Hepatitis B viraemia: Its heritability and association with common genetic variation in the interferon γ signalling pathway

Hsuan Hao Huang; Wei Liang Shih; Yi Hsiu Li; Chih Feng Wu; Pei Jer Chen; Chih Lin Lin; Chun Jen Liu; Yun Fan Liaw; Shi Ming Lin; Shou Dong Lee; Ming Whei Yu

doi:10.1136/gut.2010.207670

Hepatitis B viraemia: Its heritability and association with common genetic variation in the interferon γ signalling pathway

Hsuan Hao Huang, Wei Liang Shih, Yi Hsiu Li, Chih Feng Wu, Pei Jer Chen, Chih Lin Lin, Chun Jen Liu, Yun Fan Liaw, Shi Ming Lin, Shou Dong Lee, Ming Whei Yu^*

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Journal Article › peer-review

24 Scopus citations

Abstract

Objective: High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon γ (IFNγ) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV. Methods: We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFNγ-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years. Results: After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother - child pairs. Heritability accounted for approximately 30% (p<0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFNγ receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p<0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of ≥4.39 log copies/ml (all p<0.0001) in unrelated individuals. Conclusions: HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.

Original language	English
Pages (from-to)	99-107
Number of pages	9
Journal	Gut
Volume	60
Issue number	1
DOIs	https://doi.org/10.1136/gut.2010.207670
State	Published - 01 2011

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@article{5b664a4a7885430ab5aac33d34d40e29,

title = "Hepatitis B viraemia: Its heritability and association with common genetic variation in the interferon γ signalling pathway",

abstract = "Objective: High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon γ (IFNγ) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV. Methods: We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFNγ-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years. Results: After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother - child pairs. Heritability accounted for approximately 30% (p<0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFNγ receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p<0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of ≥4.39 log copies/ml (all p<0.0001) in unrelated individuals. Conclusions: HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.",

author = "Huang, {Hsuan Hao} and Shih, {Wei Liang} and Li, {Yi Hsiu} and Wu, {Chih Feng} and Chen, {Pei Jer} and Lin, {Chih Lin} and Liu, {Chun Jen} and Liaw, {Yun Fan} and Lin, {Shi Ming} and Lee, {Shou Dong} and Yu, {Ming Whei}",

year = "2011",

month = jan,

doi = "10.1136/gut.2010.207670",

language = "英语",

volume = "60",

pages = "99--107",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "1",

}

TY - JOUR

T1 - Hepatitis B viraemia

T2 - Its heritability and association with common genetic variation in the interferon γ signalling pathway

AU - Huang, Hsuan Hao

AU - Shih, Wei Liang

AU - Li, Yi Hsiu

AU - Wu, Chih Feng

AU - Chen, Pei Jer

AU - Lin, Chih Lin

AU - Liu, Chun Jen

AU - Liaw, Yun Fan

AU - Lin, Shi Ming

AU - Lee, Shou Dong

AU - Yu, Ming Whei

PY - 2011/1

Y1 - 2011/1

N2 - Objective: High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon γ (IFNγ) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV. Methods: We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFNγ-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years. Results: After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother - child pairs. Heritability accounted for approximately 30% (p<0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFNγ receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p<0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of ≥4.39 log copies/ml (all p<0.0001) in unrelated individuals. Conclusions: HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.

AB - Objective: High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon γ (IFNγ) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV. Methods: We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFNγ-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years. Results: After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother - child pairs. Heritability accounted for approximately 30% (p<0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFNγ receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p<0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of ≥4.39 log copies/ml (all p<0.0001) in unrelated individuals. Conclusions: HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.

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U2 - 10.1136/gut.2010.207670

DO - 10.1136/gut.2010.207670

M3 - 文章

AN - SCOPUS:84984559313

SN - 0017-5749

VL - 60

SP - 99

EP - 107

JO - Gut

JF - Gut

IS - 1

ER -

Hepatitis B viraemia: Its heritability and association with common genetic variation in the interferon γ signalling pathway

Abstract

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