A missense variant in complement factor B (CFB) is a potential predictor of 24‐week off‐treatment response to PegIFNα therapy in Chinese HBeAg‐positive chronic hepatitis B patients

Abstract

Background: To date, 14 single-nucleotide polymorphisms (SNPs) have been identified as susceptibility loci for chronic hepatitis B (CHB). Aim: To investigate if these SNPs are associated with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. Methods: We performed a retrospective analysis of 1623 Han Chinese HBeAg-positive CHB patients (782 patients treated with pegylated interferon alpha [PegIFNα] for 48 weeks plus 24 weeks follow-up, and 841 patients treated with nucleos(t)ide analogues [NUCs] for 104 weeks) included in four phase-IV multicentre randomised controlled trials. All 14 SNPs were genotyped for each CHB patient. A polygenic score (PGS) was used to evaluate the cumulative effect of multiple SNPs. The associations of SNPs or PGS with combined response (CR) and hepatitis B s antigen (HBsAg) loss were assessed.Results: We found that rs12614, a missense variant of complement factor B (CFB), was significantly associated with CR in PegIFNα-treated patients, and the CR rate in patients with the rs12614 TT/CT genotype was less than one-third of that in patients with the CC genotype (7.4% vs 22.6%, P = 0.009). Moreover, a PGS integrating CFB rs12614 and STAT4 rs7574865 (previously reported to be associated with response to PegIFNα) was significantly associated with both CR (P-trend = 4.000 × 10 −4 ) andHBsAg loss (P-trend = 0.010) in PegIFNα-treated patients. However, none of the SNPs were associated with treatment response in NUCs-treated patients.Conclusions: CFB rs12614 is an independent predictor of response to PegIFNα therapy in Chinese HBeAg-positive CHB patients. A PGS integrating CFB rs12614 with STAT4 rs7574865 can effectively discriminate responders to PegIFNα from nonresponders.

A Missense Variant in Granulysin is Associated with the Efficacy of Pegylated-Interferon-Alpha Therapy in Chinese Patients with HBeAg-Positive Chronic Hepatitis B

“…8,16 Similarly, another SNP, rs12614, which is located in the second exon of CFB and identified as a susceptibility locus for CHB, was also significantly associated with the response to PegIFNα therapy in patients with HBeAg-positive CHB. 17,18 Granulysin (GNLY) is a saposin-like pore-forming protein that acts as a cytotoxic granule and is mainly secreted by cytotoxic T lymphocytes and natural killer (NK) cells in mammals. It exerts a toxic role with respect to bacteria, fungi, parasites, and tumors, 19,20 and acts as an anti-virus biomarker, such as in Epstein-Barr virus (EBV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.…”

“… 8 , 16 Similarly, another SNP, rs12614, which is located in the second exon of CFB and identified as a susceptibility locus for CHB, was also significantly associated with the response to PegIFNα therapy in patients with HBeAg-positive CHB. 17 , 18 …”

A Non-Synonymous Variant rs12614 of Complement Factor B Associated with Risk of Chronic Hepatitis B in a Korean Population

“…According to our previous GWASs, several genes in HLA regions, such as transcription factor 19 (TCF19), and valyl-tRNA synthetase 2 (VARS2)-surfactant associated 2 (SFTA2), euchromatin histone-lysine-methyltransferase2 (EHMT2), showed signi cant genetic effects on CHB susceptibility in a Korean population [5][6][7][8][9]. Interestingly, genetic variants of CFB, found on the nearby gene of EHMT2, have strong association with CHB susceptibility in Chinese studies [10][11][12].…”

A Non-Synonymous Variant rs12614 of Complement Factor B Associated with Risk of Chronic Hepatitis B in a Korean Population

“…According to our previous GWASs, several genes in HLA regions, such as transcription factor 19 (TCF19), and valyl-tRNA synthetase 2 (VARS2)-surfactant associated 2 (SFTA2), euchromatin histone-lysine-methyltransferase 2 (EHMT2), showed signi cant genetic effects on CHB susceptibility in a Korean population [5][6][7][8][9]. Interestingly, genetic variants of CFB, found on the nearby gene of EHMT2, have strong association with CHB susceptibility in Chinese studies [10][11][12].…”