Identification of novel susceptibility loci associated with hepatitis B surface antigen seroclearance in chronic hepatitis B

Tae Hyung Kim, Eun Ju Lee, Ji Hye Choi, Sun Young Yim, Sunwon Lee, Jaewoo Kang, Yoo Ra Lee, Han Ah Lee, Hyuk Soon Choi, Eun-Sun Kim, Bora Keum, Yeon Seok Seo, Hyung Joon Yim, Yoon Tae Jeen, Hoon-Jai Chun, Hong Sik Lee, Chang Duck Kim, Hyun Goo Woo, Soon-Ho Um

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Abstract

Background/Aims The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype. Methods One hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants. Results We identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 × 10−6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27–7.63) at 11q12.1, rs171941 (P = 3.52×10−6, OR = 3.69, 95% CI = 2.13–6.42) at 5q14.1, and rs6462008 (P = 3.40×10−6, OR = 0.34, 95% CI = 0.22–0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related. Conclusions To the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology.

Original languageEnglish
Article numbere0199094
JournalPLoS One
Volume13
Issue number7
DOIs
Publication statusPublished - 2018 Jul 1

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chronic hepatitis B
Chronic Hepatitis B
Surface Antigens
Hepatitis B Surface Antigens
surface antigens
Hepatitis B virus
Viruses
loci
Genes
Genome-Wide Association Study
odds ratio
confidence interval
Odds Ratio
Virus Diseases
Confidence Intervals
Genotype
Functional analysis
Polymorphism
genotype
pathophysiology

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Identification of novel susceptibility loci associated with hepatitis B surface antigen seroclearance in chronic hepatitis B. / Kim, Tae Hyung; Lee, Eun Ju; Choi, Ji Hye; Yim, Sun Young; Lee, Sunwon; Kang, Jaewoo; Lee, Yoo Ra; Lee, Han Ah; Choi, Hyuk Soon; Kim, Eun-Sun; Keum, Bora; Seo, Yeon Seok; Yim, Hyung Joon; Jeen, Yoon Tae; Chun, Hoon-Jai; Lee, Hong Sik; Kim, Chang Duck; Woo, Hyun Goo; Um, Soon-Ho.

In: PLoS One, Vol. 13, No. 7, e0199094, 01.07.2018.

Research output: Contribution to journalArticle

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abstract = "Background/Aims The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype. Methods One hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants. Results We identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 × 10−6, odds ratio [OR] = 4.16, 95{\%} confidence interval [CI] = 2.27–7.63) at 11q12.1, rs171941 (P = 3.52×10−6, OR = 3.69, 95{\%} CI = 2.13–6.42) at 5q14.1, and rs6462008 (P = 3.40×10−6, OR = 0.34, 95{\%} CI = 0.22–0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related. Conclusions To the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology.",
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AU - Kim, Tae Hyung

AU - Lee, Eun Ju

AU - Choi, Ji Hye

AU - Yim, Sun Young

AU - Lee, Sunwon

AU - Kang, Jaewoo

AU - Lee, Yoo Ra

AU - Lee, Han Ah

AU - Choi, Hyuk Soon

AU - Kim, Eun-Sun

AU - Keum, Bora

AU - Seo, Yeon Seok

AU - Yim, Hyung Joon

AU - Jeen, Yoon Tae

AU - Chun, Hoon-Jai

AU - Lee, Hong Sik

AU - Kim, Chang Duck

AU - Woo, Hyun Goo

AU - Um, Soon-Ho

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N2 - Background/Aims The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype. Methods One hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants. Results We identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 × 10−6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27–7.63) at 11q12.1, rs171941 (P = 3.52×10−6, OR = 3.69, 95% CI = 2.13–6.42) at 5q14.1, and rs6462008 (P = 3.40×10−6, OR = 0.34, 95% CI = 0.22–0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related. Conclusions To the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology.

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