■帕金森病(PD)是一种神经变性和多基因疾病,其特征在于神经多巴胺的进行性丧失和运动障碍的发作。我们先前描述了8个位于6号染色体的人类白细胞抗原(HLA)基因组区域内并表达的SINE-VNTR-Alu(SVA)逆转录转座子插入多态性(RIPs),它们调节了71个不同基因的差异共表达,包括帕金森氏进展标志物(PPMI)队列中的HLA经典I类和II类基因。
■在本研究中,我们(1)重新分析了从1521个人(867例病例和654例对照)的全血获得的PPMI基因组和转录组测序数据,以推断由八个经典HLAI类和II类基因以及DRA和DRB3/4/5单倍型表达的转录本的基因型。(2)检查了三个不同PD亚组(病例)和健康对照(HC)之间HLA和SVA转录基因型和推断单倍型的统计学差异。
■对于57个表达的HLA等位基因(21个HLAI类和36个HLAII类等位基因),在三个不同的PD亚组中的一个或另一个(750个患有PD的个体,57个前驱体,60名扫描没有多巴胺缺陷证据的人[SWEDD]),当与PPMI队列中的一组654个HC进行比较时,以及当没有通过Bonferroni检验进行多重比较校正时。20个显著等位基因中有14个是PD-HC比较所特有的,而57个等位基因中有31个在两个或多个不同的亚组比较之间重叠。只有表达的HLA-DRA*01:01:01和-DQA1*03:01:01保护性等位基因(PDvHC),-DQA1*03:03:01风险(HCvProdrome)或保护性等位基因(PDvProdrome),-DRA*01:01:02和-DRB4*01:03:02风险等位基因(SWEDDvHC),在Bonferroni校正后,在HLA-DPA1附近以5%纯合插入频率的NR_SVA_381存在的基因型(PDvHC)显着(Pc<0.1)。同源NR_SVA_381插入显着降低了PPMI队列中HLA-DPA1和HLA-DPB1的转录水平,并且其作为纯合基因型的存在是PD的危险因素(Pc=0.012)。PPMI队列中最常见的NR_SVA_381插入单倍型是NR_SVA_381/DPA1*02/DPB1*01(3.7%)。尽管HLAC*07/B*07/DRB5*01/DRB1*15/DQB1*06是最常见的HLA5基因座分期单倍型(n,76)在PPMI队列中,NR_SVA_381插入只存在于其中的六个(8%)中。
■这些数据表明,循环白细胞中表达的SVA和HLA基因等位基因在调节免疫反应和PD的长期发作和进展方面存在差异。其机制尚未阐明。
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 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.
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 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%).
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.