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Functional Genetics to Understand the Etiology of Autoimmunity.

ABSTRACT: Common variants strongly influence the risk of human autoimmunity. Two categories of variants contribute substantially to the risk: (i) coding variants of HLA genes and (ii) non-coding variants at the non-HLA loci. We recently developed a novel analytic pipeline of T cell receptor (TCR) repertoire to understand how HLA coding variants influence the risk. We identified that the risk variants increase the frequency of auto-reactive T cells. In addition, to understand how non-coding variants contribute to the risk, the researchers conducted integrative analyses using expression quantitative trait loci (eQTL) and splicing quantitative trait loci (sQTL) and demonstrated that the risk non-coding variants dysregulate specific genes' expression and splicing. These studies provided novel insight into the immunological consequences of two major genetic risks, and we will introduce these research achievements in detail in this review.

SUBMITTER: Hatano H

PROVIDER: S-EPMC10048754 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Functional Genetics to Understand the Etiology of Autoimmunity.

Hatano Hiroaki H Ishigaki Kazuyoshi K

Genes 20230224 3

Common variants strongly influence the risk of human autoimmunity. Two categories of variants contribute substantially to the risk: (i) coding variants of HLA genes and (ii) non-coding variants at the non-HLA loci. We recently developed a novel analytic pipeline of T cell receptor (TCR) repertoire to understand how HLA coding variants influence the risk. We identified that the risk variants increase the frequency of auto-reactive T cells. In addition, to understand how non-c ...[more]

PMID: 36980846

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Project description:Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA's clinical presentation exhibits several overlapping features with other members including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies.

Dataset Information

Functional Genetics to Understand the Etiology of Autoimmunity.

Publications

Functional Genetics to Understand the Etiology of Autoimmunity.

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