A cis-eQTL of HLA-DPB1 Affects Susceptibility to Type 1 Autoimmune Hepatitis

Tomoo Yamazaki,Eiji Tanaka,Masao Ota,Satoru Joshita,Takeji Umemura,Kaname Yoshizawa

doi:10.1038/s41598-018-30406-9

Tomoo Yamazaki, Eiji Tanaka + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-30406-9

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Journal: Scientific Reports	Publication Date: Aug 9, 2018
Citations: 9	License type: open-access

Affiliation: Shinshu University, Kameda Medical Center

Abstract

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. A single nucleotide polymorphism in the 3′ untranslated region of HLA-DPB1, rs9277534, is associated with HLA-DPB1 expression. rs9277534 has been linked to hepatitis B virus recovery/persistence and the risk of graft-versus-host disease with HLA-DPB1 mismatching transplantation of hematopoietic cells, but its role along with that of HLA-DP expression in AIH have not been fully clarified. We genotyped rs9277534 in 146 Japanese patients with AIH and 326 healthy subjects. HLA-DPB1 expression was determined by quantitative PCR. HLA-DPB1 expression was significantly higher for rs9277534G than for rs9277534A (P < 0.05). rs9277534 genotype was in strong linkage disequilibrium with the HLA-DPB1 allele (pairwise D′ = 0.82–1.00). Although HLA-DP alleles were not significantly associated with AIH, the frequency of the rs9277534G allele was significantly higher in AIH patients compared with healthy subjects (P = 0.002, odds ratio [OR] = 1.56). Logistic regression analysis revealed that the HLA-DRB1*04:05 allele (P < 0.001, OR = 4.61) and rs9277534 (P = 0.004, OR = 1.67) were independently associated with AIH susceptibility. rs9277534G in the HLA-DP gene is an eQTL that affects gene expression and may contribute to AIH susceptibility.

Highlights

Logistic regression analysis revealed that the human leukocyte antigen (HLA)-DRB1*04:05 allele (P < 0.001, odds ratio (OR) = 4.61, 95% confidence interval (CI) = 2.86–7.41) and rs9277534 (P = 0.004, OR = 1.67, 95% CI = 1.18–2.37) were independently associated with Autoimmune hepatitis (AIH) susceptibility
Logistic regression analysis showed that rs9277534G was an independent susceptibility allele to AIH in addition to the HLA-DRB1*04:05 allele. rs9277534 is an expression quantitative trait locus that affects gene expression. eQTL single nucleotide polymorphism (SNP) are linked to transcription factor binding, DNA methylation, alternative splicing, small RNA, and other regulatory variants
Our study confirmed that HLA-DPB1 mRNA expression in cells from Japanese donors correlated with rs9277534A/G genotypes, as reported previously[21,22]

Summary

Introduction

The DRB1*04:04 and DRB1:04:05 alleles are linked to susceptibility in Mexican[5] and Japanese[6,7,8] and Korean[9] populations, respectively, and studies including recent genome-wide association analyses have shown that DRB1*03:01 and DRB1*04:01 contribute to AIH susceptibility in European populations[10,11,12]. HLA-DP genes have not been examined for their impact on human disease relative to HLA-DR and -DQ because they are less polymorphic and HLA-DP cell surface expression levels are believed to be lower than those of HLA-DR or -DQ13–15. Other current findings[21,22] suggest that this SNP is associated with HLA-DP expression levels and may influence the strength of autoimmune responses, representing a new and crucial role of HLA in human disease. We sought to determine whether rs9277534 and HLA-DP expression were associated with AIH in a Japanese population

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Conclusion