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

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.

SUBMITTER: Kim TH

PROVIDER: S-EPMC6033413 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Kim Tae Hyung TH Lee Eun-Ju EJ Choi Ji-Hye JH Yim Sun Young SY Lee Sunwon S Kang Jaewoo J Lee Yoo Ra YR Lee Han Ah HA Choi Hyuk Soon HS Kim Eun Sun ES Keum Bora B Seo Yeon Seok YS Yim Hyung Joon HJ Jeen Yoon Tae YT Chun Hoon Jai HJ Lee Hong Sik HS Kim Chang Duck CD Woo Hyun Goo HG Um Soon Ho SH

PloS one 20180705 7

<h4>Background/aims</h4>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 pres ...[more]

PMID: 29975729

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Project description:Early?onset cardiovascular and renal diseases have a strong genetic component. In the present study, exome?wide association studies (EWASs) were performed to identify genetic variants that confer susceptibility to early?onset myocardial infarction (MI), hypertension, or chronic kidney disease (CKD) in Japanese individuals. A total of 8,093 individuals aged ?65 years was enrolled in the study. The EWASs for MI, hypertension, and CKD were performed in 6,926 subjects (1,152 cases, 5,774 controls), 8,080 subjects (3,444 cases, 4,636 controls), and 2,556 subjects (1,051 cases, 1,505 controls), respectively. Genotyping of single nucleotide polymorphisms (SNPs) was performed with Illumina Human Exome?12 DNA Analysis BeadChip or Infinium Exome?24 BeadChip arrays. The associations of allele frequencies for 31,245, 31,276, or 31,514 SNPs that passed quality control to MI, hypertension, and CKD, respectively, was examined with Fisher's exact test. Bonferroni's correction for statistical significance of association was applied to compensate for multiple comparisons of genotypes with MI, hypertension, or CKD. The EWASs of allele frequencies revealed that 25, 11, and 11 SNPs were significantly associated with MI (P<1.60x10?6), hypertension (P<1.60x10?6), or CKD (P<1.59x10?6), respectively. Multivariable logistic regression analysis with adjustment for covariates showed that all 25, 11, and 11 SNPs were significantly associated with MI (P<0.0005), hypertension (P<0.0011), or CKD (P<0.0011), respectively. On examination of the results from previous genome?wide association studies and linkage disequilibrium of the identified SNPs, 11 loci (TMOD4, COL6A3, ADGRL3?CXCL8?MARCH1, OR52E4, TCHP?GIT2, CCDC63, 12q24.1, OAS3, PLCB2?VPS33B, GOSR2, ZNF77), six loci (MOB3C?TMOD4, COL6A3, COL6A5, CXCL8?MARCH1, NFKBIL1?6p21.3?NCR3, PLCB2?VPS33B), and seven loci (MOB3C?TMOD4, COL6A3, COL6A5, ADGRL3?CXCL8?MARCH1, MUC17, PLCB2?VPS33B, ZNF77) were identified as novel loci significantly associated with MI, hypertension, and CKD, respectively. Furthermore, six genes (TMOD4, COL6A3, CXCL8, MARCH1, PLCB2, VPS33B) were significantly associated with MI, hypertension and CKD; two genes (ADGRL3, ZNF77) with MI and CKD; and two genes (COL6A5, MOB3C) with hypertension and CKD. Therefore, 13 novel loci (MOB3C?TMOD4, COL6A3, ADGRL3?CXCL8?MARCH1, OR52E4, TCHP?GIT2, CCDC63, 12q24.1, OAS3, PLCB2?VPS33B, ZNF77, COL6A5, NFKBIL1?NCR3, MUC17) were identified that confer susceptibility to early?onset MI, hypertension, or CKD. The determination of genotypes for the SNPs at these loci may provide informative for assessment of the genetic risk for MI, hypertension, or CKD.

Dataset Information

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

Publications

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

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