Allele‐Specific Quantification of HLA–DRB1 Transcripts Reveals Imbalanced Allelic Expression That Modifies the Amino Acid Effects in HLA–DRβ1.
Objective: HLA association fine‐mapping studies have shown the effects of missense variants in HLA–DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA–DRB1 remain poorly understood. Therefore, we inves...
| Publicado en: | Arthritis & Rheumatology Vol. 73; no. 3; pp. 381 - 392 |
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| Autores principales: | , , , , , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
Mar2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=148997868&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 148997868 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 23265191 H06R jtl: Arthritis & Rheumatology issn: 23265191 maglogo: N pubinfo: dt: Mar2021 vid: 73 iid: 3 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 148997868 148442424 148997868 148997868 10.1002/art.41535 148997868 ppf: 381 ppct: 11 formats: tig: atl: Allele‐Specific Quantification of HLA–DRB1 Transcripts Reveals Imbalanced Allelic Expression That Modifies the Amino Acid Effects in HLA–DRβ1. aug: au: Chun, Sehwan Bang, So‐Young Ha, Eunji Cui, Jing Gu, Ki‐Nam Lee, Hye‐Soon Kim, Kwangwoo Bae, Sang‐Cheol affil: Kyung Hee University, Seoul, Republic of Korea sug: subj: Alleles HLA Antigens Gene Expression Amino Acids Pharmacodynamics Arthritis, Rheumatoid Phenotype Human South Korea RNA Genotype Autoantibodies Anti-Citrullinated Protein Antibodies Logistic Regression Heterosexuals ab: Objective: HLA association fine‐mapping studies have shown the effects of missense variants in HLA–DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, the phenotypic effects of expression changes in HLA–DRB1 remain poorly understood. Therefore, we investigated the allele‐specific expression of HLA–DRB1 and its effect on an HLA–DRβ1 structure–associated trait in RA. Methods: We quantified the allele‐specific expression of each HLA–DRB1 3‐field classic allele in 48 Korean RA patients with anti–citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA–DRB1 genotype data to calculate the relative expression strength of multiple HLA–DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA–DRβ1 in ACPA‐positive RA was revisited to understand the phenotypic effect of allele‐specific expression of HLA–DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala‐74 in 2 independent sets of 1,723 Korean RA patients with ACPA. Results: The relative expression strength was highly allele‐specific, causing imbalanced allelic expression in HLA–DRB1 heterozygotes. The association between HLA‐DRβ1 Ala‐74 and ACPA level in RA was better explained by relative expression dosage of Ala‐74 than by the genomic dosage (change in Akaike's information criterion = −6.98). Moreover, the expression variance of Ala‐74 in Ala‐74 heterozygotes with no genomic variance of Ala‐74 was significantly associated with ACPA level (P = 2.26 × 10−3). Conclusion: Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA–DRB1 into a single model for understanding HLA–DRB1 associations. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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