfate sodium-induced colitis in rodents.

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“…Particularly, the activated microglia can release proinflammatory cytokines such as interleukins (ILs) and tumor necrosis factor-a (TNF-a), which eventually produce damage to dopaminergic neurons (6,7). To make matters worse, immune cells from the peripheral circulation infiltrate the brain parenchyma through the compromised blood-brain barrier (BBB) and trigger immune responses via several pathways (8)(9)(10). Meanwhile, higher levels of inflammatory factors released by immune cells, such as IL-6, IL-1b, and TNF-a are also found in peripheral blood of PD patients, indicating the occurrence of peripheral inflammation (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…There are a high number of infiltrating T cells in the ventral midbrain of PD patients, which are autoreactive and can recognize disease-altered self-proteins (e.g., a-syn) as foreign antigens through histocompatibility complex (MHC) molecules and drive helper and cytotoxic T cell responses (10,15). The alleles and haplotypes of MHC class II genes, like HLA-DRB, has been extensively studied in its association with the risk of PD (8,16,17). Physiologically, a carefully regulated immune network is involved in mitigating the progression of inflammation to reduce the tissue damage it causes (14,18).…”

Section: Introductionmentioning

confidence: 99%

Quantitative and causal analysis for inflammatory genes and the risk of Parkinson’s disease

Jian

et al. 2023

Front. Immunol.

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BackgroundThe dysfunction of immune system and inflammation contribute to the Parkinson’s disease (PD) pathogenesis. Cytokines, oxidative stress, neurotoxin and metabolism associated enzymes participate in neuroinflammation in PD and the genes involved in them have been reported to be associated with the risk of PD. In our study, we performed a quantitative and causal analysis of the relationship between inflammatory genes and PD risk.MethodsStandard process was performed for quantitative analysis. Allele model (AM) was used as primary outcome analysis and dominant model (DM) and recessive model (RM) were applied to do the secondary analysis. Then, for those genes significantly associated with the risk of PD, we used the published GWAS summary statistics for Mendelian Randomization (MR) to test the causal analysis between them.ResultsWe included 36 variants in 18 genes for final pooled analysis. As a result, IL-6 rs1800795, TNF-α rs1799964, PON1 rs854560, CYP2D6 rs3892097, HLA-DRB rs660895, BST1 rs11931532, CCDC62 rs12817488 polymorphisms were associated with the risk of PD statistically with the ORs ranged from 0.66 to 3.19 while variants in IL-1α, IL-1β, IL-10, MnSOD, NFE2L2, CYP2E1, NOS1, NAT2, ABCB1, HFE and MTHFR were not related to the risk of PD. Besides, we observed that increasing ADP-ribosyl cyclase (coded by BST1) had causal effect on higher PD risk (OR[95%CI] =1.16[1.10-1.22]) while PON1(coded by PON1) shown probably protective effect on PD risk (OR[95%CI] =0.81[0.66-0.99]).ConclusionSeveral polymorphisms from inflammatory genes of IL-6, TNF-α, PON1, CYP2D6, HLA-DRB, BST1, CCDC62 were statistically associated with the susceptibility of PD, and with evidence of causal relationships for ADP-ribosyl cyclase and PON1 on PD risk, which may help understand the mechanisms and pathways underlying PD pathogenesis.

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Association of HLA–DRB1, DQA1 and DQB1 alleles and haplotype in Parkinson’s disease from South India

Cited by 6 publications

References 69 publications

Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson’s disease

Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson’s disease

Inflammatory Animal Models of Parkinson’s Disease

Quantitative and causal analysis for inflammatory genes and the risk of Parkinson’s disease

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