Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma

AbstractBackground/AimsDietary aflatoxin B1 (AFB1) exposure, which induces DNA damage and codon 249 mutation of the TP53 gene, is one of the major risk factors for hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) infection and AFB1 exert synergistic effects to promote carcinogenesis and TP53 R249S mutation in HCC.MethodsA genome-wide association study (GWAS) was conducted on 485 cases of HCC with chronic HBV infection, followed by a two-stage replication study on 270 cases with chronic HBV infection. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both GWAS and replication analysis. The associations of identified variants with expression levels of their located genes were validated in 20 paired independent samples.ResultsOur results showed that TP53 R249S was significantly associated with ADAMTS18 rs9930984 (adjusted P = 4.84×10−6), WDR49 rs75218075 (adjusted P = 7.36 × 10−5) and SLC8A3 rs8022091 (adjusted P = 0.042). Additionally, ADAMTS18 mRNA expression was significantly higher in HCC tissue, compared with paired non-tumor tissue (P = 0.041) and patients carrying the TT genotype at rs9930984 showed lower ADAMTS18 expression in non-tumor tissue, compared with those carrying the GT genotype (P = 0.0028).ConclusionsTP53 expression is significantly associated with R249S mutation in HCC. Our collective results suggest that rs9930984, rs75218075 and rs8022091 are associated with susceptibility to the R249S mutation in cases of HCC exposed to AFB1 and HBV infection.

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Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study

Clinical Infectious Diseases ◽

10.1093/cid/ciz084 ◽

2019 ◽

Vol 69 (11) ◽

pp. 1969-1979

Author(s):

Willem P Brouwer ◽

Henry L Y Chan ◽

Pietro Lampertico ◽

Jinlin Hou ◽

Pisit Tangkijvanich ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B ◽

Association Study ◽

Chronic Hepatitis B ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Pegylated Interferon ◽

Hbv Dna ◽

Genome Wide Association ◽

Genome Wide

AbstractBackground(Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand.MethodsIn this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients.ResultsOf 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= −0.74, standard error [SE] = 0.16, P = 3.44 ×10–6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10–6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele.ConclusionsAlthough no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies.Clinical Trials RegistationNCT01401400.

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