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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2014, Vol. 8 Issue (2) : 217-226    https://doi.org/10.1007/s11684-014-0326-2
RESEARCH ARTICLE
Association of miRNA-122-binding site polymorphism at the interleukin-1 α gene and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk
Du Yan,Han Xue2,Pu Rui,Xie Jiaxin,Zhang Yuwei,Cao Guangwen1,()
Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
Division of Chronic Diseases, Center for Disease Control and Prevention of Yangpu District, Shanghai 200090, China
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Abstract

This study was designed to investigate the contribution of miRNA-122-binding site polymorphism at the IL-1A gene and its multiplicative interactions with hepatitis B virus (HBV) mutations in the risk of hepatocellular carcinoma (HCC). A total of 1021 healthy controls, 302 HBV surface antigen (HBsAg) seroclearance subjects, and 2011 HBsAg-positive subjects (including 1021 HCC patients) were enrolled in this study. Quantitative PCR was used to genotype rs3783553. HBV mutations were determined by direct sequencing. Multivariate logistic regression analyses were performed to test the associations of rs3783553, mutations, and their interactions with the risk of HCC. No significant association was found between rs3783553 and the risk of HCC among healthy controls, HBsAg seroclearance subjects, HBsAg-positive subjects without HCC, and all controls. Additionally, rs3783553 was not significantly associated with chronic HBV infection, liver cirrhosis, HBV e antigen seroconversion, abnormal alanine aminotransferase, and high viral load (>104 copies/ml). However, the TTCA insertion allele of rs3783553 was significantly associated with an increased frequency of HBV C7A mutation compared with homozygous TTCA deletion carriers [(del/ins+ ins/ins) vs. del/del, adjusted odds ratio (OR)=1.48, 95% confidence interval (CI)=1.09-2.02, P=0.013]. Multiplicative interaction of rs3783553 with HBV preS deletion significantly reduced the risk of HCC in males, with an adjusted OR of 0.64 (95% CI=0.42-0.98; P=0.041) after age and HBV genotype were adjusted. Although rs3783553 did not significantly affect genetic susceptibility to HBV-related HCC, its variant allele may predispose the host to selecting HBV C7A mutation during evolution and significantly reduce the risk of HCC caused by HBV preS deletion. This study provides an insight into the complex host-virus interaction in HBV-induced hepatocarcinogenesis and is helpful in determining HBsAg-positive subjects who are likely to develop HCC.

Keywords hepatocellular carcinoma (HCC)      interaction      miRNA-122-binding site      IL-1A      rs3783553      hepatitis B virus (HBV) mutations     
Corresponding Author(s): Cao Guangwen   
Online First Date: 04 May 2014    Issue Date: 21 May 2014
 Cite this article:   
Du Yan,Han Xue,Pu Rui, et al. Association of miRNA-122-binding site polymorphism at the interleukin-1 α gene and its interaction with hepatitis B virus mutations with hepatocellular carcinoma risk[J]. Front. Med., 2014, 8(2): 217-226.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-014-0326-2
https://academic.hep.com.cn/fmd/EN/Y2014/V8/I2/217
CharacteristicsGroup A(n = 1012)Group B(n = 302)HBV-infected subjects without HCCgroups (n = 990)Group F(n = 1021)P value
C (n = 316)D (n = 316)E (n = 358)
Male, n (%)763 (75.40)169 (55.96)186 (58.86)230 (72.78)264 (73.74)864 (84.13)<0.001a,b,c,e,f 0.001d
Age (mean ± SD)59.56 ± 15.1058.40 ± 11.7245.08 ± 10.6144.18 ± 14.5150.68 ± 11.3452.92 ± 11.17<0.001a,b,c,d,e,f
HBV genotype, n (%)
BNANA97 (34.28)52 (25.00)56 (22.86)107 (16.39)<0.001b,c
CNANA186 (65.72)156 (75.00)189 (77.14)546 (83.61)
HBeAg, n (%)
PositiveNANA130 (41.14)132 (45.36)107 (35.55)241 (25.08)<0.001b, c
NegativeNANA186 (58.86)159 (54.64)194 (64.45)720 (74.92)
HBV DNA (log10 copies/ml) (mean±SD)NANA3.88±1.804.43±1.674.13±1.373.83±1.18<0.001c
ALT (log10 U/L)(mean±SD)NANA1.36±0.211.97±0.541.75 ± 0.441.66 ± 0.35<0.001b,c
Tab.1  
GenotypeGroup AGroup BGroups (C+ D+ E)Group FAdjusted OR (95% CI)
Group F versus group AGroup F versus group BGroup F versus Groups (C+ D+ E)Group F versus groups (A+ B+ C+ D+ E)
Total
del/del4311324394341.001.001.001.00
del/ins4631344304510.98 (0.88-1.08)1.01 (0.86-1.18)1.03 (0.94-1.14)1.01 (0.93-1.10)
ins/ins111331151131.09 (0.79-1.49)1.01 (0.63-1.62)1.08 (0.79-1.48)1.04 (0.81-1.34)
Dominant a0.98 (0.81-1.18)1.01 (0.76-1.35)1.07 (0.89-1.29)1.03 (0.88-1.20)
Recessive b1.11 (0.83-1.52)1.01 (0.65-1.56)1.03 (0.78-1.39)0.97 (0.76-1.23)
HWE P0.420.910.540.80
Females
del/del10259135591.001.001.001.00
del/ins11559130741.02 (0.81-1.28)1.08 (0.84-1.40)1.17 (0.94-1.45)1.10 (0.91-1.33)
ins/ins291244251.34 (0.69-2.57)1.89 (0.86-4.12)1.59 (0.86-2.96)1.44 (0.84-2.46)
Dominant a1.10 (0.71-1.70)1.29 (0.79-2.09)1.40 (0.93-2.11)1.25 (0.87-1.79)
Recessive b1.30 (0.70-2.38)1.69 (0.81-3.57)1.27 (0.72-2.17)0.78 (0.48-1.27)
HWE P0.690.610.170.82
Males
del/del329733043751.001.001.001.00
del/ins348753003770.97 (0.87-1.08)0.97 (0.80-1.18)1.00 (0.90-1.12)0.99 (0.91-1.09)
ins/ins822171881.04 (0.72-1.48)0.72 (0.40-1.27)0.96 (0.67-1.38)0.96 (0.72-1.28)
Dominant a0.95 (0.77-1.18)0.89 (0.61-1.28)1.00 (0.81-1.23)0.98 (0.83-1.16)
Recessive b1.08 (0.76-1.52)0.75 (0.44-1.27)0.96 (0.68-1.35)1.03 (0.78-1.35)
HWE P0.480.800.810.64
Tab.2  
GenotypeHCC-free chronic HBV infection aLCHBeAg seroconversion bAbnormal ALT (U/L) bViral load(copies/ml) b
HBV-infected ones versus healthy controlsAdjusted OR (95% CI)LC patients versus (ASCs+ CHB patients)Adjusted OR (95% CI)Negative versus positiveAdjusted OR (95% CI)<40 vs.≥40Adjusted OR (95% CI)<104 vs.≥104Adjusted OR(95% CI)
Total
del\del1.001.001.001.001.00
del\ins0.99 (0.89-1.10)0.91 (0.79-1.05)0.97 (0.87-1.08)0.95 (0.85-1.07)1.03 (0.92-1.15)
ins\ins1.11 (0.79-1.57)1.42 (0.91-2.19)0.84 (0.61-1.17)0.84 (0.59-1.19)1.04 (0.73-1.49)
Dominant c1.01 (0.82-1.23)0.93 (0.71-1.22)0.91 (0.75-1.12)0.89 (0.72-1.11)1.06 (0.85-1.31)
Recessive d1.11 (0.81-1.54)1.54 (1.03-2.33)0.86 (0.63-1.16)0.88 (0.64-1.22)1.01 (0.73-1.41)
Females
del\del1.001.001.001.001.00
del\ins0.94 (0.76-1.15)0.83 (0.62-1.11)1.09 (0.88-1.36)0.97 (0.75-1.26)1.02 (0.79-1.32)
ins\ins0.99 (0.53-1.84)1.55 (0.73-3.32)0.72 (0.40-1.29)0.68 (0.34-1.36)1.01 (0.49-2.05)
Dominant c0.91 (0.61-1.35)0.87 (0.51-1.47)1.04 (0.70-1.55)0.86 (0.53-1.38)1.03 (0.64-1.66)
Recessive d1.06 (0.60-1.89)1.82 (0.90-3.70)0.66 (0.38-1.12)0.68 (0.36-1.28)0.99 (0.51-1.92)
Males
del\del1.001.001.001.001.00
del\ins1.01 (0.89-1.14)0.94 (0.79-1.11)0.93 (0.82-1.05)0.95 (0.83-1.08)1.03 (0.91-1.17)
ins\ins1.12 (0.74-1.70)1.41 (0.82-2.41)0.90 (0.60-1.34)0.93 (0.62-1.40)1.09 (0.73-1.64)
Dominant c1.04 (0.82-1.31)0.96 (0.70-1.32)0.87 (0.69-1.10)0.90 (0.71-1.15)1.07 (0.84-1.37)
Recessive d1.10 (0.75-1.61)1.52 (0.92-2.50)0.97 (0.67-1.41)0.99 (0.68-1.45)1.05 (0.71-1.56)
Tab.3  
VariablesAdjusted OR (95% CI)P value
HBV EnhII/BCP/PC region
Age (year)1.04 (1.03-1.06)<0.0001
Gender (male)1.74 (1.20-2.54)0.004
T1674C/G2.18 (1.46-3.24)<0.000
A1762T/G1764A2.38 (1.65-3.43)<0.0001
G1896A2.07 (1.49-2.86)<0.0001
T1753V1.55 (1.03-2.33)0.037
HBV preS region
Age (year)1.05 (1.04-1.07)<0.0001
Gender (male)2.62 (1.73-3.99)<0.0001
HBV Genotype C4.19 (2.11-8.34)<0.0001
preS deletion1.92 (1.24-2.96)0.004
preS2 start codon mutation1.97 (1.23-3.15)0.005
C2875A2.22 (1.34-3.70)0.002
C76A9.51 (4.22-21.44)<0.0001
C7A3.92 (2.25-6.82)0.000
Tab.4  
rs3783553HBV mutationFemalesMales
Non-HCCaHCCbOR (95% CI)Adjusted OR (95% CI)cNon-HCCaHCCbOR (95% CI)Adjusted OR (95% CI)c
T1674C/G
del/delT5421RefRef136118RefRef
del/delC/G13112.18 (0.84-5.62)3.27 (1.06-10.09)24663.17 (1.87-5.38)2.83 (1.56-5.13)
ins/delT51180.91 (0.43-1.90)0.93 (0.62-1.38)1401180.97 (0.69-1.38)0.97 (0.80-1.17)
ins/delC/G6239.86 (3.52-27.62)11.06 (3.57-34.28)27532.26 (1.34-3.82)1.89 (1.04-3.45)
For interaction2.23 (1.10-4.53)2.06 (0.96-4.40)0.86 (0.59-1.24)0.85 (0.57-1.28)
A1762T/G1764A
del/delAG/AA/TG489RefRef8837RefRef
del/delTA34233.61 (1.49-8.76)4.28 (1.49-12.29)881423.84 (2.41-6.12)3.48 (2.07-5.85)
ins/delAG/AA/TG5780.75 (0.27-2.09)0.78 (0.46-1.35)85330.92 (0.53-1.61)0.98 (0.73-1.33)
ins/delTA22358.48 (3.49-20.65)10.94 (3.56-33.61)921303.36 (2.11-5.37)2.89 (1.76-4.74)
For interaction1.77 (0.94-3.35)1.96 (0.99-3.88)0.97 (0.70-1.36)0.91 (0.64-1.30)
G1896A
del/delG6420RefRef12373RefRef
del/delA18132.31 (0.97-5.53)2.22 (0.83-5.98)59892.54 (1.64-3.94)2.31 (1.40-3.79)
ins/delG59191.03 (0.50-2.12)0.94 (0.61-1.43)125781.05 (0.70-1.58)0.98 (0.79-1.23)
ins/delA22223.20 (1.47-6.95)2.94 (1.29-6.71)54762.37 (1.51-3.73)2.01 (1.22-3.31)
For interaction1.16 (0.65-2.08)1.22 (0.63-2.36)0.94 (0.69-1.29)0.94 (0.67-1.32)
T1753V
del/delT7019RefRef156118RefRef
del/delV14133.42 (1.38-8.49)4.74 (1.65-13.60)26613.10 (1.85-5.21)3.24 (1.80-5.81)
ins/delT73291.46 (0.75-2.85)1.21 (0.85-1.73)1571100.93 (0.66-1.30)1.00 (0.83-1.21)
ins/delV7126.32 (2.19-18.25)7.40 (2.14-25.61)28532.50 (1.49-4.20)1.79 (0.99-3.21)
OR for interaction1.12 (0.57-2.23)1.05 (0.50-2.20)0.93 (0.65-1.35)0.77 (0.51-1.14)
Tab.5  
rs3783553HBV mutationFemalesMales
Non-HCCaHCCbOR (95%CI)Adjusted OR(95% CI)cNon-HCCaHCCbOR (95%CI)Adjusted OR (95% CI)c
preS deletion
del/del05411RefRef10296RefRef
del/del151413.75 (4.10-46.08)11.40 (3.20-40.60)18482.83 (1.54-5.21)2.54 (1.33-4.84)
ins/del051252.41(1.08-5.39)1.48 (0.97-2.26)83971.24 (0.83-1.86)1.18 (0.95-1.47)
ins/del1874.30 (1.29-14.32)4.43 (1.27-15.46)31501.72 (1.01-2.91)1.49 (0.85-2.61)
For interaction0.36 (0.16-0.82)0.46 (0.19-1.11)0.70 (0.47-1.05)0.64 (0.42-0.98)
preS2 start codon mutation
del/del05219RefRef102102RefRef
del/del1772.74 (0.85-8.84)2.55 (0.73-8.90)18492.72 (1.49-4.99)2.48 (1.31-4.70)
ins/del053271.39 (0.69-2.81)1.19 (0.82-1.73)951231.30 (0.88-1.90)1.16 (0.94-1.42)
ins/del1683.65 (1.12-11.90)2.86 (0.84-9.75)19311.63 (0.87-3.07)1.67 (0.85-3.28)
For interaction0.98 (0.43-2.23)0.89 (0.37-2.14)0.68 (0.44-1.05)0.70 (0.44-1.11)
C2875A
del/delC4317RefRef99113RefRef
del/delA19111.46 (0.58-3.72)2.22 (0.70-7.06)42521.09 (0.67-1.77)2.12 (1.10-4.12)
ins/delC46231.27 (0.60-2.68)1.14 (0.76-1.72)941091.02 (0.69-1.49)1.00 (0.81-1.22)
ins/delA17101.49 (0.57-3.89)5.18 (1.37-19.58)47541.01 (0.63-1.62)1.83 (0.96-3.48)
For interaction0.90 (0.47-1.73)0.77 (0.37-1.60)0.96 (0.68-1.35)1.02 (0.70-1.48)
C76A
del/delC5519RefRef105117RefRef
del/delA365.79 (1.32-25.45)36.94(2.75-497.51)11312.53 (1.21-5.28)5.62 (1.98-15.98)
ins/delC52331.84 (0.93-3.63)1.46 (1.00-2.12)1011231.09 (0.75-1.59)1.04 (0.85-1.27)
ins/delA421.45 (0.25-8.55)1.79 (0.21-15.15)12312.32 (1.13-4.75)7.94 (2.56-24.59)
For interaction0.37 (0.12-1.16)0.14 (0.04-0.54)0.92 (0.55-1.53)1.26 (0.72-2.23)
C7A
del/delC306RefRef5035RefRef
del/delA27183.33 (1.16-9.62)2.90 (0.78-10.83)621022.35 (1.38-4.01)2.06 (1.09-3.87)
ins/delC2530.60 (0.14-2.65)0.69 (0.32-1.51)36381.51 (0.81-2.83)1.34 (0.93-1.93)
ins/delA31315.00 (1.83-13.70)4.30 (1.31-14.14)701092.22 (1.32-3.76)1.94 (1.03-3.64)
OR for interaction1.58 (0.68-3.65)1.76 (0.74-4.15)0.79 (0.54-1.16)0.73 (0.48-1.10)
Tab.6  
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