Sehwan's paper published in A&R

Sehwan CHUN (MSc 2019) developed an allele-specific quantification method for HLA-DRB1 using both total RNA-seq and HLA-DRB1 sequencing data. He found highly allele-specific expression of HLA-DRB1 that leads to the imbalanced expression of two HLA-DRB1 classical alleles in heterozygotes, eventually modifying phenotypic effects of HLA-DRB1 amino acid residues.

His work was conducted at KimLab during his two-year graduate program. His paper was accepted for publication in Arthritis & Rheumatology (with an impact factor of 9.586), on Sep 14, 2020. Congrats!

Allele-specific quantification of HLA-DRB1 transcripts reveals imbalanced allelic expression that modifies the amino acid effects in HLA-DRβ1

Sehwan Chun^, So-Young Bang^, Eunji Ha, Jing Cui, Ki-Nam Gu, Hye-Soon Lee, Kwangwoo Kim*, Sang-Cheol Bae*

Abstract

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 three-field classical 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 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 (Ala74) 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 Ala74 in two 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 Ala74 and the ACPA level in RA was better explained by relative expression dosage of Ala74 than the genomic dosage (ΔAIC=-6.98). Moreover, the expressional variance of Ala74 in Ala74 heterozygotes with no genomic variance of Ala74 was significantly associated with the ACPA level (P=2.26×10^-3). Conclusion: Our finding illustrates the advantage of integrating quantitative and qualitative changes in HLA-DRB1 into a single model for understanding HLA-DRB1 associations.