A global perspective on hepatitis B‐related single nucleotide polymorphisms and evolution during human migration


A Global Perspective on Hepatitis B-
Related Single Nucleotide Polymorphisms
and Evolution During Human Migration
Dar-In Tai, Wen-Juei Jeng, and Chun-Yen Lin

Genome-wide association studies have indicated that human leukocyte antigen (HLA)-DP and HLA-DQ play roles in persis-

tent hepatitis B virus (HBV) infection in Asia. To understand the evolution of HBV-related single nucleotide polymorphisms

(SNPs) and to correlate these SNPs with chronic HBV infection among different populations, we conducted a global perspective

study on hepatitis-related SNPs. We selected 12 HBV-related SNPs on the HLA locus and two HBV and three hepatitis C

virus immune-related SNPs for analysis. Five nasopharyngeal carcinoma-related SNPs served as controls. All SNP data world-

wide from 26 populations were downloaded from 1,000 genomes. We found a dramatic difference in the allele frequency in most

of the HBV- and HLA-related SNPs in East Asia compared to the other continents. A sharp change in allele frequency in 8 of

12 SNPs was found between Bengali populations in Bangladesh and Chinese Dai populations in Xishuangbanna, China (P <

0.001); these areas represent the junction of South and East Asia. For the immune-related SNPs, significant changes were found

after leaving Africa. Most of these genes shifted from higher expression genotypes in Africa to lower expression genotypes in

either Europe or South Asia (P < 0.001). During this two-stage adaptation, immunity adjusted toward a weak immune

response, which could have been a survival strategy during human migration to East Asia. The prevalence of chronic HBV infec-

tion in Africa is as high as in Asia; however, the HBV-related SNP genotypes are not present in Africa, and so the genetic mech-

anism of chronic HBV infection in Africa needs further exploration. Conclusion: Two stages of genetic changes toward a weak

immune response occurred when humans migrated out of Africa. These changes could be a survival strategy for avoiding cyto-

kine storms and surviving in new environments. (Hepatology Communications 2017;1:1005-1013)

Introduction

C
hronic hepatitis B virus (HBV) is a global dis-
ease. The majority of carriers of hepatitis B
surface antigen (HBsAg) are inhabitants of

Africa and Asia.(1,2) Immune tolerance is a hallmark of
persistent HBV infection.(3) Typically, patients with
chronic hepatitis B are infected through their parents
in the early stage of life.(4) Remarkably, the immune
system of the host may respond to the HBV(5) but

does not produce the immune clearance of HBV.
HBV may replicate in host cells peacefully until they
enter immune clearance phases 2-4 decades later.(3) If

the HBV can be eradicated, HBV replication will be

terminated, and ultimately 50% of hosts may clear
HBsAg by 80 years of age.(6) Genome-wide associa-

tion studies from Asia have revealed that the human

leukocyte antigen (HLA)-DP and HLA-DQ loci play
roles in persistent HBV infection. (7-13) Our objective

is to understand the evolution of the single nucleotide

Abbreviations: BEB, Bengali in Bangladesh; CD40, clusters of differentiation molecule 40; CDX, Chinese Dai in Xishuangbanna, China; CFB,

complement factor B; GIH, Gujarati in India; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HLA,

human leukocyte antigen; IFNL4, interferon lambda 4; LWK, Luhya in Webuye, Kenya; NPC, nasopharyngeal carcinoma; SNP, single nucleotide

polymorphism.

Received February 26, 2017; accepted September 27, 2017.
Supported by grant CMRPG3F0331 from Chang Gung Memorial Hospital, Linkou.
Copyright VC 2017 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of

Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which

permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or

adaptations are made.

View this article online at wileyonlinelibrary.com.

DOI 10.1002/hep4.1113

Potential conflict of interest: Nothing to report.

1005

ORIGINALS | HEPATOLOGY COMMUNICATIONS, VOL. 1, NO. 10, 2017

http://creativecommons.org/licenses/by-nc-nd/4.0/


polymorphisms (SNPs) that were responsible for
HBV-related immune tolerance during human migra-
tion and to correlate the HBV-related SNPs with a
prevalence of chronic HBV infection among global
populations. Based on the data from 1,000 genomes
collected worldwide, we conducted a global perspective
study on the allele frequency of hepatitis-related SNPs.

Materials and Methods
Based on a literature review, 12 HBV- and HLA-

related SNPs,(7-13) five hepatitis- and immune-related
SNPs in complement factor B (CFB), clusters of dif-
ferentiation molecule 40 (CD40), and interferon
lambda 4 (IFNL4) loci

(14-18)
, and five nasopharyngeal

carcinoma (NPC)-related SNPs in HLA regions(19-21)

were selected for this analysis (Tables 1 and 2). These
SNP data from around the world were downloaded
from the phase 3 data of 1,000 genomes (http://www.
1000genomes.org/).

(22)
The subjects participating in

the 1,000 genome project were older than 18 years and
had three out of four grandparents who identified
themselves as members of the group. The location of
the 26 populations evaluated in the 1,000 genomes are
shown by abbreviation on a global HBsAg prevalence
map reported by Hou et al.(2) (Fig. 1). The allele fre-
quencies of different geographic groups in viral
hepatitis-related SNPs and NPC-related SNPs are
illustrated in Fig. 2. The SNP genotype differences
between groups are listed in Tables 1 and 2. We used
interactive chi-square tests to calculate the difference
in genotypes between groups (http://quantpsy.org).

Results
Among two HBV- and immune-related SNPs in

the CFB and CD40 regions(14,15) and three hepatitis
C virus-related SNPs in the IFNL4 regions,

(16-18)

allele type differences can be found between Africa and
Europe or between Africa and South Asia (Fig. 2A).
All these immune-related SNP genotypes differed sig-
nificantly between Esan in Nigeria and Toscani in Italy
and between Luhya in Webuye, Kenya (LWK) and
Gujarati in India (GIH) (Table 1; P < 0.001).
Among 12 HBV- and HLA-related SNPs,

(7-13)
the

allele frequency showed marked differences between
South and East Asian genome samples (Fig. 2B).
Eight of the 12 SNPs differed significantly between
Bengali in Bangladesh (BEB) and Chinese Dai in
Xishuangbanna, China (CDX); these areas represent
the junction of South and East Asia (Table 2; P <
0.001).
Three of the 12 HBV- and HLA-related SNPs

(Fig. 2B, dotted lines; rs9276370, rs3128917, and
rs9380343) also showed significant differences
between LWK in Africa and GIH in South Asia
(Table 2; P < 0.001). In contrast, we found the allele
frequency of NPC-related SNPs(18-20) to be relatively
stable among different populations (Fig. 2C).

Discussion
Based on the well-known human migration path-

ways
(23,24)

and the recent data from 1,000 genomes,
(22)

our analysis of hepatitis- and immune-related SNPs
demonstrate a significant change in allele frequency
shortly after the migration out of Africa (Fig. 2A). All
genotypes of five immune-related SNPs differed sig-
nificantly between Esan in Nigeria in Africa and
Toscani in Italy in Europe and between LWK in
Africa and GIH in South Asia (Table 1; P < 0.001).
In addition, both CFB and CD40 shifted from a
higher expression in African genotypes (rs12614:TT;
rs1883832:CC) to a lower expression in European
and South Asian genotypes (rs12614:CC; rs1883832:
TT).(14,15) These changes conferred a decrease in the
strength of immune responses. The CC genotype of

ARTICLE INFORMATION:

From the Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical

Center, Taoyuan City, Taiwan.

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:

Dar-In Tai, M.D., Ph.D.

Division of Hepatology, Department of Gastroenterology and Hepatology

Chang Gung Memorial Hospital and Chang Gung University College of

Medicine

199 Tung-Hwa North Road

Taipei, Taiwan 105

E-mail: tai48978@adm.cgmh.org.tw

Tel: 1886-3-328-1200 ext. 8107

TAI, JENG, LIN HEPATOLOGY COMMUNICATIONS, December 2017

1006

http://www.1000genomes.org/
http://www.1000genomes.org/
http://quantpsy.org/


T
A
B
L
E

1
.
G
E
N
O
T
Y
P
E

D
IF

F
E
R
E
N
C
E
S
B
E
T
W

E
E
N

G
E
O
G
R
A
P
H
IC

A
R
E
A
S
O
N

H
E
P
A
T
IT

IS
-
A
N
D

IM
M
U
N
E
-R

E
L
A
T
E
D

S
N
P
S

TS
I

(n
5

1
0
7
)

E
S
N

(n
5

9
9
)

TS
I
V
s.

E
S
N

LW
K

(n
5

1
0
3
)

G
IH

(n
5

9
9
)

LW
K

V
s.

G
IH

B
E
B

(n
5

8
6
)

C
D

X
(n

5
9
3
)

B
E
B

V
s.

C
D

X
S
N

P
G

en
o
ty

p
e

N
o

%
N

o
%

P
va

lu
e

N
o

%
N

o
%

P
va

lu
e

N
o

%
N

o
%

P
va

lu
e

rs
1
2
6
1
4

C
C

7
6

7
1
.0

3
7

3
7
.4

4
5

4
5
.5

7
4

7
1
.9

6
8

7
9
.1

9
0

9
6
.8

C
FB

C
T

2
9

2
7
.1

4
7

4
7
.5

4
5

4
5
.5

2
5

2
4
.3

1
7

1
9
.8

3
3
.2

TT
2

1
.9

1
5

1
5
.1

1
.1

3
1
0

2
6

9
9
.0

4
3
.9

6
.2

5
3

1
0

2
6

1
1
.2

0
0

1
.1

3
1
0

2
3

rs
1
2
9
7
9
8
6
0

C
C

3
7

3
4
.6

8
8
.1

1
8

1
8
.2

6
2

6
0
.2

5
3

6
1
.6

7
5

8
0
.6

IF
N

L4
C
T

5
5

5
1
.4

4
1

4
1
.4

6
0

6
0
.6

3
3

3
2
.0

3
2

3
7
.2

1
7

1
8
.3

TT
1
5

1
4
.0

5
0

5
0
.5

0
.0

0
0
0

2
1

2
1
.2

8
7
.8

6
.6

3
1
0

2
4

1
1
.2

1
1
.1

1
.7

3
1
0

2
2

rs
3
6
8
2
3
4
8
1
5

--
1
5

1
4
.0

5
2

5
2
.5

2
5

2
5
.3

8
7
.8

1
1
.2

1
1
.1

IF
N

L4
-T

5
6

5
2
.3

3
8

3
8
.4

6
0

6
0
.6

3
3

3
2
.0

3
3

3
8
.4

1
7

1
8
.3

TT
3
6

3
3
.7

9
9
.1

0
.0

0
0
0

1
4

1
4
.1

6
2

6
0
.2

0
.0

0
0
0

5
2

6
0
.5

7
5

8
0
.6

1
.1

3
1
0

2
2

rs
8
0
9
9
9
1
7

TT
6
4

5
9
.8

9
5

9
6
.0

8
4

8
4
.8

7
2

6
9
.9

6
7

7
7
.9

7
5

8
0
.6

IF
N

L4
M

S
R
B
1
P
1

G
T

4
2

3
9
.3

4
4
.0

1
5

1
5
.2

2
9

2
8
.2

1
9

2
2
.1

1
8

1
9
.4

G
G

1
0
.9

0
0

1
3

1
0

2
8

0
0

2
1
.9

2
.6

3
1
0

2
2

0
0

0
.0

0
.0

1
.0

0
0
0

rs
1
8
8
3
8
3
2

TT
2

1
.9

0
0

0
0

6
5
.8

9
1
0
.5

2
9

3
1
.2

C
D

4
0

C
T

6
0

5
6
.1

0
0

8
8
.1

4
6

4
4
.7

3
6

4
1
.9

4
4

4
7
.3

C
C

4
5

4
2
.1

9
9

1
0
0

0
.0

0
0
0

9
1

9
1
.9

5
1

4
9
.5

0
.0

0
0
0

4
1

4
7
.7

2
0

2
1
.5

1
.7

3
1
0

2
2

A
b
b
re
vi
at
io
n
s:
B
E
B
,
B
en
g
al
i
p
o
p
u
la
ti
o
n
s
fr
o
m

B
an
g
la
d
es
h
;
C
D
X
,
C
h
in
es
e
D
ai

p
o
p
u
la
ti
o
n
s
in

X
is
h
u
an
g
b
an
n
a,

C
h
in
a;

E
S
N
,
E
sa
n
in

N
ig
er
ia
;
G
IH

,
G
u
ja
ra
ti
in

In
d
ia

fr
o
m

H
o
u
s-

to
n
,
T
X
;
L
W

K
,
L
u
h
ya

in
W

eb
u
ye
,
K
en
ya
;
M
S
R
B
1
P
1
,
m
et
h
io
n
in
e
su
lf
o
xi
d
e
re
d
u
ct
as
e
B
1
p
se
u
d
o
g
en
e
1
;
T
S
I,
T
o
sc
an
i
in

It
al
y.

HEPATOLOGY COMMUNICATIONS, Vol. 1, No. 10, 2017 TAI, JENG, LIN

1007



T
A
B
L
E

2
.
G
E
N
O
T
Y
P
E

D
IF

F
E
R
E
N
C
E
S
B
E
T
W

E
E
N

G
E
O
G
R
A
P
H
IC

A
R
E
A
S
O
N

H
B
V
-
A
N
D

H
L
A
-R

E
L
A
T
E
D

S
N
P
S

TS
I

(n
5

1
0
7
)

E
S
N

(n
5

9
9
)

TS
I
V
s.

E
S
N

LW
K

(n
5

1
0
3
)

G
IH

(n
5

9
9
)

LW
K

V
s.

G
IH

B
E
B

(n
5

8
6
)

C
D

X
(n

5
9
3
)

B
E
B

V
s.

C
D

X
S
N

P
G

en
o
ty

p
e

N
o

%
N

o
%

P
va

lu
e

N
o

%
N

o
%

P
va

lu
e

N
o

%
N

o
%

P
va

lu
e

rs
9
2
7
6
3
7
0

G
G

1
6

1
5
.0

5
3

5
3
.5

4
1

4
1
.4

6
5
.8

0
0
.0

0
0
.0

H
LA

-D
Q

A
2

G
T

4
2

3
9
.3

4
1

4
1
.4

4
3

4
3
.4

3
4

3
3
.0

2
2

2
5
.6

1
8

1
9
.4

TT
4
9

4
5
.8

5
5
.1

0
.0

0
0
0

1
5

1
5
.2

6
3

6
1
.2

0
.0

0
0
0

6
4

7
4
.4

7
5

8
0
.6

0
.6

0
7
1

rs
7
7
5
6
5
1
6

C
C

1
3

1
2
.1

4
1

4
1
.4

2
9

2
9
.3

1
3

1
2
.6

2
2
.3

0
0
.0

H
LA

-D
Q

B
2

C
T

5
4

5
0
.5

4
9

4
9
.5

4
7

4
7
.5

4
7

4
5
.6

3
5

4
0
.7

2
0

2
1
.5

TT
4
0

3
7
.4

9
9
.1

4
.0

3
1
0

2
8

2
3

2
3
.2

4
3

4
1
.7

2
.3

3
1
0

2
3

4
9

5
7
.0

7
3

7
8
.5

5
.1

3
1
0

2
3

rs
7
4
5
3
9
2
0

A
A

1
2

1
1
.2

8
8
.1

7
7
.1

6
5
.8

0
0
.0

0
0
.0

H
LA

-D
Q

B
2

A
G

4
1

3
8
.3

4
8

4
8
.5

4
2

4
2
.4

2
9

2
8
.2

1
9

2
2
.1

1
1

1
1
.8

G
G

5
4

5
0
.5

4
3

4
3
.4

0
.3

1
8
1

5
0

5
0
.5

6
8

6
6
.0

0
.0

7
7
1

6
7

7
7
.9

8
2

8
8
.2

0
.1

8
5
0

rs
9
2
7
7
3
4
1

TT
4
4

4
1
.1

6
6
.1

1
8

1
8
.2

2
1

2
0
.4

1
4

1
6
.3

1
1
.1

H
LA

-D
P
A
1

C
T

4
7

4
3
.9

4
1

4
1
.4

4
3

4
3
.4

5
7

5
5
.3

4
2

4
8
.8

2
3

2
4
.7

C
C

1
6

1
5
.0

5
2

5
2
.5

0
.0

0
0
0

3
8

3
8
.4

2
5

2
4
.3

0
.0

9
0
9

3
0

3
4
.9

6
9

7
4
.2

1
.1

3
1
0

2
7

rs
3
1
3
5
0
2
1

G
G

5
5

5
1
.4

4
5

4
5
.5

3
3

3
3
.3

2
6

2
5
.2

2
9

3
3
.7

6
5

6
9
.9

H
LA

-D
P
A
1
/B

1
A
G

4
0

3
7
.4

4
3

4
3
.4

4
6

4
6
.5

6
3

6
1
.2

4
5

5
2
.3

2
7

2
9
.0

A
A

1
2

1
1
.2

1
1

1
1
.1

0
.6

5
6
1

2
0

2
0
.2

1
4

1
3
.6

0
.1

0
7
4

1
2

1
4
.0

1
1
.1

1
.1

3
1
0

2
6

rs
9
2
7
7
5
3
5

A
A

5
1

4
7
.7

6
1

6
1
.6

6
2

6
2
.6

5
2

5
0
.5

4
0

4
6
.5

1
3

1
4
.0

H
LA

-D
P
B
1

A
G

5
0

4
6
.7

3
4

3
4
.3

3
2

3
2
.3

4
8

4
6
.6

3
0

3
4
.9

4
2

4
5
.2

G
G

6
5
.6

4
4
.0

0
.1

3
2
9

5
5
.1

3
2
.9

0
.0

9
4
9

1
6

1
8
.6

3
8

4
0
.9

4
.8

3
1
0

2
6

rs
1
0
4
8
4
5
6
9

G
G

1
0
0

9
3
.5

8
3

8
3
.8

8
8

8
8
.9

9
5

9
2
.2

8
2

9
5
.3

3
3

3
5
.5

H
LA

-D
P
A
2

A
G

7
6
.5

1
5

1
5
.2

1
0

1
0
.1

8
7
.8

3
3
.5

4
1

4
4
.1

A
A

0
0
.0

1
1
.0

0
.0

7
4
8

1
1
.0

0
0
.0

0
.4

9
3
9

1
1
.2

1
9

2
0
.4

0
.0

0
0
0

rs
3
1
2
8
9
1
7

TT
5
4

5
0
.5

2
5

2
5
.3

2
8

2
8
.3

5
9

5
7
.3

4
4

5
1
.2

2
2

2
3
.7

H
LA

-D
P
A
2

G
T

4
4

4
1
.1

4
8

4
8
.5

5
1

5
1
.5

3
9

3
7
.9

3
2

3
7
.2

4
2

4
5
.2

G
G

9
8
.4

2
6

2
6
.3

8
.3

3
1
0

2
5

2
0

2
0
.2

5
4
.9

2
.1

3
1
0

2
5

1
0

1
1
.6

2
9

3
1
.2

1
.4

3
1
0

2
4

rs
2
2
8
1
3
8
8

G
G

1
0
3

9
6
.3

9
9

1
0
0
.0

9
9

1
0
0

9
6

9
3
.2

8
1

9
4
.2

3
3

3
5
.5

H
LA

-D
P
A
2

A
G

4
3
.7

0
0
.0

0
0
.0

7
6
.8

4
4
.7

4
1

4
4
.1

G
G

0
0
.0

0
0
.0

0
.1

5
1
6

0
0
.0

0
0
.0

0
.0

3
0
7

1
1
.2

1
9

2
0
.4

0
.0

0
0
0

rs
3
1
1
7
2
2
2

C
C

5
4

5
0
.5

2
5

2
5
.3

2
8

2
8
.3

5
9

5
7
.3

4
4

5
1
.2

2
1

2
2
.6

H
LA

-D
P
A
2

C
T

4
4

4
1
.1

5
0

5
0
.5

5
1

5
1
.5

3
9

3
7
.9

3
2

3
7
.2

4
3

4
6
.2

TT
9

8
.4

2
4

2
4
.2

1
.5

3
1
0

2
4

2
0

2
0
.2

5
4
.9

2
.1

3
1
0

2
5

1
0

1
1
.6

2
9

3
1
.2

8
.4

3
1
0

2
5

rs
9
3
8
0
3
4
3

C
C

9
9

9
2
.5

9
3

9
3
.9

9
5

9
6
.0

9
5

9
2
.2

8
2

9
5
.3

3
1

3
3
.3

H
LA

-D
P
B
2

C
T

8
7
.5

6
6
.1

4
4
.0

8
7
.8

3
3
.5

4
3

4
6
.2

TT
0

0
.0

0
0
.0

0
.9

2
1
7

0
0
.0

0
0
.0

0
.5

3
3
9

1
1
.2

1
9

2
0
.4

0
.0

0
0
0

rs
9
3
6
6
8
1
6

TT
6
5

6
0
.7

6
5

6
5
.7

6
4

6
4
.6

6
5

6
3
.1

5
8

6
7
.4

2
4

2
5
.8

H
LA

-D
P
A
3

C
T

3
7

3
4
.6

2
9

2
9
.3

3
2

3
2
.3

3
5

3
4
.0

2
5

2
9
.1

4
7

5
0
.5

C
C

5
4
.7

5
5
.1

0
.7

1
8
9

3
3
.0

3
2
.9

0
.9

6
9
0

3
3
.5

2
2

2
3
.7

2
.0

3
1
0

2
8

A
b
b
re
vi
at
io
n
s:
B
E
B
,
B
en
g
al
i
p
o
p
u
la
ti
o
n
s
fr
o
m

B
an
g
la
d
es
h
;
C
D
X
,
C
h
in
es
e
D
ai

p
o
p
u
la
ti
o
n
s
in

X
is
h
u
an
g
b
an
n
a,

C
h
in
a;
E
S
N
,
E
sa
n
in

N
ig
er
ia
;
G
IH

,
G
u
ja
ra
ti
in

In
d
ia

fr
o
m

H
o
u
s-

to
n
,
T
X
;
L
W

K
,
L
u
h
ya

in
W

eb
u
ye
,
K
en
ya
;
M
S
R
B
1
P
1
,
m
et
h
io
n
in
e
su
lf
o
xi
d
e
re
d
u
ct
as
e
B
1
p
se
u
d
o
g
en
e
1
;
T
S
I,
T
o
sc
an
i
in

It
al
y.

TAI, JENG, LIN HEPATOLOGY COMMUNICATIONS, December 2017

1008



rs12979860 (IFNL4), which is more prevalent in East
Asia, is associated with a lower baseline IFNL3 (inter-
leukin-28B) expression.

(16,17)
The IFNL4 open read-

ing frame is truncated by a polymorphic frame-shift
insertion (rs368234815), which turns IFNL4 into a
polymorphic pseudogene in East Asian popula-
tions.

(18)
Because the prevalence of HBsAg is higher in

Africa than in Europe or South Asia, these trends of
decreased immune protein expression are not related to
HBV-specific immune tolerance. Although it is clear
that Europeans and South Asians are two different
races, they showed similar genetic adaptions when they
migrated out of Africa. These changes suggest that the
decreased expression of immune-related genes might
have been an important survival strategy when humans
migrated into new territories and faced new pathogens.
The contact between different races of humans may
induce devastating diseases, for example, when the
New World was discovered by Christopher Columbus
in 1492.(25) A similar situation was well documented
when Japan sent troops to Taiwan in 1874 and 1895;

only 0.1% to 0.3% of soldiers died in battle, while
around 10% died of diseases in a short period of time
after arrival.

(26)

Our second principal result is that the allele frequency
of HBV- and HLA-related SNPs show marked differ-
ences between South and East Asian genome samples
(Fig. 2B). Eight of the 12 SNPs differed significantly
between BEB and CDX (Table 2; P < 0.001). These
two populations are located at the junction of South and
East Asia. The unique allele types of HBV-related SNPs
in East Asian populations are different from those of
other geographic populations. These genotypic changes
could be related to antigen presentation and could be
associated with persistent HBV infection.(7-13) Our find-
ings are in agreement with a higher prevalence of HBsAg
in East Asia than in South Asia (Fig. 1). These genotypic
populations are generally overlapped in the Y chro-
mosome haplogroup O1-O3 distribution map (https://
en.wikipedia.org/wiki/Human_Y-chromosome_DNA_
haplogroup) as they started in the Indo-China Peninsula
and travelled to northern China and Japan.

���������������������������������������������������������������������������������������������������������������������������������������

FIG. 1. Global HBsAg prevalence before HBV vaccination and the locations of the population groups of 1,000 genomes. The boxed
groups are populations used in Tables 1 and 2. (Modified from Hou et al., Int J Med Sci 2005; 2:50-57.) Abbreviations: ACB, Afri-
can Ancestry from Barbados in the Caribbean; ASW, African ancestry in Southwest United States; BEB, Bengali in Bangladesh;
CDX, Chinese Dai in Xishuangbanna, China; CEU, Utah residents with ancestry from Northern and Western Europe; CHB, Han
Chinese in Beijing, China; CHS, Han Chinese South, China; CLM, Colombians in Medellin, Colombia; ESN, Esan from Nigeria;
FIN, Finnish in Finland; GBR, British from England and Scotland, United Kingdom; GDW, Gambian in Western division, Gambia,
GIH, Gujarati Indians in Houston, TX; IBS, Iberian populations in Spain; ITU, Indian Telugu in the United Kingdom; JPT, Japanese
in Tokyo, Japan; KHV, Kinh in Hochi Minh city, Vietnam; LWK, Luhya in Webuye, Kenya; MSL, Mende in Sierra Leone; MXL,
Mexican ancestry in Los Angeles, CA; PEL, Peruvian in Lima, Peru; PJL, Punjabi in Lahore, Pakistan; PUR, Puerto Ricans in Puerto
Rico; STU, Sri Lankan Tamil in the United Kingdom; TSI, Toscani in Italy; YRI, Yoruba in Ibadan, Nigeria.

���������������������������������������������������������������������������������������������������������������������������������������

HEPATOLOGY COMMUNICATIONS, Vol. 1, No. 10, 2017 TAI, JENG, LIN

1009

https://en.wikipedia.org/wiki/Human_Y-chromosome_DNA_haplogroup
https://en.wikipedia.org/wiki/Human_Y-chromosome_DNA_haplogroup
https://en.wikipedia.org/wiki/Human_Y-chromosome_DNA_haplogroup


Given the results, we theorized on the reason behind
the dramatic allele differences in HBV-related SNPs
between BEB in South Asia and CDX in East Asia.
One possible explanation for this variation involves the
consideration of environmental landscape factors.(27)

For example, Bangladesh is a predominately rich, fer-
tile, and flat land, with many areas situated less than
12 m above sea level. On the other hand, Xishuang-
banna is situated in a mountainous and forested area

that has the largest diversity of plants and animals in
China.
Regions with higher plant and animal biodiversity

are often accompanied by an increased range and
abundance of vector-borne or nonvector-borne dis-
eases.(28-34) Accordingly, the inhabitants of these areas
should be able to tolerate an increased number of unfa-
miliar microorganisms. We speculated that the subjects
who demonstrate direct and strong immune responses

���������������������������������������������������������������������������������������������������������������������������������������

FIG. 2. Allele frequency of viral hepatitis- and NPC-related SNPs in different geographic groups. (A) Allele frequency of immune-
related SNPs (CFB, CD40, IFNL4). Significant allele type differences were found between African and European populations and
between African and South Asian populations in all of the immune-related SNPs. (B) Allele frequency of HBV- and HLA-related
SNPs (HLA-DP and -DQ). Significant allele type differences were found between South and East Asian populations in 8 of 12
HLA-related SNPs and between African and South Asian populations in 3 of 12 SNPs. (C) Allele frequency of NPC-related SNPs
(HLA regions). There was no significant difference among different populations in five NPC-related SNPs. Abbreviations: ACB,
African Ancestry from Barbados in the Caribbean; AFR, Africa, total; ALL, global, total; AMR, America, total; ASW, African
ancestry in Southwest United States; BEB, Bengali in Bangladesh; CDX, Chinese Dai in Xishuangbanna, China; CEU, Utah resi-
dents with ancestry from Northern and Western Europe; CHB, Han Chinese in Beijing, China; CHS, Han Chinese South, China;
CLM, Colombians in Medellin, Colombia; EAS, East Asia, total; ESN, Esan from Nigeria; EUR, Europe, total; FIN, Finnish in
Finland; GBR, British from England and Scotland, United Kingdom; GIH, Gujarati Indians in Houston, TX; IBS, Iberian popula-
tions in Spain; ITU, Indian Telugu in the United Kingdom; JPT, Japanese in Tokyo, Japan; KHV, Kinh in Hochi Minh city, Viet-
nam; LWK, Luhya in Webuye, Kenya; MAG, Mandinka in Gambia; MSL, Mende in Sierra Leone; MXL, Mexican ancestry in Los
Angeles, CA; PEL, Peruvian in Lima, Peru; PJL, Punjabi in Lahore, Pakistan; PUR, Puerto Ricans in Puerto Rico; SAS, South
Asia, total; STU, Sri Lankan Tamil in the United Kingdom; TSI, Toscani in Italy; YRI, Yoruba in Ibadan, Nigeria.

���������������������������������������������������������������������������������������������������������������������������������������

TAI, JENG, LIN HEPATOLOGY COMMUNICATIONS, December 2017

1010



may die of a cytokine storm in fulminant hepatitis,
severe acute respiratory syndrome, influenza, and other
infections.(30-34) This concept is supported by a lower
mortality rate from influenza H1N1 in Asia than in
Australia, New Zealand, and North America.

(35)

Cytokine storm was first described in graft-versus-
host disease and was soon also identified in many
infectious diseases

(36)
; many cytokines, chemokines,

and complements are involved.(37-39) The immune-
related SNPs selected in this study that included IFN
(IFNL4), tumor necrosis factor-receptor (CD40), and
complements (CFB) are all participants in cytokine
storms. HLA class II molecules are associated with
antigen presentation and are also modulated by cyto-
kines.

(40)
A cytokine storm is considered to be a hyper-

reaction of the immune response to a pathogen that
may cause fulminant disease and mortality.(36-39)

When humans migrate to a new territory, they face
many unfamiliar pathogens. Those subjects with a
strong immune response will die of disease, but those
subjects with a weak immune response to the patho-
gens may survive. Chronic HBV infection with an
immune tolerance stage is an example of a weak
immune response.(3-5)

East Asian populations carry similar allele types of
HBV-related SNPs (Fig. 2B), although the environ-
ments of northern China and Japan differ substantially
from those of southern China and the Indo-China
Peninsula.(41) We therefore propose that there was a
significant physical block to gene flow on the Indo-
China Peninsula. Most of the survivors in East Asia
exhibit delayed HBV-related immune clearance geno-
types. This could have been a survival strategy to pass
through the Indo-China Peninsula and southern
China during human migration. Such HLA class II
genotypes are aimed toward an immune tolerance
strategy.(7-13) These changes were successful because
this group of people spread to northern China and
Japan and have become the largest population in the
world numerically. However, such a survival benefit

may have been a trade-off with cold tolerance as these
populations were unable to cross the Bering Strait in
large numbers. Indigenous Americans do not show the
same HBV-related allele pattern; they have a low prev-
alence of chronic HBV infection and high influenza-
related mortality rates.(1,2,35)

Overall, we identified two genetic adaptations that
occurred during human migration. The first was the
decreased expression of immune-related genes after
leaving Africa; the second was the evolution of an
HLA system with migration into the Indo-China
Peninsula. Both events may have aimed to decrease the
strength of the immune response and avoid cytokine
storms when facing different types of pathogens. The
high prevalence of chronic HBV infection in East Asia
could be a consequence of such a strategy. However,
persistent HBV infection-related HLA genotypes are
not present in the African population (Fig. 2B) and
cannot be responsible for the high prevalence of
HBsAg in Africa.
Different genetic and nongenetic mechanisms of

chronic HBV infection are presented between East
Asian and African populations.(4,42-44) We summarize
the differences on HBsAg carriers between East Asia
and Africa in Table 3. These differences may provide a
clue for the mechanism of the function of SNPs in the
persistent HBV infection. The high prevalence of low-
expression-type immune-related SNPs and chronic
HBV infection-related SNPs on the HLA locus may
be a reason for a longer hepatitis B e antigen
(HBeAg)-positive phase in East Asia. IFN-alpha has
been recommended for treatment of HBeAg-positive
chronic hepatitis B. In a larger series from pediatric
patients, IFN-alpha was found to be an effective ther-
apy in chronic hepatitis B with severe inflammation
that facilitates HBeAg seroconversion in earlier life.(45)

In addition, HBV- and HLA-related SNPs are also
associated with spontaneous HBeAg seroconver-
sion.(46-48) These genetic polymorphisms could be a
reason for an early HBeAg seroconversion and a lower
vertical transmission in Africa compared to East Asia.
It is well known that HBV genotypes A, B, and D

show an earlier HBeAg seroconversion compared to
genotype C.(42,44) This early HBeAg seroconversion
was suggested to be the reason of low vertical transmis-
sion in Africa.(49) However, HBV genotype B also had
an early HBeAg seroconversion but had a high vertical
transmission rate in East Asia.(4) Therefore, host fac-
tors rather than HBV genotypes alone should be con-
sidered for the high vertical transmission rate in East
Asia. Most HBV-related genome-wide association

TABLE 3. DIFFERENCES IN CHRONIC HBV
INFECTION BETWEEN AFRICA AND EAST ASIA

Africa East Asia

HBsAg prevalence High High

Host gene pattern
HBV- and HLA- related SNPs Rare Common
Immune-related SNPs High expression Low expression

HBV genotype A,D,E B,C
Vertical transmission Low High
Early HBeAg seroconversion Common Low

HEPATOLOGY COMMUNICATIONS, Vol. 1, No. 10, 2017 TAI, JENG, LIN

1011



studies were done in East Asia. We need studies to
understand the genetic roles in persistent HBV infec-
tion in African populations.
Our study found two stages of genetic changes

toward a weak immune response when humans mig-
rated out of Africa. These changes could be a survival
strategy for avoiding cytokine storms and surviving in
new environments.

REFERENCES

1) Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Esti-

mations of worldwide prevalence of chronic hepatitis B virus

infection: a systematic review of data published between 1965

and 2013. Lancet 2015;386:1546-1555.

2) Hou J, Liu Z, Gu F. Epidemiology and prevention of hepatitis

B virus infection. Int J Med Sci 2005;2:50-57.

3) Chu CM, Karayiannis P, Fowler MJ, Monjardino J, Liaw YF,

Thomas HC. Natural history of chronic hepatitis B virus infec-

tion in Taiwan: studies of hepatitis B virus DNA in serum. Hep-

atology 1985;5:431-434.

4) Hsieh AR, Fann CS, Yeh CT, Lin HC, Wan SY, Chen YC,

et al. Effects of sex and generation on hepatitis B viral load in

families with hepatocellular carcinoma. World J Gastroenterol

2017;23:876-884.

5) Hong M, Sandalova E, Low D, Gehring AJ, Fieni S, Amadei

B, et al. Trained immunity in newborn infants of HBV-infected

mothers. Nat Commun 2015;6:6588.

6) Tai DI, Tsay PK, Chen WT, Chu CM, Liaw YF. Relative roles of

HBsAg seroclearance and mortality in the decline of HBsAg preva-

lence with increasing age. Am J Gastroenterol 2010;105:1102-1109.

7) Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T,

Takahashi A, Hosono N, et al. A genome-wide association study

identifies variants in the HLA-DP locus associated with chronic

hepatitis B in Asians. Nat Genet 2009;41:591-595.

8) Mbarek H, Ochi H, Urabe Y, Kumar V, Kubo M, Hosono N,

et al. A genome-wide association study of chronic hepatitis B

identified novel risk locus in a Japanese population. Hum Mol

Genet 2011;20:3884-3892.

9) Hu Z, Liu Y, Zhai X, Dai J, Jin G, Wang L, et al. New loci

associated with chronic hepatitis B virus infection in Han Chi-

nese. Nat Genet 2013;45:1499-1503.

10) Nishida N, Sawai H, Matsuura K, Sugiyama M, Ahn SH, Park

JY, et al. Genome-wide association study confirming association

of HLA-DP with protection against chronic hepatitis B and viral

clearance in Japanese and Korean. PLoS One 2012;7:e39175.

11) Kim YJ, Kim HY, Lee JH, Yu SJ, Yoon JH, Lee HS, et al. A

genome-wide association study identified new variants associated

with the risk of chronic hepatitis B. Hum Mol Genet 2013;22:

4233-4238.

12) Al-Qahtani AA, Al-Anazi MR, Abdo AA, Sanai FM, Al-

Hamoudi W, Alswat KA, et al. Association between HLA varia-

tions and chronic hepatitis B virus infection in Saudi Arabian

patients. PLoS One 2014;9:e80445.

13) Chang SW, Fann CS, Su WH, Wang YC, Weng CC, Yu CJ,

et al. A genome-wide association study on chronic HBV infec-

tion and its clinical progression in male Han-Taiwanese. PLoS

One 2014;9:e99724.

14) Jiang DK, Ma XP, Yu H, Cao G, Ding DL, Chen H, et al.

Genetic variants in five novel loci including CFB and CD40 pre-

dispose to chronic hepatitis B. Hepatology 2015;62:118-128.

15) Zhou C, Jin X, Tang J, Fei J, Gu C, Chen X. Association of

CD40 -1C/T polymorphism in the 50-untranslated region with

chronic HBV infection. Cell Physiol Biochem 2015;35:83-91.

16) Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K,

Sakamoto N, et al. Genome-wide association of IL28B with

response to pegylated interferon-alpha and ribavirin therapy for

chronic hepatitis C. Nat Genet 2009;41:1105-1109.

17) Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S,

Kusano-Kitazume A, et al. Impaired induction of interleukin 28B

and expression of interferon k 4 associated with nonresponse to
interferon-based therapy in chronic hepatitis C. J Gastroenterol

Hepatol 2015;30:1075-1084.

18) Key FM, Peter B, Dennis MY, Huerta-S�anchez E, Tang W,

Prokunina-Olsson L, et al. Selection on a variant associated with

improved viral clearance drives local, adaptive pseudogenization of

interferon lambda 4 (IFNL4). PLoS Genet 2014;10:e1004681.

19) Tse KP, Su WH, Chang KP, Tsang NM, Yu CJ, Tang P,

et al. Genome-wide association study reveals multiple nasopha-

ryngeal carcinoma-associated loci within the HLA region at

chromosome 6p21.3. Am J Hum Genet 2009;85:194-203.

20) Hsu WL, Tse KP, Liang S, Chien YC, Su WH, Yu KJ, et al.

Evaluation of human leukocyte antigen-A (HLA-A), other non-

HLA markers on chromosome 6p21 and risk of nasopharyngeal

carcinoma. PLoS One 2012;7:e42767.

21) Tang M, Lautenberger JA, Gao X, Sezgin E, Hendrickson SL,

Troyer JL, et al. The principal genetic determinants for nasopha-

ryngeal carcinoma in China involve the HLA class I antigen rec-

ognition groove. PLoS Genet 2012;8:e1003103.

22) 1000 Genomes Project Consortium; Auton A, Brooks LD,

Durbin RM, Garrison EP, Kang HM, Korbel JO, et al. A global

reference for human genetic variation. Nature 2015;526:68-74.

23) Stanyon R, Sazzini M, Luiselli D. Timing the first human

migration into eastern Asia. J Biol 2009;8:18.

24) Timmermann A, Friedrich T. Late Pleistocene climate drivers of

early human migration. Nature 2016;538:92-95.

25) Bianchine PJ, Russo TA. The role of epidemic infectious diseases

in the discovery of America. Allergy Proc 1992;13:225-232.

26) Katz PR. Germs of disaster: the impact of epidemics on Japanese

military campaigns in Taiwan, 1874 and 1895. Ann Demogr

Hist (Paris) 1996:195-220.

27) Winder IC, Devès MH, King GC, Bailey GN, Inglis RH,

Meredith-Williams M. Evolution and dispersal of the genus

Homo: a landscape approach. J Hum Evol 2015;87:48-65.

28) Russell RC. Vectors vs. humans in Australia--who is on top

down under? An update on vector-borne disease and research on

vectors in Australia. J Vector Ecol 1998;23:1-46.

29) Pelosse P, Kribs-Zaleta CM, Ginoux M, Rabinovich JE,

Gourbière S, Menu F. Influence of vectors’ risk-spreading strate-

gies and environmental stochasticity on the epidemiology and

evolution of vector-borne diseases: the example of Chagas’ dis-

ease. PLoS One 2013;8:e70830.

30) Zhang JY, Zhang Z, Lin F, Zou ZS, Xu RN, Jin L, et al. Inter-

leukin-17-producing CD4(1) T cells increase with severity of

liver damage in patients with chronic hepatitis B. Hepatology

2010;51:81-91.

31) Yu X, Zheng Y, Deng Y, Li J, Guo R, Su M, et al. Serum

interleukin (IL)-9 and IL-10, but not T-helper 9 (Th9) cells, are

associated with survival of patients with acute-on-chronic hepati-

tis B liver failure. Medicine (Baltimore) 2016;95:e3405.

32) Gralinski LE, Baric RS. Molecular pathology of emerging coro-

navirus infections. J Pathol 2015;235:185-195.

TAI, JENG, LIN HEPATOLOGY COMMUNICATIONS, December 2017

1012



33) La Gruta NL, Kedzierska K, Stambas J, Doherty PC. A question

of self-preservation: immunopathology in influenza virus infec-

tion. Immunol Cell Biol 2007;85:85-92.

34) Oldstone MB, Rosen H. Cytokine storm plays a direct role in

the morbidity and mortality from influenza virus infection and is

chemically treatable with a single sphingosine-1-phosphate ago-

nist molecule. Curr Top Microbiol Immunol 2014;378:129-147.

35) Wong JY, Kelly H, Cheung CM, Shiu EY, Wu P, Ni MY,

et al. Hospitalization fatality risk of influenza A(H1N1)pdm09: a

systematic review and meta-analysis. Am J Epidemiol 2015;182:

294-301.

36) Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR,

Katze MG. Into the eye of the cytokine storm. Microbiol Mol

Biol Rev 2012;76:16-32.

37) Keating SM, Heitman JW, Wu S, Deng X, Stacey AR, Zahn

RC, et al. Magnitude and quality of cytokine and chemokine

storm during acute infection distinguish nonprogressive and pro-

gressive simian immunodeficiency virus infections of nonhuman

primates. J Virol 2016;90:10339-10350.

38) Kido H. Influenza virus pathogenicity regulated by host cellular

proteases, cytokines and metabolites, and its therapeutic options.

Proc Jpn Acad Ser B Phys Biol Sci 2015;91:351-368.

39) Skjeflo EW, Christiansen D, Espevik T, Nielsen EW, Mollnes

TE. Combined inhibition of complement and CD14 efficiently

attenuated the inflammatory response induced by Staphylococcus

aureus in a human whole blood model. J Immunol 2014;192:

2857-2864.

40) Mulder DJ, Pooni A, Mak N, Hurlbut DJ, Basta S, Justinich

CJ. Antigen presentation and MHC class II expression by

human esophageal epithelial cells: role in eosinophilic esophagitis.

Am J Pathol 2011;178:744-753.

41) Xue F, Wang J, Hu P, Ma D, Liu J, Li G, et al. Identification

of spatial genetic boundaries using a multifractal model in human

population genetics. Hum Biol 2005;77:577-617.

42) Livingston SE, Simonetti JP, Bulkow LR, Homan CE, Snowball

MM, Cagle HH, et al. Clearance of hepatitis B e antigen in

patients with chronic hepatitis B and genotypes A, B, C, D, and

F. Gastroenterology 2007;133:1452-1457.

43) Navabakhsh B, Mehrabi N, Estakhri A, Mohamadnejad M,

Poustchi H. Hepatitis B virus infection during pregnancy:

transmission and prevention. Middle East J Dig Dis 2011;3:

92-102.

44) Ott JJ, Stevens GA, Wiersma ST. The risk of perinatal hepati-

tis B virus transmission: hepatitis B e antigen (HBeAg) preva-

lence estimates for all world regions. BMC Infect Dis 2012;12:

131.

45) Wu JF, Chiu YC, Chang KC, Chen HL, Ni YH, Hsu HY,

et al. Predictors of hepatitis B e antigen-negative hepatitis in

chronic hepatitis B virus-infected patients from childhood to

adulthood. Hepatology 2016;63:74-82.

46) Komatsu H, Murakami J, Inui A, Tsunoda T, Sogo T, Fujisawa

T. Association between single-nucleotide polymorphisms and

early spontaneous hepatitis B virus e antigen seroconversion in

children. BMC Res Notes 2014;7:789.

47) Tseng TC, Yu ML, Liu CJ, Lin CL, Huang YW, Hsu CS,

et al. Effect of host and viral factors on hepatitis B e

antigen-positive chronic hepatitis B patients receiving pegy-

lated interferon-a-2a therapy. Antivir Ther 2011;16:629-
637.

48) Cheng L, Sun X, Tan S, Tan W, Dan Y, Zhou Y, et al. Effect

of HLA-DP and IL28B gene polymorphisms on response to

interferon treatment in hepatitis B e-antigen seropositive chronic

hepatitis B patients. Hepatol Res 2014;44:1000-1007.

49) Allain JP. Epidemiology of hepatitis B virus and genotype.

J Clin Virol 2006;36(Suppl. 1):S12-S17.

Author names in bold designate shared co-first
authorship.

HEPATOLOGY COMMUNICATIONS, Vol. 1, No. 10, 2017 TAI, JENG, LIN

1013