Open Access

Associations between the single nucleotide polymorphisms of APOBEC3A, APOBEC3B and APOBEC3H, and chronic hepatitis B progression and hepatocellular carcinoma in a Chinese population

  • Authors:
    • Xiuting He
    • Hongqin Xu
    • Xiaomei Wang
    • Jing Wu
    • Junqi Niu
    • Pujun Gao
  • View Affiliations

  • Published online on: July 2, 2019     https://doi.org/10.3892/mmr.2019.10455
  • Pages: 2177-2188
  • Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The present study examined the relationships between the single nucleotide polymorphisms (SNPs) of three members of the apolipoprotein B mRNA‑editing catalytic polypeptide‑like 3 (A3) gene family, A3A, A3B and A3H, and hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) in a Han Chinese population. A total of 654 patients were enrolled in the study between January 2012 and July 2016, including 104 patients with chronic HBV infection (CHB), 265 patients with HBV‑related liver cirrhosis and 285 patients with HBV‑related HCC. A total of two A3A SNPs (rs7286317 and rs7290153), three A3B SNPs (rs2267398, rs2267401 and rs2076109), and five A3H SNPs (rs56695217, rs139302, rs139297, rs139316 and rs139292) were genotyped using a MassArray system. Statistical analysis and haplotype estimation were conducted using Haploview and Unphased software. No significant associations were observed between the A3A, A3B and A3H SNPs and the development of CHB and HCC. Haplotype analysis revealed that the mutant haplotypes C‑T‑A, C‑T‑G, T‑G‑G and T‑T‑G from the A3B SNPs rs2267398‑rs2267401‑rs2076109 carried a lower risk of HCC than the reference haplotype. These findings suggested that there was no relationship between A3A, A3B and A3H SNPs and CHB progression or HCC development in the Han Chinese population.

Introduction

Hepatocellular carcinoma (HCC) is a common form of liver cancer associated with high mortality. It is estimated that ~600,000 new cases are diagnosed annually worldwide; HCC is relatively common in Asia-Pacific countries and sub-Saharan Africa (1). Hepatitis B virus (HBV) infection is believed to be the most common cause of HCC development, with the clinical course of HBV infection often progressing from chronic hepatitis B (CHB) to liver cirrhosis (LC) and then HCC (1). It is estimated that ~2-10% of CHB patients develop LC, some of which subsequently develop HCC; however, some HBV carriers can also spontaneously eliminate the virus (2). HBV infection is common in China due socio-economic factors. As a consequence, the incidence of HCC in China is relatively high, contributing to ~422,100 deaths annually (3).

The apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3, A3) gene cluster is located in chromosome region 22q13.1 to q13.2 (4). This gene cluster encodes seven proteins, including A3A, A3B, A3C, A3DE, A3F, A3G and A3H (5) and is reported to perform important roles in various biological processes, including the innate immune response to viral infections (4,6). Among the seven protein family members, A3A and A3B are able to restrict the infection of a broad range of viruses, including parvovirus, HBV, hepatitis C virus, herpesvirus, human papillomavirus and human immunodeficiency virus 1 (HIV-1) (713). A3H is the most polymorphic member of the A3 subfamily, as it has various single nucleotide polymorphism (SNP) combinations that influence protein stability during resistance to HIV-1 infection (14). Besides their role in viral restriction, the dysregulation and hypermutation of A3 genes has recently been linked to carcinogenesis (15). In particular, a 29.5 kb germline deletion of A3A/B was associated with an increased risk of various cancer types, including breast and ovarian cancer. However, the effect has been inconsistent in different populations and for different types of cancer. For example, it has been suggested that the deletion of A3A/B was associated with an increased risk of breast cancer in European women (16), Chinese women (17) and southeast Iranian women (18). However, this association was not observed in Swedish (19) or Moroccan (20) populations, or in the general European population (21). Few studies have investigated the association between A3H polymorphisms and cancer risk. Zhu et al (22) reported that the T allele of the rs139293 A3H SNP was associated with reduced lung cancer risk in a Chinese population; therefore, further studies are required to confirm the associations between A3A, A3B and A3H polymorphisms and HCC risk.

The present study evaluated the associations between the SNPs of A3A, A3B and A3H, and the development of chronic HBV and HBV-related HCC in a Han Chinese population.

Materials and methods

Study population

Between January 2012 and July 2016, a total of 654 patients from the First Hospital of Jilin University were enrolled in the present study, including 104 patients with CHB, 265 patients with HBV-related LC and 285 patients with HBV-related HCC. The criteria used to diagnose CHB, HBV-related LC and HBV-related HCC have been defined previously (23). Hepatitis A-, C-, D- or E-positive patients and those with HIV were excluded. In addition, patients who had suffered another organ malignancy in the past 5 years, had combined autoimmune diseases, or had other liver diseases, such as intra- and extra-hepatic bile duct stones, alcoholic liver diseases and hemorrhagic liver diseases, were also excluded. General characteristics, including gender, age, smoking history, drinking history, HBV infection history and treatment history, were gathered using a standardized questionnaire. Whole blood (5 ml) was collected from veins of each patient within 48 h of hospital admission and their hepatitis B profile was compiled, including hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), anti-hepatitis B core antigen (HBc), anti-HBe, hepatitis C, HBV DNA quantification, liver function, renal function, α-fetoprotein, blood lipids, blood glucose, blood routine, coagulation routine and abdominal color Doppler ultrasound (or liver computed tomography or magnetic resonance imaging). Patients were also assessed using the Child-Pugh score (24,25) and those with HCC underwent Barcelona clinic liver cancer staging (26). The present study was approved by the First Hospital Ethical Committee of Jilin University and written informed consent was obtained from all participants.

SNP selection and genotyping

A3A, A3B and A3H SNPs were selected from the functional regions of the exon, promoter and untranslated regions (UTRs) by GeneView (27) based on Hapmap (https://www.genome.gov/10001688/international-hapmap-project) and the 1,000 Genomes database (http://www.internationalgenome.org/), with a minor allele frequency of >10%. The SNPs rs7286317 and rs7290153 were selected for A3A since they are located in the microRNA-binding site of the 3´UTR. The SNPs rs2267398 and rs2267401, located in the transcription factor-binding site of the promoter region, were selected for A3B due to their potential roles in gene transcription, while the SNP rs2076109 was selected as it is a missense mutation that may regulate gene function by altering the protein structure. The SNPs rs56695217, rs139302, rs139297, rs139316 and rs139292 were selected for A3H because rs56695217 is located in the transcription factor-binding site, and the others are missense mutations. Haplotype analysis was performed using Haploview version 4.2 (http://www.broad.mit.edu/mpg/haploview) with rs2076109 (A3B), rs139297 (A3H), rs139302 (A3H) and rs139316 (A3H) tag-SNPs. The locations of the A3A, A3B and A3H genes and the selected SNPs are shown in Fig. 1.

Genomic DNA was isolated from whole blood using a blood genomic DNA kit (Sigma-Aldrich; Merck KGaA), according to the manufacturer's instructions. SNP genotyping was performed using a MassArray system (Sequenom), according to the manufacturer's protocol. All SNP primers were designed using Assay Designer (http://assay.archerdx.com/, version 3.2; Table I).

Table I.

Primer sequences for SNP genotyping.

Table I.

Primer sequences for SNP genotyping.

GeneSNPsPrimer sequenceAnnealing temperature (°C)
APOBEC3Ars7286317F: 5′-ACGTTGGATGGTCAGGAGATCGAGACCATC-3′45.1
R: 5′-ACGTTGGATGCACGCCTGGCTAATTTTTTG-3′
rs7290153F: 5′-ACGTTGGATGGGAAGATTCTTAATTTTGTG-3′45.5
R: 5′-ACGTTGGATGGATTATGCTCAATATTCTCAG-3′
APOBEC3BRs2267398F: 5′-ACGTTGGATGTTCTCCCTTCCTTGGTGTCG-3′46.1
R: 5′-ACGTTGGATGATGCGTCCCCTCTTCCAAC-3′
rs2267401F: 5′-ACGTTGGATGTCTCTCAGCTGGGTCTGGA-3′52.4
R: 5′-ACGTTGGATGGGACCCAACGGAATTGCAAA-3′
rs2076109F: 5′-ACGTTGGATGAGAGGAAGCACATTTCTGCG-3′49.6
R: 5′-ACGTTGGATGTGCTCCCCCTCTCAGAGCAT-3′
APOBEC3HRs56695217F: 5′-ACGTTGGATGCCTTGTAATTTGCCCACCTC-3′47.0
R: 5′-ACGTTGGATGAAGAACAAAGGCCAGATGCG-3′
Rs139292F: 5′-ACGTTGGATGTCAGCTGGTAACACAAGAGG-3′58.2
R: 5′-ACGTTGGATGAGCCGAAACATTCCGCTTAC-3′
Rs139297F: 5′-ACGTTGGATGTTGCACCAGTGGTAGTACAG-3′48.9
R: 5′-ACGTTGGATGGCTGGTTGACTTCATCAAGG-3′
Rs139302F: 5′-ACGTTGGATGCAGGACAGTGCCTCACCTT-3′49.1
R: 5′-ACGTTGGATGCCTTCAACCCCTATAAGATG-3′
Rs139316F: 5′-ACGTTGGATGCCAGGGAAAGTCATCTTGAG-3′46.7
R: 5′-ACGTTGGATGAAGAAGTTTGCAGCTTGGAC-3′

[i] SNP, single nucleotide polymorphism; F, forward; R, reverse; APOBEC3, apolipoprotein B mRNA-editing catalytic polypeptide-like 3.

Statistical analysis

All data were analyzed using SPSS version 21.0 (IBM Corp.). Continuous variables are expressed as the mean ± standard deviation or as the median and the interquartile range (25 and 75%). Categorical variables are expressed as a percentage (%). Differences among multiple groups were compared using analysis of variance and the least significant difference multiple comparisons test. Haplotype analysis was performed using Unphased version 3.1.4 (28). The two-sided χ2 test or Fisher's exact test was used to compare allele distributions. Multivariate logistic regression analysis was performed to calculate odds ratios and 95% confidence intervals after adjusting the factors of smoking, drinking and gender differences. P<0.05 was considered to indicate a statistically significant difference.

Results

General characteristics of the study population

The main general and clinical characteristics of the study population are summarized in Table II. No statistical differences were observed between the sex, age, or the percentage of smokers and alcohol consumers in the CHB and LC patient groups (P<0.05). In comparison, the median age and percentages of smokers and alcohol consumers were significantly higher for HCC patients than for CHB patients (P=0.006, 0.013 and 0.008, respectively); however, no significant difference was observed in their sex distributions. Furthermore, no significant differences were observed in the sex, age and percentage of alcohol consumers between the LC and HCC patients (P<0.05), but the percentage of smokers differed significantly (P<0.001).

Table II.

General and clinical characteristics of study subjects.

Table II.

General and clinical characteristics of study subjects.

CharacteristicsCHB n=104 P-valueaLC n=265 P-valuebHCC n=287 P-valuecReference ranges
Sex (M/F)84/200.823210/550.063246/410.286
Aged47 (43,53)0.36849 (41.5,56)0.90150 (46,56)0.006
Smokinge 0.862 <0.001 0.013
  Have ever smoked37 (35.6) 91 (34.3) 144 (50.2)
  Have never smoked67 (64.4) 174 (65.7) 143 (49.8)
Alcohol consumptione 0.142 0.123 0.008
  Have ever consumed alcohol28 (26.9) 93 (35.1) 120 (41.8)
  Have never consumed alcohol76 (73.1) 172 (64.9) 167 (58.2)
Serum HBV-DNAe 0.002 0.004 0.107
  Positive98 (94.2) 211 (79.6) 254 (88.5)
  Negative6 (5.8) 55 (20.4) 33 (11.5)
HBV load, log10 (IU/ml)d6.1 (4.2, 7.3)<0.0014.6 (2.1, 6.3)0.5654.6 (3.1, 6.0)<0.0011.3–8.2
HBeAge 0.814 0.359 0.295
  Positive43 (48.9) 99 (46.7) 100 (42.2)
  Negative45 (51.1) 113 (53.3) 137 (57.8)
ALT (U/l)d172 (53, 496.5)<0.00142 (24, 86)0.71543.5 (27.8, 69.3)<0.00113.0–35.0
AST (U/l)d99 (39.5, 249.5)<0.00147 (31, 90)<0.00162.0 (38.0,110.0)0.0057.0–40.0
ALP (U/l)d87 (67,122.8)0.72489(68,125.5)<0.001129.5 (86.0,190.5)<0.00150.0–135.0
GGT (U/l)d93 (38.3, 161.8)<0.00149.5 (27, 100.8)<0.001112.5 (51.3, 254.3)0.0187.0–45.0
Prealbumin (g/l)d0.16 (0.13, 0.20)<0.0010.12 (0.09, 0.16)0.1920.13 (0.08, 0.17)<0.0010.18–0.39
Albumin (g/l)d37.5 (32.0, 41.2)<0.00130.5 (25.3, 36.0)<0.00133.1 (28.3, 37.3)<0.00140.0–55.0
Total bilirubin (µmol/l)d19.6 (13.3, 48.0)0.03527.6 (16.2, 61.4)0.31425.9 (16.5, 44.2)0.1010.0–8.6
Cholinesterase (U/l)d6,019 (4,343, 8,281)<0.0013,289 (2,356, 4,744)0.0123,918.0 (2,488.3, 5,762.0)<0.0014,300–12,000
Platelet count (×109/l)d145 (117, 188)<0.00177 (53, 121)<0.001118.5 (78.8, 172.0)<0.001100–300

a CHB vs. LC

b LC vs. HCC

c CHB vs. HCC, calculated by analysis of variance and the least significant difference multiple comparisons test.

d Data are expressed as the median (25, 75%).

e Data are expressed as N (%). HBV, hepatitis B virus; CHB, chronic hepatitis B; LC, liver cirrhosis; HCC, hepatocellular carcinoma; ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase; GGT, glutamyl transpeptidase; M, male; F, female; HBeAg, hepatitis B e antigen.

No significant differences were observed between the HBeAg positive rate or alkaline phosphatase (ALP) level of the CHB and LC patients. However, the serum HBV-DNA positive rate, HBV load, and alanine transaminase (ALT), aspartate transaminase (AST) and glutamyl transpeptidase (GGT) levels of the CHB patients were significantly higher compared with those of the LC patients (P<0.05), suggesting that hepatocellular damage was more severe in CHB patients. Furthermore, the prealbumin, albumin and cholinesterase levels, and the platelet count were all significantly higher in CHB patients compared with LC patients (P<0.05), while the total bilirubin level was significantly lower in CHB patients compared with LC patients (P<0.05). The HBeAg positive rate, HBV load, ALT level, prealbumin level and total bilirubin level did not differ significantly between LC and HCC patients (P<0.05). Additionally, the levels of AST, ALP, GGT, albumin and cholinesterase, and the platelet count were all significantly lower in LC patients compared with HCC patients (P<0.05), suggesting that the LC patients had a lower level of hepatocellular damage than the HCC patients.

Associations between genotype and allele frequency in A3A, A3B and A3H SNPs

The genotype and allele frequency of the A3A polymorphisms in CHB patients and healthy individuals are displayed in Table III. No significant associations were detected between the genotype and allele frequency of the two A3A SNPs (rs7286317 and rs7290153) and chronic hepatitis B progression or HCC occurrence (P<0.05). Furthermore, as shown in Tables IV and V, no significant associations were observed between the three A3B SNPs (rs2267398, rs2267401 and rs2076109) or the five A3H SNPs (rs56695217, rs139302, rs139297, rs139316 and rs139292) and chronic hepatitis B progression or HCC occurrence (P<0.05).

Table III.

Genotype and allele frequencies of two SNPs of APOBEC3A.

Table III.

Genotype and allele frequencies of two SNPs of APOBEC3A.

A, Rs7286317 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valuea  N (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec
Number detectedn=102 n=265 n=285
AA75 (73.5)1 197 (74.3)1 200 (70.2)1
AG27 (26.5)0.95 (0.56,1.60)0.8568 (25.7)1.30 (0.89,191)0.1885 (29.8)1.24 (0.74,2.08)0.42
A Allele177 (86.8)1 462 (87.2) 485 (85.1)1
G Allele27 (13.2)0.96 (0.60,1.56)0.8868 (12.8)0.84 (0.60,1.18)0.3285 (14.9)0.87 (0.55,1.39)0.56

B, Rs7290153 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec

Number detectedn=97 n=246 n=267
CC78 (80.4)1 198 (80.5)1 217 (81.3)1
CT14 (14.4)0.88 (0.44,1.75)0.7231 (12.6)0.83 (0.48,1.47)0.5230 (11.2)0.78 (0.39,1.57)0.48
TT5 (5.2)1.30 (0.46,3.70)0.6217 (6.9)1.02 (0.51,2.04)0.9520 (7.5)1.41 (0.51,3.92)0.51
CT+TT190.99 (0.55,1.80)0.97480.90 (0.57,1.41)0.65500.95 (0.52,1.73)0.86
C Allele170 (87.6)1 427 (86.8)1 464 (86.9)1
T Allele24 (12.4)1.0 (0.65,1.78)0.7765 (13.2)1.01 (0.70,1.45)0.9670 (13.1)0.94 (0.57,1.54)0.79

{ label (or @symbol) needed for fn[@id='tfn7-mmr-20-03-2177'] } The two-sided χ2 test or Fisher's exact test was used in the comparison of allele distributions.

a CHB vs. LC

b LC vs. HCC

c CHB vs. HCC, adjusted for age, gender, smoking and alcohol consumption by logistic regression analysis. APOBEC3, apolipoprotein B mRNA-editing catalytic polypeptide-like 3; SNPs, single nucleotide polymorphisms; CHB, chronic hepatitis B; LC, liver cirrhosis; HCC, hepatocellular carcinoma; OR, odds ratio; CI, confidence intervals.

Table IV.

Genotype and allele frequencies of three SNPs of APOBEC3B.

Table IV.

Genotype and allele frequencies of three SNPs of APOBEC3B.

A, Rs2267398 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec
Number detectedn=96 n=256 n=272
CC28 (29.2)1 90 (35.2)1 93 (34.2)1
CT50 (52.1)0.75 (0.44,1.29)0.31125 (48.8)1.11 (0.75,1.63)0.61135 (49.6)0.85 (0.50,1.47)0.57
TT18 (18.8)0.71 (0.35,1.44)0.3441 (16.0)1.15 (0.68,1.94)0.6144 (16.2)0.77 (0.38,1.56)0.47
CT+TT680.74 (0.44,1.24)0.261661.12 (0.77,1.61)0.561790.83 (0.50,1.39)0.49
C Allele106 (55.2)1 305 (59.6)1 321 (59.0)1
T Allele86 (44.8)0.84 (0.60,1.17)0.30207 (40.4)0.98 (0.76,1.25)0.85223 (41.0)1.17 (0.84,1.63)0.36

B, Rs2267401 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec

Number detectedn=102 n=265 n=284
GG25 (24.5)1 58 (21.9) 63 (22.2)
GT29 (28.4)0.93 (0.49,1.77)0.8265 (24.5)0.89 (0.53,1.46)0.6261 (21.5)0.88 (0.47,1.69)0.69
TT48 (47.1)1.25 (0.70,2.22)0.45142 (53.6)1.00 (0.65,1.54)0.99160 (56.3)1.29 (0.72,2.29)0.39
GT+TT771.13 (0.66,1.93)0.672070.97 (0.64,1.46)0.872211.13 (0.66,1.93)0.65
G Allele79 (38.7)1 181 (34.2)1 187 (32.9)1
T Allele125 (61.3)1.22 (0.87,1.70)0.25349 (65.8)0.95 (0.74,1.22)0.67381 (67.1)1.00 (0.71,1.42)0.98
C, Rs2076109 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec

Number detectedn=94 n=234 n=246
AA24 (25.5)1 57 (24.4)1 54 (22.0)1
AG20 (21.3)1.30 (0.65,2.61)0.4662 (26.5)1.12 (0.67,1.89)0.6764 (26.0)1.70 (0.83,3.50)0.15
GG50 (53.2)0.95 (0.53,1.71)0.87115 (49.1)0.13 (0.72,1.79)0.59128 (52.0)1.21 (0.67,2.21)0.53
AG+GG701.05 (0.61,1.83)0.861771.13 (0.73,1.74)0.581921.03 (0.63,1.69)0.89
A Allele68 (36.2)1 176 (37.6)1 172 (35.0)1
G Allele120 (63.8)0.94 (0.66,1.37)0.73292 (62.4)0.89 (0.69,1.16)0.39320 (65.0)1.35 (0.76,2.39)0.31

{ label (or @symbol) needed for fn[@id='tfn11-mmr-20-03-2177'] } The two-sided χ2 test or Fisher's exact test was used in the comparison of allele distributions.

a CHB vs. LC

b LC vs. HCC

c CHB vs. HCC, adjusted for age, gender, smoking and alcohol consumption by logistic regression analysis. APOBEC3, apolipoprotein B mRNA-editing catalytic polypeptide-like 3; SNPs, single nucleotide polymorphisms; CHB, chronic hepatitis B; LC, liver cirrhosis; HCC, hepatocellular carcinoma; OR, odds ratio; CI, confidence intervals.

Table V.

Genotype and allele frequencies of five SNPs of APOBEC3H.

Table V.

Genotype and allele frequencies of five SNPs of APOBEC3H.

A, Rs56695217 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec
Number detectedn=89 n=235 n=241
CC11 (12.4)1 29 (12.3) 26 (10.8)
CG76 (85.4)1.03 (0.49,2.17)0.94203 (86.4)1.26 (0.71,2.25)0.43214 (88.8)1.17 (0.54,2.56)0.69
GG2 (2.2)0.60 (0.09,4.13)0.603 (1.3)0.34 (0.03,3.64)0.361 (0.4)0.11 (0.01,1.37)0.08
CG+GG781.02 (0.48,2.15)0.962061.25 (0.70,2.22)0.452151.14 (0.53,2.47)0.74
C Allele98 (55.1)1 261 (55.5)1 266 (55.2)1
G Allele80 (44.9)0.98 (0.69,1.39)0.91209 (44.5)0.99 (0.76,1.27)0.92216 (44.8)1.00 (0.71,1.42)0.98

B, Rs139292 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec

Number detectedn=95 n=247 n=250
DEL42 (44.2)1 111 (44.9)1 112 (44.8)1
CAA.DEL53 (55.8)0.97 (0.60,1.57)0.90134 (54.3)1.04 (0.72,1.49)0.84137 (54.8)1.03 (0.91,0.63)0.91
CAA0 (0.0)0.73 (0.66,0.80)1.002 (0.8)0.50 (0.60,7.09)0.681 (0.4)0.73 (0.66,0.80)1.00
DEL+CAA530.99 (0.61,1.60)0.951361.03 (0.72,1.48)0.861381.03 (0.63,1.69)0.89
DEL Allele137 (72.1)1 356 (72.1)1 361 (72.2)1
CAA Allele  53 (27.9)0.69 (1.00,1.46)1.00138 (27.9)0.99 (0.75,1.31)1.00139 (27.8)0.99 (0.69,1.45)1.00

C, Rs139297 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec

Number detectedn=102 n=263 n=280
CC41 (40.2)1 115 (43.7)1 118 (42.1)1
CG16 (15.7)0.84 (0.42,1.68)0.6338 (14.4)0.95 (056,1.62)0.8536 (12.9)0.85 (0.42,1.72)0.65
GG45 (44.1)0.87 (0.52,1.44)0.58110 (41.8)1.78 (0.81,1.70)0.39126 (45.0)1.07 (0.64,1.79)0.79
CG+GG610.86 (0.54,1.38)0.531431.12 (0.79,1.58)0.531741.01 (0.63,1.63)0.97
C Allele98 (49.4)1 268 (49.8) 272 (77.0)1
G Allele106 (50.6)0.89 (0.64,1.23)0.48258 (50.2)1.15 (0.89,1.48)0.28288 (23.0)0.98 (0.71,1.35)0.90

D, Rs139302 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec

Number detectedn=89 n=229 n=255
CC34 (38.2)1 86 (37.6)1 81 (31.8)1
CG20 (22.5)1.1 (0.57,2.11)0.7956 (24.5)1.38 (0.86,2.20)0.1874 (29.0)1.53 (0.80,2.94)0.20
GG35 (39.3)0.98 (0.55,1.72)0.9387 (30.8)1.25 (0.82,1.91)0.30100 (39.2)1.31 (0.73,2.33)0.37
CG+GG551.02 (0.61,1.70)0.941431.30 (0.89,1.90)0.181741.39 (0.83,2.24)0.21
C Allele88 (49.4)1 228 (49.8)1 236 (46.3)1
G Allele90 (50.6)0.99 (0.70,1.40)0.94230 (50.2)0.87 (0.68,1.12)0.28274 (53.7)0.88 (0.63,1.24)0.47

E, Rs139316 genotype and allele

CHB patients (n=104)LC patients (n=265)HCC patients (n=287)



SNPN (%)OR (95%Cl) P-valueaN (%)OR (95%Cl) P-valuebN (%)OR (95%Cl) P-valuec

Number detectedn=103 n=263 n=281
CC17 (16.5)1 43 (16.3)1 37 (13.2)1
CT46 (44.7)1.02 (0.52,1.97)0.96117 (44.5)0.26 (0.75,2.10)0.39133 (47.3)1.36 (0.69,2.69)0.38
TT40 (38.8)1.01 (0.51,2.00)0.97103 (39.2)1.24 (0.73,2.10)0.42111 (39.5)1.40 (0.69,2.77)0.37
CT+TT861.01 (0.54,1.89)0.972201.25 (0.77,2.03)0.372441.37 (0.72,2.60)0.34
C Allele80 (38.3)1 203 (38.6)1 207 (36.8)1
T Allele126 (61.2)1.01 (0.73,1.41)0.95323 (61.4)0.93 (0.73,1.86)0.55355 (63.2)1.09 (0.78,1.51)0.61

{ label (or @symbol) needed for fn[@id='tfn15-mmr-20-03-2177'] } The two-sided χ2 test or Fisher's exact test was used in the comparison of allele distributions.

a CHB vs. LC

b LC vs. HCC

c CHB vs. HCC, adjusted for age, gender, smoking and alcohol consumption by logistic regression analysis. APOBEC3, apolipoprotein B mRNA-editing catalytic polypeptide-like 3; SNPs, single nucleotide polymorphisms; CHB, chronic hepatitis B; LC, liver cirrhosis; HCC, hepatocellular carcinoma; OR, odds ratio; CI, confidence intervals.

Haplotype analysis of A3A, A3B and A3H

Haplotype analysis was also performed on the two A3A SNPs, three A3B SNPs and five A3H SNPs using Unphased version 3.1.4. No haplotypes were found for the two A3A SNPs or five A3H SNPs (data not shown). The distribution of the A3B haplotype rs2267398-rs2267401-rs2076109 was significantly different between the LC and HCC groups (Table VI). The C-G-G haplotype was used as a reference, with the results showing that the mutant C-T-A, C-T-G, T-G-G and T-T-G haplotypes of rs2267398-rs2267401-rs2076109 were associated with a lower risk of HCC compared with the reference haplotype (Table VII).

Table VI.

Distributions of SNPs of apolipoprotein B mRNA-editing catalytic polypeptide-like 3B in the different groups.

Table VI.

Distributions of SNPs of apolipoprotein B mRNA-editing catalytic polypeptide-like 3B in the different groups.

GroupsSNPsχ2dfP-value
CHB vs. LC rs2267398-rs22674013.8730.276
rs2267398-rs20761095.2530.153
rs2267401-rs20761092.5130.472
rs2267398-rs226740-rs20761097.3360.291
CHB vs. HCC rs2267398-rs22674011.0130.798
rs2267398-rs20761090.14930.985
rs2267401-rs20761090.40530.939
rs2267398-rs2267401-rs20761091.76460.940
LC vs. HCC rs2267398-rs22674018.21030.042
rs2267398-rs20761091.36830.713
rs2267401-rs20761093.27830.351
rs2267398-rs2267401-rs207610914.2560.027

[i] CHB, chronic hepatitis B; LC, liver cirrhosis; HCC, hepatocellular carcinoma; SNP, single nucleotide polymorphism.

Table VII.

Analysis of the rs2267398-rs2267401-rs2076109 haplotypes of apolipoprotein B mRNA-editing catalytic polypeptide-like 3B in patients with LC and HCC.

Table VII.

Analysis of the rs2267398-rs2267401-rs2076109 haplotypes of apolipoprotein B mRNA-editing catalytic polypeptide-like 3B in patients with LC and HCC.

HaplotypeLC (%)HCC (%)OR (95%CI)P-value
C-G-G8 (1.1)9 (5.6)1
C-T-A254 (33.8)56 (34.6)0.19 (0.07, 0.53)<0.001
C-T-G191 (25.4)35 (21.6)0.16 (0.06, 0.45)<0.001
T-G-A2 (0.3)0 (0.0)0.47 (0.28,0.78)0.474
T-G-G246 (32.7)50 (30.9)0.18 (0.07, 0.49)<0.001
T-T-A25 (3.3)10 (6.2)0.36 (0.11,1.18)0.087
T-T-G26 (3.5)2 (1.2)0.07 (0.01, 0.38)0.001

[i] CHB, hepatitis B virus; LC, liver cirrhosis; HCC, hepatocellular carcinoma; OR, odds ratio; CI, confidence intervals.

Discussion

It is estimated that ~55% of HCC cases are associated with CHB (29,30). Members of the A3 protein family have been reported to edit the HBV genome and reduce HBV replication in vivo and in vitro (31,32). However, the effects of the SNPs of A3 genes have not yet been evaluated in a Chinese population. To the best of the authors' knowledge, the present study is the first to investigate the association between A3A, A3B and A3H SNPs and the development of CHB and HBV-related HCC in a Chinese population. There were two major findings of the present study: i) The rs7286317 and rs7290153 SNPs of A3A, and the rs56695217, rs139292, rs139297, rs139302 and rs139316 SNPs of A3H, had no relationship with CHB progression or HCC development; and ii) the rs2267398, rs2267401 and rs2076109 SNPs of A3B may not affect the likelihood of CHB progression or HCC development. However, the C-T-A, C-T-G, T-G-G and T-T-G haplotypes of rs2267398-rs2267401-rs2076109 were associated with a lower risk of HCC development than the reference haplotype C-G-G.

APOBEC cytosine deaminases are known to confer innate immunity against retroviruses by generating lethal hypermutations in viral genomes (33). Köck and Blum (31) assessed the ability of A3G, A3C and A3H to edit HBV genomes, finding that each gene could edit HBV DNA and that each protein was likely to contribute (to varying degrees) to genome modification in human liver cells. Previously, it was demonstrated that the A3G rs8177832 SNP was associated with a decreased risk of CHB infection and HCC, while the rs2011861 SNP was associated with an increased risk of HCC (23). Furthermore, it has been shown that A3A is an efficient HBV DNA editor, while A3A and A3B serve crucial roles in inducing the degradation of HBV covalently closed circular DNA (34). Therefore, it was speculated that these three genes may be associated with disease progression following HBV infection.

The present study analyzed the association between A3A, A3B and A3H SNPs and the progression of HBV infection. A total of 654 patients were included in the study, consisting of 104 patients with CHB, 265 patients with HBV-related LC and 285 patients with HBV-related HCC. However, the results demonstrated that the SNPs of these three genes were not associated with disease progression following HBV infection. Haplotype analysis suggested that the C-T-A, C-T-G, T-G-G and T-T-G haplotypes of rs2267398-rs2267401-rs2076109 were associated with a lower risk of HCC compared with the reference haplotype C-G-G. It was hypothesized that this may be due to the linkage between different functional genes. Previous studies have shown that APOBEC-specific mutations are common in tumor genomes (35,36) and that the expression level of APOBEC mRNA is positively correlated with the APOBEC-specific mutation rate (37). In vitro, A3B has been shown to promote the proliferation of the hepatoma cell line HepG2 by upregulating the expression of heat shock protein 1 (38). Therefore, A3B may be the predominant APOBEC-specific mutation-inducing gene in the development of primary liver cancer. Notably, clinical data have demonstrated that the deletion of ~29.5 kb between A3A exon 5 and A3B exon 8 causes the loss of the entire A3B coding region and increases the risk of HCC (39,40). Furthermore, genome sequencing has revealed that A3B deletion can increase the APOBEC-specific mutation rate in the tumor genome (38). Consequently, it has been hypothesized that A3B gene deletion may cause the expression of A3AΔA3B (A3A after A3B deletion) to be more stable and efficient (41,42) and that A3AΔA3B may be the predominant mutagenic factor. Therefore, haplotype changes may affect HCC occurrence by altering the gene expression and editing the functions of A3A and A3B. However, the exact mechanisms by which this occurs requires further investigation.

The present study had a number of limitations. First, healthy controls were not enrolled in this study to evaluate the effect of the A3A, A3B and A3H SNPs on susceptibility to HBV infection. Second, some disease factors were not considered in the present study, such as the age at which HBV infection occurred, which is closely associated with the outcome of HBV infection (43). However, exact HBV infection age data are not available from most places in China due to socioeconomic factors. According to previous studies, ~90% of infants infected perinatally become chronic carriers, unless vaccinated at birth. The risk of CHB decreases to 30% in children infected between ages 1 and 4 years, and to <5% in persons infected as adults (4446). Therefore, most patients with CHB infection are likely to have been infected in infancy. Since it was not possible to acquire the exact infection age, the present study assumed the age of patients as the length of infection. Therefore, age-matched patients with CHB, HBV-related LC and HBV-related HCC were recruited. Third, the associations were analyzed solely by statistical analysis and were not validated experimentally. Therefore, further studies using larger sample sizes from different populations alongside experimental validation should be conducted to verify the results of the present study.

In conclusion, the present study demonstrated that there was no association between the rs7286317 and rs7290153 SNPs of A3A, the rs2267398, rs2267401 and rs2076109 SNPs of A3B, and the rs56695217, rs139292, rs139297, rs139302 and rs139316 SNPs of A3H and CHB progression or HCC development. However, the C-T-A, C-T-G, T-G-G and T-T-G haplotypes of rs2267398-rs2267401-rs2076109 were associated with a lower risk of HCC than the reference haplotype C-G-G.

Acknowledgements

Not applicable.

Funding

The present study was supported by The Youth Development Science Foundation of the First Hospital of Jilin University (grant no. JDYY82017023).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

XH, JN and PG conceived and designed the study. XH, HX and XW acquired the data. HX and JN analyzed and interpreted the data. JW performed the statistical analysis. XH drafted the manuscript. JN and PG revised the manuscript for important intellectual content. All authors given final approval of the version to be published.

Ethics approval and consent to participate

The present study was approved by the First Hospital Ethical Committee of Jilin University. Written informed consent was obtained from all participants.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

APOBEC3

apolipoprotein B mRNA-editing catalytic polypeptide-like 3

SNPs

single nucleotide polymorphisms

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

CHB

chronic hepatitis B

LC

liver cirrhosis

HIV-1

human immunodeficiency virus 1

HBeAg

hepatitis B e antigen

HBeAb

hepatitis B e antibody

UTRs

untranslated regions

OR

odds ratio

CI

confidence intervals

References

1 

Sawai H, Nishida N, Khor SS, Honda M, Sugiyama M, Baba N, Yamada K, Sawada N, Tsugane S, Koike K, et al: Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma. Sci Rep. 8:79582018. View Article : Google Scholar : PubMed/NCBI

2 

Chu CM: Natural history of chronic hepatitis B virus infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol. 15 (Suppl):E25–E30. 2000. View Article : Google Scholar : PubMed/NCBI

3 

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Henderson S and Fenton T: APOBEC3 genes: Retroviral restriction factors to cancer drivers. Trends Mol Med. 21:274–284. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Teng B, Burant CF and Davidson NO: Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science. 260:1816–1819. 1993. View Article : Google Scholar : PubMed/NCBI

6 

Swanton C, McGranahan N, Starrett GJ and Harris RS: APOBEC enzymes: Mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov. 5:704–712. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Doehle BP, Schafer A and Cullen BR: Human APOBEC3B is a potent inhibitor of HIV-1 infectivity and is resistant to HIV-1 Vif. Virology. 339:281–288. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Prasetyo AA, Sariyatun R, Revion o, Sari Y, Hudiyon o, Haryati S, Adnan ZA, Harton o and Kageyama S: The APOBEC3B deletion polymorphism is associated with prevalence of hepatitis B virus, hepatitis C virus, Torque Teno virus, and Toxoplasma gondii co-infection among HIV-infected individuals. J Clin Virol. 70:67–71. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Berger G, Durand S, Fargier G, Nguyen XN, Cordeil S, Bouaziz S, Muriaux D, Darlix JL and Cimarelli A: APOBEC3A is a specific inhibitor of the early phases of HIV-1 infection in myeloid cells. PLoS Pathog. 7:e10022212011. View Article : Google Scholar : PubMed/NCBI

10 

Nakaya Y, Stavrou S, Blouch K, Tattersall P and Ross SR: In vivo examination of mouse APOBEC3- and human APOBEC3A- and APOBEC3G-mediated restriction of parvovirus and herpesvirus infection in mouse models. J Virol. 90:8005–8012. 2016. View Article : Google Scholar : PubMed/NCBI

11 

Minkah N, Chavez K, Shah P, Maccarthy T, Chen H, Landau N and Krug LT: Host restriction of murine gammaherpesvirus 68 replication by human APOBEC3 cytidine deaminases but not murine APOBEC3. Virology. 454-455:215–226. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Henry M, Guetard D, Suspene R, Rusniok C, Wain-Hobson S and Vartanian JP: Genetic editing of HBV DNA by monodomain human APOBEC3 cytidine deaminases and the recombinant nature of APOBEC3G. PLoS One. 4:e42772009. View Article : Google Scholar : PubMed/NCBI

13 

Warren CJ, Xu T, Guo K, Griffin LM, Westrich JA, Lee D, Lambert PF, Santiago ML and Pyeon D: APOBEC3A functions as a restriction factor of human papillomavirus. J Virol. 89:688–702. 2015. View Article : Google Scholar : PubMed/NCBI

14 

OhAinle M, Kerns JA, Li MM, Malik HS and Emerman M: Antiretroelement activity of APOBEC3H was lost twice in recent human evolution. Cell Host Microbe. 4:249–259. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Gansmo LB, Romundstad P, Hveem K, Vatten L, Nik-Zainal S, Lønning PE and Knappskog S: APOBEC3A/B deletion polymorphism and cancer risk. Carcinogenesis. 39:118–124. 2018. View Article : Google Scholar : PubMed/NCBI

16 

Xuan D, Li G, Cai Q, Deming-Halverson S, Shrubsole MJ, Shu XO, Kelley MC, Zheng W and Long J: APOBEC3 deletion polymorphism is associated with breast cancer risk among women of European ancestry. Carcinogenesis. 34:2240–2243. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Long J, Delahanty RJ, Li G, Gao YT, Lu W, Cai Q, Xiang YB, Li C, Ji BT, Zheng Y, et al: A common deletion in the APOBEC3 genes and breast cancer risk. J Natl Cancer Inst. 105:573–579. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Rezaei M, Hashemi M, Hashemi SM, Mashhadi MA and Taheri M: APOBEC3 deletion is associated with breast cancer risk in a sample of southeast iranian population. Int J Mol Cell Med. 4:103–108. 2015.PubMed/NCBI

19 

Gohler S, Da Silva Filho MI, Johansson R, Enquist-Olsson K, Henriksson R, Hemminki K, Lenner P and Försti A: Impact of functional germline variants and a deletion polymorphism in APOBEC3A and APOBEC3B on breast cancer risk and survival in a Swedish study population. J Cancer Res Clin Oncol. 142:273–276. 2016. View Article : Google Scholar : PubMed/NCBI

20 

Marouf C, Gohler S, Filho MI, Hajji O, Hemminki K, Nadifi S and Försti A: Analysis of functional germline variants in APOBEC3 and driver genes on breast cancer risk in Moroccan study population. BMC Cancer. 16:1652016. View Article : Google Scholar : PubMed/NCBI

21 

Klonowska K, Kluzniak W, Rusak B, Jakubowska A, Ratajska M, Krawczynska N, Vasilevska D, Czubak K, Wojciechowska M, Cybulski C, et al: The 30 kb deletion in the APOBEC3 cluster decreases APOBEC3A and APOBEC3B expression and creates a transcriptionally active hybrid gene but does not associate with breast cancer in the European population. Oncotarget. 8:76357–76374. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Zhu M, Wang Y, Wang C, Shen W, Liu J, Geng L, Cheng Y, Dai J, Jin G, Ma H, et al: The eQTL-missense polymorphisms of APOBEC3H are associated with lung cancer risk in a Han Chinese population. Sci Rep. 5:149692015. View Article : Google Scholar : PubMed/NCBI

23 

He XT, Xu HQ, Wang XM, He XS, Niu JQ and Gao PJ: Association between polymorphisms of the APOBEC3G gene and chronic hepatitis B viral infection and hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol. 23:232–241. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Pons F, Varela M and Llovet JM: Staging systems in hepatocellular carcinoma. HPB (Oxford). 7:35–41. 2005. View Article : Google Scholar : PubMed/NCBI

25 

Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D and Burroughs AK: Systematic review: The model for end-stage liver disease-should it replace Child-Pugh's classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther. 22:1079–1089. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Selby LK, Tay RX, Woon WW, Low JK, Bei W, Shelat VG, Pang TC and Junnarkar SP: Validity of the barcelona clinic liver cancer and hong kong liver cancer staging systems for hepatocellular carcinoma in singapore. J Hepatobiliary Pancreat Sci. 24:143–152. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Dohi H, Ishizuka M, Minoshima S and Shimizu N: GeneView: Multi-language human gene mapping library with a graphical user interface. Comput Appl Biosci. 9:459–464. 1993.PubMed/NCBI

28 

Dudbridge F: Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered. 66:87–98. 2008. View Article : Google Scholar : PubMed/NCBI

29 

Cougot D, Neuveut C and Buendia MA: HBV induced carcinogenesis. J Clin Virol. 34 (Suppl 1):S75–S78. 2005. View Article : Google Scholar : PubMed/NCBI

30 

Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Kock J and Blum HE: Hypermutation of hepatitis B virus genomes by APOBEC3G, APOBEC3C and APOBEC3H. J Gen Virol. 89:1184–1191. 2008. View Article : Google Scholar : PubMed/NCBI

32 

Suspene R, Guetard D, Henry M, Sommer P, Wain-Hobson S and Vartanian JP: Extensive editing of both hepatitis B virus DNA strands by APOBEC3 cytidine deaminases in vitro and in vivo. Proc Natl Acad Sci USA. 102:8321–8326. 2005. View Article : Google Scholar : PubMed/NCBI

33 

Chiu YL and Greene WC: The APOBEC3 cytidine deaminases: An innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu Rev Immunol. 26:317–353. 2008. View Article : Google Scholar : PubMed/NCBI

34 

Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl MF, Koppensteiner H, Makowska Z, Volz T, et al: Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 343:1221–1228. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, Kiezun A, Kryukov GV, Carter SL, Saksena G, et al: An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet. 45:970–976. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, et al: Signatures of mutational processes in human cancer. Nature. 500:415–421. 2013. View Article : Google Scholar : PubMed/NCBI

37 

Burns MB, Temiz NA and Harris RS: Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet. 45:977–983. 2013. View Article : Google Scholar : PubMed/NCBI

38 

Xu R, Zhang X, Zhang W, Fang Y, Zheng S and Yu XF: Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B × antigen mutants and hepatocellular carcinoma. Hepatology. 46:1810–1820. 2007. View Article : Google Scholar : PubMed/NCBI

39 

Zhang T, Cai J, Chang J, Yu D, Wu C, Yan T, Zhai K, Bi X, Zhao H, Xu J, et al: Evidence of associations of APOBEC3B gene deletion with susceptibility to persistent HBV infection and hepatocellular carcinoma. Hum Mol Genet. 22:1262–1269. 2013. View Article : Google Scholar : PubMed/NCBI

40 

He X, Li J, Wu J, Zhang M and Gao P: Associations between activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like cytidine deaminase expression, hepatitis B virus (HBV) replication and HBV-associated liver disease (Review). Mol Med Rep. 12:6405–6414. 2015. View Article : Google Scholar : PubMed/NCBI

41 

Chan K, Roberts SA, Klimczak LJ, Sterling JF, Saini N, Malc EP, Kim J, Kwiatkowski DJ, Fargo DC, Mieczkowski PA, et al: An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet. 47:1067–1072. 2015. View Article : Google Scholar : PubMed/NCBI

42 

Caval V, Suspene R, Shapira M, Vartanian JP and Wain-Hobson S: A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3′UTR enhances chromosomal DNA damage. Nat Commun. 5:51292014. View Article : Google Scholar : PubMed/NCBI

43 

Gerlich WH: Medical virology of hepatitis B: How it began and where we are now. Virol J. 10:2392013. View Article : Google Scholar : PubMed/NCBI

44 

Hyams KC: Risks of chronicity following acute hepatitis B virus infection: A review. Clin Infect Dis. 20:992–1000. 1995. View Article : Google Scholar : PubMed/NCBI

45 

McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP and Maynard JE: Acute hepatitis B virus infection: Relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis. 151:599–603. 1985. View Article : Google Scholar : PubMed/NCBI

46 

Ott JJ, Stevens GA, Groeger J and Wiersma ST: Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 30:2212–2219. 2012. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September 2019
Volume 20 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
He, X., Xu, H., Wang, X., Wu, J., Niu, J., & Gao, P. (2019). Associations between the single nucleotide polymorphisms of APOBEC3A, APOBEC3B and APOBEC3H, and chronic hepatitis B progression and hepatocellular carcinoma in a Chinese population. Molecular Medicine Reports, 20, 2177-2188. https://doi.org/10.3892/mmr.2019.10455
MLA
He, X., Xu, H., Wang, X., Wu, J., Niu, J., Gao, P."Associations between the single nucleotide polymorphisms of APOBEC3A, APOBEC3B and APOBEC3H, and chronic hepatitis B progression and hepatocellular carcinoma in a Chinese population". Molecular Medicine Reports 20.3 (2019): 2177-2188.
Chicago
He, X., Xu, H., Wang, X., Wu, J., Niu, J., Gao, P."Associations between the single nucleotide polymorphisms of APOBEC3A, APOBEC3B and APOBEC3H, and chronic hepatitis B progression and hepatocellular carcinoma in a Chinese population". Molecular Medicine Reports 20, no. 3 (2019): 2177-2188. https://doi.org/10.3892/mmr.2019.10455