Date Published: July 5, 2018
Publisher: Public Library of Science
Author(s): 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, Ferruccio Bonino.
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.
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.
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.
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.
Approximately 686,000 people die each year due to severe and advanced liver diseases such as cirrhosis and cancer induced by chronic hepatitis B (CHB) infection [1–3]. In Korea, public vaccination programs have decreased the incidence of hepatitis B virus (HBV) surface antigen (HBsAg) seropositive patients, but the incidence remains as high as 3% of the entire population because of higher carrier rates among the people over 30 years old who did not undergo universal vaccination and presumed to have been at risk of perinatal (vertical) transmission and horizontal transmission in early childhood .
Almost all healthy adults who are not immunosuppressed will rapidly recover from HBV infection following a short-term acute phase. Those rare people who progress to chronicity with adulthood HBV infection might have some genetic defects in the process of clearing HBV. On the other hand, people infected with HBV in infancy or early childhood almost always progress to chronic infections probably because of immature immunity against HBV in that age , and recovery from HBV infection in these patients is very rare. Thus, genetic factors associated with HBsAg seroclearance in CHB patients who had been infected in childhood are likely to differ from those determining the chronicization of adulthood HBV infections. In this respect, it is somewhat difficult to define what previous GWASs really meant by their results, since those studies did not exactly clarify the onset time of HBV infection for both patients with and without HBsAg. In all probability, however, the findings of previous GWASs mainly appear to represent genetic markers associated with the chronicization of adult HBV infection rather than viral remission in CHB patients infected in early childhood, for most of previous GWASs were conducted in East Asia, and almost all the participants assigned in the control group without HBsAg are presumed to have recovered from acute phase of adult-onset HBV infection.