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
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.
. [J]. Frontiers of Medicine, 2014, 8(2): 217-226.
Du Yan, Han Xue, Pu Rui, Xie Jiaxin, Zhang Yuwei, Cao Guangwen. 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. Front. Med., 2014, 8(2): 217-226.
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\del
1.00
1.00
1.00
1.00
1.00
del\ins
0.99 (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\ins
1.11 (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 c
1.01 (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 d
1.11 (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\del
1.00
1.00
1.00
1.00
1.00
del\ins
0.94 (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\ins
0.99 (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 c
0.91 (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 d
1.06 (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\del
1.00
1.00
1.00
1.00
1.00
del\ins
1.01 (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\ins
1.12 (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 c
1.04 (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 d
1.10 (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
Variables
Adjusted 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/G
2.18 (1.46-3.24)
<0.000
A1762T/G1764A
2.38 (1.65-3.43)
<0.0001
G1896A
2.07 (1.49-2.86)
<0.0001
T1753V
1.55 (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 C
4.19 (2.11-8.34)
<0.0001
preS deletion
1.92 (1.24-2.96)
0.004
preS2 start codon mutation
1.97 (1.23-3.15)
0.005
C2875A
2.22 (1.34-3.70)
0.002
C76A
9.51 (4.22-21.44)
<0.0001
C7A
3.92 (2.25-6.82)
0.000
Tab.4
rs3783553
HBV mutation
Females
Males
Non-HCCa
HCCb
OR (95% CI)
Adjusted OR (95% CI)c
Non-HCCa
HCCb
OR (95% CI)
Adjusted OR (95% CI)c
T1674C/G
del/del
T
54
21
Ref
Ref
136
118
Ref
Ref
del/del
C/G
13
11
2.18 (0.84-5.62)
3.27 (1.06-10.09)
24
66
3.17 (1.87-5.38)
2.83 (1.56-5.13)
ins/del
T
51
18
0.91 (0.43-1.90)
0.93 (0.62-1.38)
140
118
0.97 (0.69-1.38)
0.97 (0.80-1.17)
ins/del
C/G
6
23
9.86 (3.52-27.62)
11.06 (3.57-34.28)
27
53
2.26 (1.34-3.82)
1.89 (1.04-3.45)
For interaction
2.23 (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/del
AG/AA/TG
48
9
Ref
Ref
88
37
Ref
Ref
del/del
TA
34
23
3.61 (1.49-8.76)
4.28 (1.49-12.29)
88
142
3.84 (2.41-6.12)
3.48 (2.07-5.85)
ins/del
AG/AA/TG
57
8
0.75 (0.27-2.09)
0.78 (0.46-1.35)
85
33
0.92 (0.53-1.61)
0.98 (0.73-1.33)
ins/del
TA
22
35
8.48 (3.49-20.65)
10.94 (3.56-33.61)
92
130
3.36 (2.11-5.37)
2.89 (1.76-4.74)
For interaction
1.77 (0.94-3.35)
1.96 (0.99-3.88)
0.97 (0.70-1.36)
0.91 (0.64-1.30)
G1896A
del/del
G
64
20
Ref
Ref
123
73
Ref
Ref
del/del
A
18
13
2.31 (0.97-5.53)
2.22 (0.83-5.98)
59
89
2.54 (1.64-3.94)
2.31 (1.40-3.79)
ins/del
G
59
19
1.03 (0.50-2.12)
0.94 (0.61-1.43)
125
78
1.05 (0.70-1.58)
0.98 (0.79-1.23)
ins/del
A
22
22
3.20 (1.47-6.95)
2.94 (1.29-6.71)
54
76
2.37 (1.51-3.73)
2.01 (1.22-3.31)
For interaction
1.16 (0.65-2.08)
1.22 (0.63-2.36)
0.94 (0.69-1.29)
0.94 (0.67-1.32)
T1753V
del/del
T
70
19
Ref
Ref
156
118
Ref
Ref
del/del
V
14
13
3.42 (1.38-8.49)
4.74 (1.65-13.60)
26
61
3.10 (1.85-5.21)
3.24 (1.80-5.81)
ins/del
T
73
29
1.46 (0.75-2.85)
1.21 (0.85-1.73)
157
110
0.93 (0.66-1.30)
1.00 (0.83-1.21)
ins/del
V
7
12
6.32 (2.19-18.25)
7.40 (2.14-25.61)
28
53
2.50 (1.49-4.20)
1.79 (0.99-3.21)
OR for interaction
1.12 (0.57-2.23)
1.05 (0.50-2.20)
0.93 (0.65-1.35)
0.77 (0.51-1.14)
Tab.5
rs3783553
HBV mutation
Females
Males
Non-HCCa
HCCb
OR (95%CI)
Adjusted OR(95% CI)c
Non-HCCa
HCCb
OR (95%CI)
Adjusted OR (95% CI)c
preS deletion
del/del
0
54
11
Ref
Ref
102
96
Ref
Ref
del/del
1
5
14
13.75 (4.10-46.08)
11.40 (3.20-40.60)
18
48
2.83 (1.54-5.21)
2.54 (1.33-4.84)
ins/del
0
51
25
2.41(1.08-5.39)
1.48 (0.97-2.26)
83
97
1.24 (0.83-1.86)
1.18 (0.95-1.47)
ins/del
1
8
7
4.30 (1.29-14.32)
4.43 (1.27-15.46)
31
50
1.72 (1.01-2.91)
1.49 (0.85-2.61)
For interaction
0.36 (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/del
0
52
19
Ref
Ref
102
102
Ref
Ref
del/del
1
7
7
2.74 (0.85-8.84)
2.55 (0.73-8.90)
18
49
2.72 (1.49-4.99)
2.48 (1.31-4.70)
ins/del
0
53
27
1.39 (0.69-2.81)
1.19 (0.82-1.73)
95
123
1.30 (0.88-1.90)
1.16 (0.94-1.42)
ins/del
1
6
8
3.65 (1.12-11.90)
2.86 (0.84-9.75)
19
31
1.63 (0.87-3.07)
1.67 (0.85-3.28)
For interaction
0.98 (0.43-2.23)
0.89 (0.37-2.14)
0.68 (0.44-1.05)
0.70 (0.44-1.11)
C2875A
del/del
C
43
17
Ref
Ref
99
113
Ref
Ref
del/del
A
19
11
1.46 (0.58-3.72)
2.22 (0.70-7.06)
42
52
1.09 (0.67-1.77)
2.12 (1.10-4.12)
ins/del
C
46
23
1.27 (0.60-2.68)
1.14 (0.76-1.72)
94
109
1.02 (0.69-1.49)
1.00 (0.81-1.22)
ins/del
A
17
10
1.49 (0.57-3.89)
5.18 (1.37-19.58)
47
54
1.01 (0.63-1.62)
1.83 (0.96-3.48)
For interaction
0.90 (0.47-1.73)
0.77 (0.37-1.60)
0.96 (0.68-1.35)
1.02 (0.70-1.48)
C76A
del/del
C
55
19
Ref
Ref
105
117
Ref
Ref
del/del
A
3
6
5.79 (1.32-25.45)
36.94(2.75-497.51)
11
31
2.53 (1.21-5.28)
5.62 (1.98-15.98)
ins/del
C
52
33
1.84 (0.93-3.63)
1.46 (1.00-2.12)
101
123
1.09 (0.75-1.59)
1.04 (0.85-1.27)
ins/del
A
4
2
1.45 (0.25-8.55)
1.79 (0.21-15.15)
12
31
2.32 (1.13-4.75)
7.94 (2.56-24.59)
For interaction
0.37 (0.12-1.16)
0.14 (0.04-0.54)
0.92 (0.55-1.53)
1.26 (0.72-2.23)
C7A
del/del
C
30
6
Ref
Ref
50
35
Ref
Ref
del/del
A
27
18
3.33 (1.16-9.62)
2.90 (0.78-10.83)
62
102
2.35 (1.38-4.01)
2.06 (1.09-3.87)
ins/del
C
25
3
0.60 (0.14-2.65)
0.69 (0.32-1.51)
36
38
1.51 (0.81-2.83)
1.34 (0.93-1.93)
ins/del
A
31
31
5.00 (1.83-13.70)
4.30 (1.31-14.14)
70
109
2.22 (1.32-3.76)
1.94 (1.03-3.64)
OR for interaction
1.58 (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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