I
nte
rna
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l J
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urna
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f
P
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(
I
J
P
H
S)
Vo
l.
15
,
No
.
3
,
Sep
tem
b
er
20
26
,
p
p
.
8
4
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8
5
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I
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N:
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co
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Integ
ra
tive
fu
ncti
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na
l anno
tatio
n of rheu
ma
toid a
rth
ritis risk
g
enes using
a mul
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inf
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a
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Rh
e
u
m
a
to
id
a
rth
rit
is
(RA)
is
a
n
a
u
to
imm
u
n
e
d
ise
a
se
in
v
o
lv
i
n
g
th
e
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tera
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ti
o
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o
f
g
e
n
e
ti
c
a
n
d
imm
u
n
o
lo
g
ica
l
fa
c
to
rs.
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e
n
o
m
e
-
wid
e
a
ss
o
c
iatio
n
stu
d
ies
(G
WAS
)
h
a
v
e
id
e
n
ti
fie
d
m
a
n
y
RA
risk
lo
c
i
,
b
u
t
th
e
b
i
o
lo
g
ica
l
m
e
c
h
a
n
ism
s
li
n
k
in
g
g
e
n
e
ti
c
v
a
ri
a
ti
o
n
to
d
ise
a
se
p
a
th
o
g
e
n
e
sis
a
re
n
o
t
y
e
t
fu
ll
y
u
n
d
e
rsto
o
d
.
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is
stu
d
y
a
ims
to
p
rio
r
it
ize
RA
c
a
n
d
id
a
te
g
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n
e
s
th
ro
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g
h
a
m
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d
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tab
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se
b
i
o
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n
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rm
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ti
c
s
a
p
p
ro
a
c
h
.
S
NPs
sig
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ifi
c
a
n
t
ly
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ss
o
c
iate
d
with
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re
o
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tain
e
d
fro
m
th
e
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a
talo
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ll
o
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d
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y
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in
k
a
g
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ise
q
u
il
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m
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re
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in
g
a
n
d
fu
n
c
ti
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n
a
l
a
n
n
o
tatio
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o
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e
n
t
ify
m
isse
n
se
v
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rian
ts.
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e
d
a
ta
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re
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teg
ra
ted
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is
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x
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re
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q
u
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n
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trait
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(c
is
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QTL)
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n
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rm
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ti
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O)
a
n
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o
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d
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En
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e
s
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n
d
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n
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GG
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lar
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a
t
h
wa
y
m
a
p
p
in
g
.
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e
n
e
s
with
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to
tal
sc
o
re
≥2
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re
c
las
sified
a
s
RA
risk
g
e
n
e
s.
A
to
tal
o
f
3
.
1
4
5
RA
-
sig
n
ifi
c
a
n
t
S
NPs
we
re
id
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t
ifi
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d
,
o
f
wh
ic
h
5
8
we
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m
isse
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se
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rian
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h
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t
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l
d
p
o
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ll
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ff
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c
t
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ro
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n
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ti
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n
.
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h
e
i
n
teg
ra
ti
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f
c
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QTL
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n
d
fu
n
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ti
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l
a
n
n
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su
lt
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n
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a
n
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i
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g
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n
e
s
with
t
h
e
h
ig
h
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st
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o
re
s
(sc
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=
4
),
wh
e
re
T
Y
K
2
,
IL
2
3
R
,
a
n
d
IR
AK1
we
re
id
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n
ti
fie
d
a
s
p
rio
rit
y
RA
g
e
n
e
s
in
th
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m
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p
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th
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n
a
m
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ly
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n
a
l
in
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IL
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3
/T
h
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a
x
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s,
a
n
d
To
ll
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k
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re
c
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p
to
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–
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κB
sig
n
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li
n
g
.
Th
e
se
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d
i
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g
s
d
e
m
o
n
stra
te
th
a
t
th
is
m
u
lt
i
-
d
a
ta
b
a
se
-
b
a
se
d
b
io
i
n
fo
rm
a
ti
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s
a
p
p
ro
a
c
h
su
c
c
e
ss
fu
ll
y
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n
t
ifi
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s
RA
c
a
n
d
id
a
te
g
e
n
e
s
wit
h
str
o
n
g
b
io
l
o
g
ica
l
re
lev
a
n
c
e
.
K
ey
w
o
r
d
s
:
B
io
in
f
o
r
m
atics
eQT
L
KE
GG
Miss
en
s
e
S
NPs
m
u
tatio
n
R
h
eu
m
ato
id
ar
th
r
itis
T
h
is i
s
a
n
o
p
e
n
a
c
c
e
ss
a
rticle
u
n
d
e
r th
e
CC B
Y
-
SA
li
c
e
n
se
.
C
o
r
r
e
s
p
o
nd
ing
A
uth
o
r
:
L
o
lita
Facu
lty
o
f
Ph
ar
m
ac
y
,
Un
iv
e
r
s
itas
Ah
m
ad
Dah
lan
Yo
g
y
ak
ar
ta,
I
n
d
o
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esia
E
m
ail:
lo
lita@
p
h
ar
m
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u
ad
.
ac
.
i
d
1.
I
NT
RO
D
UCT
I
O
N
R
h
eu
m
ato
id
ar
th
r
itis
(
R
A)
is
a
ch
r
o
n
ic
a
u
to
im
m
u
n
e
d
is
ea
s
e
th
at
p
r
im
ar
ily
a
f
f
ec
ts
th
e
jo
in
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an
d
is
ch
ar
ac
ter
ized
b
y
p
e
r
s
is
ten
t
s
y
n
o
v
ial
in
f
lam
m
atio
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,
ca
r
ti
lag
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d
estru
ctio
n
,
b
o
n
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er
o
s
i
o
n
,
an
d
lo
n
g
-
ter
m
f
u
n
ctio
n
al
d
is
ab
ilit
y
[
1
]
.
Glo
b
ally
,
th
e
p
r
e
v
alen
ce
o
f
R
A
is
ap
p
r
o
x
im
ately
1
7
.
6
m
illi
o
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c
ases
,
with
a
h
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in
cid
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ce
in
w
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m
en
th
a
n
in
m
en
,
an
d
th
e
b
u
r
d
en
o
f
d
i
s
ea
s
e
in
cr
ea
s
es
with
ag
e
[
2
]
.
I
n
I
n
d
o
n
esia,
th
e
p
r
ev
alen
ce
o
f
R
A
was
r
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te
d
b
y
R
is
k
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1
1
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ased
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m
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4
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ased
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m
s
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p
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t o
f
R
A
o
n
th
e
p
u
b
lic
h
ea
lt
h
s
y
s
tem
[
3
]
.
R
A
is
a
c
o
m
p
l
e
x
d
is
e
as
e
w
it
h
a
s
t
r
o
n
g
g
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ti
c
c
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t
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b
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n
.
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v
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m
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ll
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c
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p
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b
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o
R
A
[
4
]
-
[
6
]
.
G
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f
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c
r
e
a
s
e
d
r
i
s
k
o
f
R
A
.
P
r
e
v
i
o
u
s
s
t
u
d
i
e
s
h
a
v
e
r
e
p
o
r
t
e
d
t
h
a
t
2
3
n
o
n
-
s
y
n
o
n
y
m
o
u
s
S
N
P
s
d
i
r
e
c
t
l
y
a
f
f
e
c
t
p
r
o
t
e
i
n
f
u
n
c
t
i
o
n
,
i
n
c
l
u
d
i
n
g
r
s
2
4
7
6
6
0
1
i
n
t
h
e
P
T
P
N
2
2
g
e
n
e
,
r
s
5
0
2
9
9
4
1
a
n
d
r
s
2
2
3
0
9
2
6
i
n
t
h
e
T
N
F
A
I
P
3
g
e
n
e
,
a
n
d
r
s
3
4
5
3
6
4
4
3
i
n
t
h
e
T
Y
K
2
g
e
n
e
[
9
]
.
A
d
d
i
t
i
o
n
a
l
l
y
,
o
t
h
e
r
g
e
n
e
t
i
c
v
a
r
i
a
t
i
o
n
s
i
n
v
o
l
v
e
d
i
n
T
c
e
l
l
a
c
t
i
v
a
t
i
o
n
a
n
d
r
e
g
u
l
a
t
i
o
n
,
s
u
c
h
a
s
r
s
1
8
1
7
5
8
1
0
0
i
n
t
h
e
T
N
F
S
F
4
g
e
n
e
,
r
s
3
1
8
1
0
9
6
i
n
t
h
e
C
D
2
8
g
e
n
e
,
a
n
d
r
s
1
1
5
7
1
3
1
9
i
n
t
h
e
C
T
L
A
4
g
e
n
e
[
1
0
]
.
M
e
a
n
w
h
i
l
e
,
S
N
P
s
r
s
1
6
9
1
7
4
9
6
i
n
t
h
e
3
-
U
T
R
r
e
g
i
o
n
o
f
t
h
e
S
E
T
8
g
e
n
e
h
a
s
b
e
e
n
r
e
p
o
r
t
e
d
t
o
a
c
t
a
s
a
p
r
e
d
i
c
t
o
r
o
f
R
A
r
i
s
k
t
h
r
o
u
g
h
t
h
e
r
e
g
u
l
a
t
i
o
n
o
f
r
e
a
c
t
i
v
e
o
x
y
g
e
n
s
p
e
c
i
e
s
(
R
O
S
)
a
n
d
i
n
t
e
r
l
e
u
k
i
n
-
1
0
(
I
L
-
1
0
)
l
e
v
e
l
s
[
1
1
]
.
H
o
w
e
v
e
r
,
m
o
s
t
o
f
t
h
e
S
N
P
s
i
d
e
n
t
i
f
i
e
d
t
h
r
o
u
g
h
G
W
A
S
a
r
e
l
o
c
a
t
e
d
i
n
n
o
n
-
c
o
d
i
n
g
r
e
g
i
o
n
s
o
r
h
a
v
e
f
u
n
c
t
i
o
n
a
l
e
f
f
e
c
t
s
t
h
a
t
a
r
e
n
o
t
y
e
t
f
u
l
l
y
u
n
d
e
r
s
t
o
o
d
,
d
o
e
s
t
h
e
r
e
l
a
t
i
o
n
s
h
i
p
b
e
t
w
e
e
n
g
e
n
e
t
i
c
v
a
r
i
a
t
i
o
n
a
n
d
t
h
e
m
o
l
e
c
u
l
a
r
m
e
c
h
a
n
i
s
m
s
o
f
R
A
i
s
s
t
i
l
l
n
o
t
e
n
t
i
r
e
l
y
c
l
e
a
r
.
I
n
ad
d
itio
n
to
g
e
n
etic
v
ar
iatio
n
,
th
e
p
ath
o
g
e
n
esis
o
f
R
A
i
s
a
ls
o
in
f
lu
en
ce
d
b
y
th
e
r
eg
u
latio
n
o
f
g
en
e
ex
p
r
ess
io
n
th
r
o
u
g
h
(
cis
-
eQT
L
)
m
ec
h
an
is
m
s
,
ch
an
g
es
in
p
r
o
tein
s
tr
u
ctu
r
e
an
d
f
u
n
ctio
n
d
u
e
to
m
is
s
en
s
e
m
u
tatio
n
s
,
an
d
th
e
in
v
o
lv
em
e
n
t
o
f
g
en
es
in
b
i
o
lo
g
ical
p
r
o
ce
s
s
es
an
d
m
o
lecu
lar
s
ig
n
alin
g
p
at
h
way
s
.
T
h
ese
f
ac
to
r
s
p
lay
an
i
m
p
o
r
ta
n
t
r
o
le
in
r
e
g
u
latin
g
th
e
im
m
u
n
e
r
esp
o
n
s
e
an
d
ch
r
o
n
ic
in
f
lam
m
ati
o
n
th
at
ch
ar
ac
ter
iz
e
R
A
[
1
2
]
,
[
1
3
]
.
Ho
we
v
er
,
m
o
s
t
s
tu
d
ies
s
till
ev
alu
ate
th
ese
as
p
ec
ts
s
ep
ar
ately
,
wh
eth
e
r
f
r
o
m
th
e
p
er
s
p
ec
tiv
e
o
f
m
is
s
en
s
e
m
u
tatio
n
s
,
g
en
e
ex
p
r
ess
io
n
r
eg
u
latio
n
,
o
r
f
u
n
ctio
n
al
an
n
o
tatio
n
o
f
GO
an
d
Ky
o
t
o
E
n
cy
clo
p
ed
ia
o
f
Gen
es
an
d
Gen
o
m
es
(
KE
G
G
)
m
o
lecu
lar
p
ath
wa
y
an
aly
s
is
.
As
a
r
esu
lt,
ap
p
r
o
ac
h
es
th
at
in
teg
r
ate
th
ese
v
ar
io
u
s
lay
e
r
s
o
f
g
e
n
etic
in
f
o
r
m
atio
n
i
n
to
a
co
m
p
r
eh
e
n
s
iv
e
an
aly
tical
f
r
am
ewo
r
k
r
em
ai
n
lim
ited
[
1
]
,
[
1
4
]
.
T
h
is
g
ap
lim
its
a
co
m
p
r
eh
en
s
iv
e
u
n
d
e
r
s
tan
d
in
g
o
f
th
e
f
u
n
ctio
n
al
r
o
le
o
f
R
A
r
is
k
g
en
es
an
d
h
in
d
er
s
t
h
e
id
en
tific
atio
n
o
f
m
o
lec
u
lar
p
at
h
way
s
an
d
m
o
r
e
p
r
ec
is
e
th
er
ap
eu
tic
tar
g
ets
.
Ad
v
an
ce
s
in
b
io
in
f
o
r
m
atics e
n
ab
le
th
e
in
teg
r
atio
n
o
f
v
a
r
io
u
s
p
u
b
lic
d
atab
ases
s
u
ch
as
GW
AS
c
atalo
g
,
Hap
lo
R
eg
,
W
eb
Gestalt,
Un
iPro
t,
an
d
KE
GG
to
s
y
s
tem
atica
lly
an
d
m
u
ltid
im
en
s
io
n
ally
an
n
o
tate
th
e
f
u
n
ctio
n
al
r
is
k
g
e
n
es.
T
h
is
m
u
lti
-
d
atab
ase
ap
p
r
o
ac
h
allo
ws f
o
r
m
o
r
e
co
m
p
r
eh
en
s
iv
e
m
ap
p
in
g
b
etwe
en
g
en
etic
v
ar
iati
o
n
an
d
b
i
o
lo
g
ic
al
f
u
n
ctio
n
,
an
d
h
as
th
e
p
o
ten
tial to
r
ev
ea
l k
e
y
im
m
u
n
o
lo
g
ical
p
ath
way
s
in
v
o
lv
e
d
in
R
A
p
ath
o
g
e
n
esis
[
1
5
]
,
[
1
6
]
.
Desp
ite
th
e
g
r
o
win
g
n
u
m
b
er
o
f
g
en
etic
s
tu
d
ies
o
n
r
h
eu
m
at
o
id
ar
th
r
itis
,
s
ev
er
al
im
p
o
r
tan
t
r
esear
ch
g
ap
s
r
em
ain
.
Mo
s
t
p
r
ev
io
u
s
s
tu
d
ies
h
av
e
f
o
c
u
s
ed
o
n
id
e
n
tif
y
in
g
R
A
-
ass
o
ciate
d
lo
ci
t
h
r
o
u
g
h
GW
AS
with
o
u
t
s
y
s
tem
atica
lly
in
teg
r
atin
g
f
u
n
ctio
n
al
ev
id
e
n
ce
s
u
ch
as
m
is
s
en
s
e
v
ar
ian
ts
,
g
e
n
e
e
x
p
r
ess
io
n
r
e
g
u
latio
n
,
an
d
p
ath
way
in
v
o
lv
em
e
n
t
in
to
a
u
n
if
ied
p
r
io
r
itizatio
n
f
r
am
ewo
r
k
[
1
4
]
.
Mo
r
e
o
v
er
,
ex
is
tin
g
b
io
in
f
o
r
m
atics
s
tu
d
ies
o
f
ten
ev
alu
ate
th
ese
g
en
etic
lay
er
s
in
d
ep
en
d
e
n
tly
,
lim
itin
g
th
eir
ab
ilit
y
to
id
en
tify
g
e
n
es
with
co
n
s
is
ten
t
b
io
lo
g
ical
r
ele
v
an
ce
ac
r
o
s
s
m
u
ltip
le
f
u
n
cti
o
n
al
d
im
e
n
s
io
n
s
[
1
5
]
.
I
n
th
e
I
n
d
o
n
esian
co
n
tex
t,
wh
e
r
e
R
A
p
r
e
v
alen
ce
an
d
d
is
ea
s
e
b
u
r
d
en
ar
e
in
cr
ea
s
in
g
,
an
d
m
o
lecu
lar
ep
id
em
io
lo
g
ical
d
ata
r
em
ain
s
ca
r
ce
,
th
is
lack
o
f
in
teg
r
ativ
e
g
en
etic
an
aly
s
is
h
am
p
er
s
th
e
tr
an
s
latio
n
o
f
g
en
o
m
ic
f
in
d
in
g
s
in
to
p
u
b
lic
h
ea
lth
s
tr
ateg
ies,
in
clu
d
in
g
ea
r
ly
r
is
k
id
en
tific
a
tio
n
an
d
tar
g
et
ed
in
ter
v
e
n
tio
n
p
lan
n
in
g
[
3
]
.
T
h
er
ef
o
r
e,
an
ex
p
licit
in
teg
r
ativ
e
b
io
in
f
o
r
m
atics
ap
p
r
o
ac
h
th
at
co
n
n
ec
ts
GW
AS
s
ig
n
als
with
f
u
n
ctio
n
al
an
n
o
tatio
n
an
d
p
r
io
r
itizatio
n
is
n
ee
d
ed
to
b
r
id
g
e
th
is
g
ap
a
n
d
p
r
o
v
id
e
m
o
lecu
lar
in
s
ig
h
ts
th
at
ar
e
r
elev
an
t
n
o
t
o
n
l
y
f
o
r
b
io
lo
g
ica
l
u
n
d
er
s
tan
d
in
g
b
u
t
also
f
o
r
p
u
b
lic
h
ea
lth
d
ec
is
io
n
-
m
ak
in
g
i
n
I
n
d
o
n
esia.
B
ased
o
n
th
is
b
ac
k
g
r
o
u
n
d
,
th
is
s
tu
d
y
aim
s
to
p
er
f
o
r
m
in
te
g
r
ated
f
u
n
ctio
n
al
an
n
o
tatio
n
o
f
R
A
r
is
k
g
en
es
u
s
in
g
a
m
u
lti
-
d
atab
ase
b
io
in
f
o
r
m
atics
ap
p
r
o
ac
h
.
T
h
is
ap
p
r
o
ac
h
c
o
m
b
in
es
m
is
s
en
s
e
SNPs
an
aly
s
is
,
cis
-
eQT
L
,
GO
an
n
o
tatio
n
,
an
d
K
E
GG
m
o
lecu
lar
p
at
h
way
an
al
y
s
is
.
I
t
is
ex
p
ec
ted
to
s
tr
en
g
th
en
th
e
u
n
d
er
s
tan
d
i
n
g
o
f
th
e
f
u
n
ctio
n
al
r
o
le
o
f
R
A
r
is
k
g
en
es
an
d
s
u
p
p
o
r
t
th
e
d
ev
elo
p
m
e
n
t
o
f
a
s
cien
tific
f
r
am
ewo
r
k
f
o
r
m
o
r
e
p
r
ec
is
e
m
o
lecu
lar
tar
g
e
t id
en
ti
f
icatio
n
.
2.
M
E
T
H
O
D
T
h
is
s
tu
d
y
is
a
m
u
lti
-
d
atab
ase
b
io
in
f
o
r
m
atics
s
tu
d
y
th
at
aim
s
to
i
d
en
tify
an
d
p
r
io
r
itize
R
A
r
is
k
g
en
es
th
r
o
u
g
h
in
teg
r
ated
f
u
n
ctio
n
al
an
n
o
tatio
n
u
s
in
g
p
u
b
lic
g
en
o
m
ic
d
atab
ases
.
T
h
e
an
aly
s
is
was
co
n
d
u
cted
b
y
co
m
b
in
in
g
in
f
o
r
m
atio
n
f
r
o
m
m
is
s
en
s
e
SNP
s
,
cis
-
eQT
L
s
,
GO,
an
d
Un
iPro
t
KB
-
KE
GG
m
o
lecu
lar
p
ath
way
s
to
o
b
tain
a
m
o
r
e
co
m
p
r
eh
e
n
s
iv
e
b
io
lo
g
ical
u
n
d
er
s
tan
d
in
g
o
f
R
A
p
ath
o
g
en
esis
.
2
.
1
.
B
io
info
r
m
a
t
ics
da
t
a
s
o
u
rc
es
T
h
is
s
tu
d
y
is
b
ased
o
n
a
s
ec
o
n
d
ar
y
an
aly
s
is
u
tili
zin
g
v
ar
io
u
s
p
u
b
licly
a
v
ailab
le
b
io
in
f
o
r
m
atics
d
ata,
in
clu
d
in
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ttp
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h
ttp
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atic
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e
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2
.
1
.
1
.
Da
t
a
s
elec
t
io
n r
a
t
io
na
l
e
T
h
e
s
elec
tio
n
o
f
b
io
in
f
o
r
m
ati
cs
d
atab
ases
in
th
is
s
tu
d
y
was
b
ased
o
n
th
eir
s
cien
tific
v
alid
ity
,
d
ata
cu
r
atio
n
s
tan
d
ar
d
s
,
an
d
r
elev
an
ce
to
g
e
n
etic
an
d
f
u
n
ctio
n
a
l
an
n
o
tatio
n
o
f
r
h
e
u
m
ato
id
ar
th
r
itis
.
T
h
e
GW
AS
c
atalo
g
was
ch
o
s
en
as
th
e
p
r
i
m
ar
y
s
o
u
r
ce
o
f
g
en
eti
c
v
a
r
ian
t
s
b
ec
au
s
e
it
p
r
o
v
id
es
s
y
s
tem
at
ically
cu
r
ated
,
p
ee
r
-
r
ev
iewe
d
ass
o
ciatio
n
s
with
s
t
an
d
ar
d
ized
s
ig
n
if
ican
ce
th
r
es
h
o
ld
s
,
en
s
u
r
in
g
r
o
b
u
s
t
an
d
r
e
p
r
o
d
u
cib
le
v
ar
ian
t
s
elec
tio
n
.
Hap
lo
R
eg
v
4
.
2
was
s
elec
ted
d
u
e
to
its
a
b
ilit
y
to
i
n
teg
r
ate
lin
k
a
g
e
d
is
eq
u
ilib
r
i
u
m
in
f
o
r
m
atio
n
with
f
u
n
ctio
n
al
an
n
o
tatio
n
s
,
in
clu
d
in
g
m
is
s
en
s
e
v
ar
ian
ts
an
d
cis
-
ex
p
r
ess
io
n
q
u
an
titativ
e
tr
ait
lo
ci
(
cis
-
eQT
L
s
)
,
wh
ich
ar
e
ess
en
tial
f
o
r
ass
ess
i
n
g
r
eg
u
lato
r
y
a
n
d
f
u
n
ctio
n
al
ef
f
ec
ts
o
f
g
en
etic
v
ar
ia
n
ts
.
W
eb
Gestalt
was
u
s
ed
f
o
r
g
en
e
o
n
to
lo
g
y
(
GO)
an
al
y
s
is
b
ec
au
s
e
it
en
ab
les
s
tati
s
tic
ally
co
n
tr
o
lled
o
v
er
-
r
e
p
r
esen
t
atio
n
an
aly
s
is
ac
r
o
s
s
b
io
lo
g
ical
p
r
o
ce
s
s
es,
m
o
lecu
l
ar
f
u
n
ctio
n
s
,
an
d
ce
llu
lar
co
m
p
o
n
en
ts
.
Un
iPro
tKB
an
d
KE
G
G
wer
e
s
elec
ted
f
o
r
p
ath
way
m
ap
p
in
g
as
th
ey
p
r
o
v
id
e
m
an
u
all
y
cu
r
ated
p
r
o
t
ein
an
d
p
ath
way
in
f
o
r
m
atio
n
,
allo
win
g
r
eliab
le
in
ter
p
r
etatio
n
o
f
m
o
lecu
la
r
m
ec
h
an
is
m
s
in
v
o
lv
ed
i
n
im
m
u
n
e
an
d
in
f
lam
m
at
o
r
y
s
ig
n
alin
g
.
T
h
e
co
m
b
i
n
ed
u
s
e
o
f
th
ese
d
atab
ases
en
ab
le
s
a
co
m
p
lem
en
tar
y
an
d
m
u
lti
-
lay
er
ed
ass
ess
m
en
t
o
f
R
A
r
is
k
g
en
es
th
at
ca
n
n
o
t
b
e
ac
h
iev
ed
u
s
in
g
a
s
in
g
le
d
ata
s
o
u
r
ce
[
1
5
]
,
[
1
7
]
.
2
.
1
.
2
.
G
WAS
c
a
t
a
lo
g
T
h
e
GW
AS
c
atalo
g
is
u
s
ed
as
th
e
p
r
im
ar
y
s
o
u
r
ce
f
o
r
id
en
tif
y
in
g
all
SNPs
th
at
h
av
e
b
ee
n
r
ep
o
r
ted
to
b
e
ass
o
ci
ated
with
R
A.
SN
Ps
s
ea
r
ch
es
ar
e
p
er
f
o
r
m
ed
u
s
in
g
th
e
k
ey
wo
r
d
“r
h
eu
m
ato
id
a
r
th
r
itis
”
an
d
f
ilter
ed
b
ased
o
n
th
e
s
tan
d
ar
d
g
en
o
m
ic
s
ig
n
if
ican
ce
th
r
esh
o
ld
(
p
<
5
×1
0
⁻⁸)
t
o
e
n
s
u
r
e
th
at
o
n
ly
s
tr
o
n
g
a
n
d
r
eliab
le
ass
o
ciatio
n
v
ar
ian
ts
ar
e
an
aly
ze
d
f
u
r
th
e
r
.
T
h
is
s
ig
n
if
ican
ce
th
r
esh
o
ld
is
in
ac
co
r
d
an
c
e
with
th
e
o
f
f
icial
GW
AS
c
atalo
g
g
u
id
elin
es,
wh
ich
ar
e
u
p
d
ate
d
r
eg
u
lar
l
y
an
d
wid
ely
u
s
ed
in
g
en
o
m
ic
s
tu
d
ies
to
im
p
r
o
v
e
d
ata
co
n
s
is
ten
cy
an
d
r
e
p
r
o
d
u
cib
ilit
y
[
1
7
]
,
[
1
8
]
.
2
.
1
.
3
.
H
a
plo
Reg
v
er
s
io
n 4
.
2
Hap
lo
R
eg
v
4
.
2
is
u
s
ed
f
o
r
f
u
n
ctio
n
al
an
n
o
tatio
n
o
f
SNPs
o
b
tain
ed
f
r
o
m
th
e
GW
AS
c
at
alo
g
.
T
h
is
d
atab
ase
p
r
o
v
i
d
es in
f
o
r
m
atio
n
o
n
v
ar
ian
t ty
p
es,
in
clu
d
in
g
id
en
tific
atio
n
o
f
m
is
s
en
s
e
SNPs
,
as we
ll a
s
L
D
d
ata
to
ass
es
s
r
elatio
n
s
h
ip
s
b
etwe
e
n
v
ar
ian
ts
with
in
a
g
en
etic
lo
c
u
s
.
I
n
ad
d
itio
n
,
Ha
p
lo
R
eg
is
u
s
ed
to
ev
alu
ate
th
e
p
o
ten
tial
r
eg
u
lato
r
y
r
o
le
o
f
SNPs
th
r
o
u
g
h
r
e
g
u
lato
r
y
elem
e
n
t
an
n
o
tatio
n
,
cis
-
eQT
L
an
aly
s
is
,
an
d
m
in
o
r
allele
f
r
eq
u
e
n
cy
(
MA
F)
in
f
o
r
m
atio
n
r
elev
an
t to
u
n
d
e
r
s
tan
d
in
g
v
ar
i
an
t d
is
tr
ib
u
tio
n
in
p
o
p
u
latio
n
s
[
1
9
]
,
[
2
0
]
.
2
.
1
.
4
.
WebG
es
t
a
lt
W
eb
Gestalt
wa
s
u
s
ed
f
o
r
GO
an
n
o
tatio
n
a
n
aly
s
is
o
f
id
en
tifi
ed
ca
n
d
id
ate
g
en
es.
GO
an
aly
s
is
co
v
er
s
th
r
ee
m
ain
ca
teg
o
r
ies,
n
am
ely
b
io
lo
g
ical
p
r
o
ce
s
s
,
ce
llu
lar
co
m
p
o
n
en
t,
an
d
m
o
lecu
lar
f
u
n
ctio
n
,
to
id
en
tify
th
e
d
o
m
in
an
t
b
io
l
o
g
ical
f
u
n
ctio
n
s
o
f
R
A
r
is
k
g
en
es.
T
h
e
o
v
er
-
r
ep
r
esen
tatio
n
an
aly
s
is
(
OR
A)
m
eth
o
d
is
ap
p
lied
to
d
eter
m
in
e
s
ig
n
if
ica
n
tly
en
r
i
ch
ed
GO
ca
teg
o
r
ies,
en
a
b
lin
g
f
u
n
ctio
n
al
i
n
ter
p
r
etatio
n
o
f
g
en
es
in
th
e
co
n
tex
t
o
f
R
A
p
ath
o
g
e
n
esis
[
2
1
]
,
[
2
2
]
.
2
.
1
.
5
.
UniPr
o
t
K
B
-
K
E
G
G
Un
ip
r
o
t
KB
is
u
s
ed
to
o
b
tai
n
c
u
r
ated
p
r
o
tein
in
f
o
r
m
atio
n
,
in
clu
d
in
g
p
r
o
tein
f
u
n
ctio
n
,
s
tr
u
ctu
r
al
d
o
m
ain
s
,
a
n
d
p
r
o
tein
in
v
o
lv
e
m
en
t
in
s
p
ec
if
ic
b
i
o
lo
g
ical
p
r
o
ce
s
s
es.
Data
f
r
o
m
Un
iPro
t
KB
is
th
en
m
ap
p
ed
in
to
m
o
lecu
lar
p
ath
way
s
u
s
in
g
KE
GG
to
id
en
tify
b
io
lo
g
ic
al
an
d
im
m
u
n
o
l
o
g
ical
p
ath
wa
y
s
r
elev
an
t
to
R
A.
T
h
is
p
ath
way
an
aly
s
is
aim
s
to
lin
k
r
is
k
g
en
es to
s
p
ec
if
ic
m
o
lecu
lar
m
ec
h
an
is
m
s
u
n
d
er
ly
i
n
g
in
f
lam
m
atio
n
an
d
im
m
u
n
e
d
y
s
r
eg
u
latio
n
in
R
A
[
2
3
]
-
[
2
5
]
.
I
n
teg
r
ativ
e
m
u
lti
-
d
at
ab
ase
b
io
in
f
o
r
m
atics c
an
b
e
s
e
en
in
Fig
u
r
e
1
.
2
.
2
.
B
io
info
r
m
a
t
ics a
na
ly
s
i
s
2
.
2
.
1
.
Da
t
a
co
llect
io
n a
nd
qu
a
lity
co
ntr
o
l
o
f
v
a
ria
nts
Gen
etic
v
ar
ian
ts
ass
o
ciate
d
with
R
A
wer
e
co
llected
f
r
o
m
th
e
GW
A
S
c
atalo
g
u
s
in
g
th
e
k
ey
wo
r
d
“
r
h
eu
m
ato
id
ar
th
r
itis
.
”
All
SNPs
wer
e
f
ilter
ed
b
ased
o
n
t
h
e
s
tan
d
ar
d
g
en
o
m
ic
s
ig
n
i
f
ican
ce
th
r
esh
o
ld
(
p
<
5
×1
0
⁻⁸)
to
e
n
s
u
r
e
th
at
o
n
l
y
v
ar
ian
ts
with
s
tr
o
n
g
ass
o
ciatio
n
s
wer
e
an
aly
ze
d
f
u
r
th
er
.
T
h
e
ap
p
licatio
n
o
f
th
is
th
r
esh
o
ld
aim
s
to
m
in
im
ize
t
h
e
p
o
s
s
ib
ilit
y
o
f
f
alse
p
o
s
itiv
es
d
u
e
to
lar
g
e
-
s
ca
le
g
en
o
m
ic
ass
o
ciatio
n
tes
tin
g
.
T
h
is
p
r
o
ce
s
s
r
esu
lted
in
a
to
ta
l
o
f
3
,
1
4
5
SNPs
th
at
m
et
th
e
q
u
ality
cr
iter
ia
f
o
r
a
n
aly
s
is
in
th
e
n
ex
t
s
tag
e.
All
g
en
e
s
y
m
b
o
ls
wer
e
v
e
r
if
ied
an
d
s
tan
d
ar
d
ize
d
u
s
in
g
th
e
HUGO
Gen
e
No
m
en
clatu
r
e
C
o
m
m
ittee
(
HGNC)
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
I
n
teg
r
a
tive
fu
n
ctio
n
a
l a
n
n
o
ta
ti
o
n
o
f rh
eu
m
a
to
id
a
r
th
r
itis
r
is
k
g
en
es u
s
in
g
a
…
(
Mu
h
a
mma
d
N
u
h
)
851
da
tab
ase
to
en
s
u
r
e
co
n
s
is
ten
t
an
d
ac
cu
r
ate
g
e
n
e
id
en
tific
ati
o
n
.
Dep
r
ec
ated
s
y
m
b
o
ls
an
d
aliases
wer
e
cr
o
s
s
-
ch
ec
k
ed
a
n
d
u
p
d
ated
p
r
io
r
to
d
o
wn
s
tr
ea
m
an
aly
s
es
[
2
6
]
,
[
2
7
]
.
Fig
u
r
e
1
.
I
n
teg
r
ativ
e
m
u
lti
-
d
at
ab
ase
b
io
in
f
o
r
m
atics a
n
aly
s
is
o
f
r
h
e
u
m
ato
id
a
r
th
r
itis
r
is
k
g
e
n
es
2
.
2
.
2
.
L
ink
a
g
e
d
is
equil
ibr
iu
m
(
L
D)
s
cr
ee
nin
g
L
D
s
cr
ee
n
in
g
was
p
er
f
o
r
m
ed
u
s
in
g
Hap
lo
R
eg
v
4
.
2
with
a
co
r
r
elatio
n
co
ef
f
icie
n
t
th
r
esh
o
ld
o
f
r
²
>
0
.
8
.
T
h
is
s
tep
aim
s
to
r
ed
u
ce
v
ar
ian
t
r
e
d
u
n
d
an
cy
o
r
ig
in
ati
n
g
f
r
o
m
th
e
s
am
e
g
en
etic
ass
o
ciati
o
n
s
ig
n
al
in
a
s
in
g
le
lo
cu
s
.
B
y
elim
in
atin
g
h
ig
h
ly
co
r
r
elate
d
SNPs
,
th
e
an
aly
s
is
f
o
cu
s
es
o
n
th
e
m
o
s
t
r
ep
r
esen
tativ
e
v
ar
ian
ts
in
ea
ch
L
D
b
l
o
ck
.
T
h
is
s
tr
ate
g
y
is
c
o
m
m
o
n
ly
u
s
ed
in
th
e
f
in
e
-
m
ap
p
in
g
p
r
o
ce
s
s
to
p
r
io
r
itize
v
ar
ian
ts
with
h
ig
h
er
p
o
ten
tial b
io
lo
g
ica
l r
el
ev
an
ce
[
1
8
]
,
[
2
8
]
.
2
.
2
.
3
.
F
un
ct
io
na
l
a
nn
o
t
a
t
io
n
:
m
is
s
ens
e
m
uta
t
io
ns
a
nd
m
ino
r
a
llele
f
re
qu
ency
(
M
AF
)
SNPs
r
esu
ltin
g
f
r
o
m
L
D
s
c
r
ee
n
in
g
wer
e
a
n
aly
ze
d
u
s
in
g
Hap
lo
R
eg
v
4
.
2
to
id
e
n
tify
m
is
s
en
s
e
v
ar
iatio
n
s
,
n
am
ely
n
u
cleo
tid
e
v
ar
ian
ts
th
at
ca
u
s
e
am
in
o
ac
id
ch
an
g
es a
n
d
h
av
e
t
h
e
p
o
ten
tia
l to
d
ir
ec
tly
im
p
ac
t
p
r
o
tein
s
tr
u
ctu
r
e
a
n
d
f
u
n
ctio
n
.
Fro
m
th
is
an
aly
s
is
,
5
8
m
is
s
en
s
e
S
NPs
wer
e
p
r
io
r
itized
as
ca
n
d
id
ates
with
d
ir
ec
t
f
u
n
ctio
n
al
im
p
ac
t.
I
n
a
d
d
itio
n
,
ea
ch
SNPs
was
an
n
o
tated
with
MA
F
in
f
o
r
m
atio
n
in
Asi
an
,
Af
r
ica
n
,
E
u
r
o
p
ea
n
,
a
n
d
Am
er
ican
p
o
p
u
latio
n
s
to
ev
alu
ate
cr
o
s
s
-
p
o
p
u
latio
n
allele
d
is
tr
ib
u
tio
n
an
d
ass
ess
v
ar
ian
t
r
elev
an
ce
ac
r
o
s
s
p
o
p
u
latio
n
s
[
2
9
]
-
[
3
1
]
.
2
.
2
.
4
.
G
ene
ex
press
io
n r
eg
ula
t
io
n a
nn
o
t
a
t
i
o
n
(
cis
-
eQ
T
L
)
C
is
-
e
Q
T
L
a
n
a
l
y
s
i
s
w
a
s
p
e
r
f
o
r
m
e
d
u
s
i
n
g
H
a
p
l
o
R
e
g
v
4
.
2
t
o
e
v
a
l
u
a
t
e
t
h
e
p
o
t
e
n
t
i
a
l
i
n
f
l
u
e
n
c
e
o
f
S
N
P
s
o
n
g
e
n
e
e
x
p
r
e
s
s
i
o
n
r
e
g
u
l
a
t
i
o
n
a
r
o
u
n
d
t
a
r
g
e
t
l
o
c
a
t
i
o
n
s
.
S
N
P
s
s
h
o
w
i
n
g
a
n
a
s
s
o
c
i
a
t
i
o
n
w
i
t
h
c
h
a
n
g
e
s
i
n
g
e
n
e
e
x
p
r
e
s
s
i
o
n
l
e
v
e
l
s
w
e
r
e
r
e
c
o
r
d
e
d
a
s
v
a
r
i
a
n
t
s
w
i
t
h
p
o
t
e
n
t
i
a
l
r
e
g
u
l
a
t
o
r
y
f
u
n
c
t
i
o
n
s
.
T
h
i
s
s
t
a
g
e
i
s
i
m
p
o
r
t
a
n
t
f
o
r
l
i
n
k
i
n
g
g
e
n
e
t
i
c
v
a
r
i
a
t
i
o
n
w
i
t
h
t
r
a
n
s
c
r
i
p
t
i
o
n
a
l
r
e
g
u
l
a
t
o
r
y
m
e
c
h
a
n
i
s
m
s
t
h
a
t
c
o
n
t
r
i
b
u
t
e
t
o
R
A
p
a
t
h
o
g
e
n
e
s
i
s
[
3
2
]
,
[
3
3
]
.
2
.
2
.
5
.
G
ene
o
nto
lo
g
y
(
G
O
)
a
na
ly
s
is
GO
an
aly
s
is
was
p
er
f
o
r
m
ed
u
s
in
g
W
eb
Gestal
t
with
th
e
OR
A
ap
p
r
o
ac
h
.
T
h
e
an
al
y
s
is
co
v
er
ed
th
r
ee
m
ain
ca
teg
o
r
ies,
n
am
ely
b
io
l
o
g
ical
p
r
o
ce
s
s
,
ce
llu
lar
co
m
p
o
n
en
t,
a
n
d
m
o
lec
u
lar
f
u
n
ctio
n
,
to
id
en
tif
y
th
e
d
o
m
in
an
t
b
io
lo
g
ical
f
u
n
ctio
n
s
o
f
ca
n
d
i
d
ate
g
e
n
es.
T
h
e
s
ig
n
i
f
ican
ce
th
r
esh
o
ld
was
s
et
at
a
f
alse
d
is
co
v
er
y
r
ate
(
FDR
)
<
0
.
0
5
to
co
n
tr
o
l
f
o
r
er
r
o
r
s
d
u
e
to
m
u
ltip
le
test
in
g
.
T
h
e
r
esu
lts
o
f
th
e
GO
an
aly
s
is
wer
e
u
s
ed
to
s
y
s
tem
atica
lly
in
ter
p
r
et
th
e
b
i
o
lo
g
ical
r
o
les o
f
R
A
r
is
k
g
en
e
s
[
3
4
]
.
2
.
2
.
6
.
M
o
lecula
r
pa
t
hwa
y
ma
pp
ing
K
E
G
G
p
a
t
hwa
y
T
h
e
n
ex
t
ca
n
d
id
ate
g
e
n
es
ar
e
m
ap
p
ed
in
to
th
e
KE
GG
m
o
lecu
lar
p
ath
way
u
s
in
g
Un
iPro
tKB
.
T
h
is
s
tep
aim
s
to
id
en
tify
b
io
l
o
g
ic
al
an
d
im
m
u
n
o
lo
g
ical
p
ath
wa
y
s
in
v
o
lv
ed
in
R
A
p
ath
o
g
en
e
s
is
.
T
h
e
id
en
tifie
d
p
ath
way
s
in
clu
d
e
m
ajo
r
im
m
u
n
e
s
ig
n
alin
g
p
ath
way
s
s
u
ch
as
J
AK
–
S
T
AT
,
NF
-
κB,
to
ll
-
lik
e
r
ec
ep
t
o
r
,
an
d
in
f
lam
m
ato
r
y
cy
to
k
i
n
e
p
ath
wa
y
s
k
n
o
wn
t
o
p
lay
a
r
o
le
in
au
t
o
im
m
u
n
e
r
esp
o
n
s
es
[
2
0
]
,
[
3
5
]
.
2
.
2
.
7
.
M
ulti
-
da
t
a
ba
s
e
inte
g
ra
t
io
n a
nd
RA
risk
g
ene
prio
rit
iza
t
io
n
All
an
n
o
tatio
n
r
esu
lts
ar
e
in
te
g
r
ated
u
s
in
g
th
e
m
u
ltil
ay
er
g
e
n
e
p
r
io
r
itizatio
n
ap
p
r
o
ac
h
.
E
ac
h
g
en
e
is
ass
ig
n
ed
a
s
co
r
e
b
ased
o
n
ev
i
d
en
ce
s
u
p
p
o
r
t
f
r
o
m
m
u
ltip
le
a
n
n
o
tatio
n
lay
er
s
,
n
am
ely
th
e
p
r
esen
ce
o
f
m
is
s
en
s
e
m
u
tatio
n
s
(
s
co
r
e
1
)
,
cis
-
eQT
L
ev
id
en
ce
(
s
co
r
e
1
)
,
in
v
o
lv
em
en
t
in
KE
GG
p
ath
way
s
(
s
co
r
e
1
)
,
an
d
GO
an
aly
s
is
s
ig
n
if
ican
ce
(
s
co
r
e
1
)
.
Gen
es
with
a
t
o
tal
s
co
r
e
≥
2
ar
e
class
if
ied
as
p
r
io
r
ity
R
A
r
i
s
k
g
en
es
t
h
at
h
a
v
e
h
ig
h
er
b
io
lo
g
ical
r
elev
a
n
ce
an
d
p
o
ten
tially
p
lay
a
n
im
p
o
r
tan
t
r
o
le
in
R
A
p
ath
o
g
en
e
s
is
.
T
h
e
in
teg
r
ativ
e
s
co
r
in
g
f
r
a
m
ewo
r
k
was
d
esig
n
ed
to
p
r
i
o
r
itize
g
en
es
s
u
p
p
o
r
ted
b
y
c
o
n
v
e
r
g
en
t
f
u
n
ctio
n
al
ev
id
en
ce
ac
r
o
s
s
m
u
ltip
le
an
n
o
tatio
n
lay
e
r
s
r
at
h
er
th
an
r
ely
in
g
o
n
a
s
in
g
le
d
ata
s
o
u
r
ce
.
E
ac
h
g
en
e
r
ec
ei
v
ed
o
n
e
s
co
r
e
p
er
f
u
n
ctio
n
al
lay
er
,
in
clu
d
i
n
g
m
is
s
en
s
e
v
ar
ian
t
an
n
o
tatio
n
,
ci
s
-
eQT
L
ev
id
en
ce
,
GO
en
r
ic
h
m
en
t,
an
d
KE
GG
p
ath
way
in
v
o
lv
em
en
t.
T
h
i
s
e
q
u
a
l
-
w
e
i
g
h
t
s
c
o
r
i
n
g
a
p
p
r
o
a
c
h
w
a
s
c
h
o
s
e
n
t
o
r
e
d
u
c
e
a
n
a
l
y
t
i
ca
l
b
i
a
s
a
n
d
i
m
p
r
o
v
e
i
n
t
e
r
p
r
e
t
a
b
i
li
t
y
.
G
e
n
es
w
i
t
h
h
i
g
h
e
r
c
u
m
u
l
a
t
i
v
e
s
c
o
r
e
s
wer
e
c
o
n
s
i
d
e
r
e
d
h
i
g
h
e
r
-
p
r
i
o
r
i
t
y
c
a
n
d
i
d
a
t
e
s
d
u
e
t
o
c
o
n
s
i
s
t
e
n
t
m
u
l
ti
-
l
a
y
e
r
b
i
o
l
o
g
ica
l
s
u
p
p
o
r
t
[
3
6
]
,
[
3
7
]
.
T
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r
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Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
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6
I
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t J Pu
b
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Vo
l.
15
,
No
.
3
,
Sep
tem
b
er
20
26
:
8
4
8
-
859
852
2
.
2
.
8
.
P
o
t
ent
ia
l
bia
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a
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lim
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t
a
t
io
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o
f
s
ec
o
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a
ry
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a
T
h
is
s
tu
d
y
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u
b
ject
to
s
ev
er
al
p
o
ten
tial
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iases
in
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er
en
t
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o
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s
ec
o
n
d
ar
y
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ata
f
r
o
m
p
u
b
lic
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atab
ases
.
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G
W
AS
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ata
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lu
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ce
d
b
y
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o
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u
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ity
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ies
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ich
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ay
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it
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f
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g
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o
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d
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n
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o
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esia.
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n
d
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f
u
n
ctio
n
a
l
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n
o
tatio
n
s
s
u
ch
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e
QT
L
s
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p
ath
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y
ass
ig
n
m
en
ts
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ep
en
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o
n
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ata
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ase
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v
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ag
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tis
s
u
e
av
ailab
ilit
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,
p
o
ten
tially
u
n
d
e
r
r
e
p
r
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tin
g
d
is
ea
s
e
-
r
elev
an
t
tis
s
u
es
in
r
h
eu
m
ato
id
ar
th
r
itis
.
T
h
ir
d
,
lin
k
a
g
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d
is
eq
u
ilib
r
iu
m
p
atter
n
s
m
ay
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ar
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cr
o
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s
p
o
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latio
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s
,
wh
ich
ca
n
af
f
ec
t
v
ar
ian
t
p
r
i
o
r
itizatio
n
.
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o
m
itig
ate
th
ese
lim
itatio
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s
,
th
is
s
tu
d
y
a
p
p
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tr
in
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en
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g
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o
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e
-
wid
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ig
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ican
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th
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esh
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i
u
m
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ilte
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d
m
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lti
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ctio
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o
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itize
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ted
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y
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id
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ac
r
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s
in
d
ep
en
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en
t
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o
tatio
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er
s
.
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eless
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e
f
in
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s
s
h
o
u
ld
b
e
in
ter
p
r
eted
as
h
y
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o
th
esis
-
g
en
er
atin
g
an
d
r
eq
u
ir
e
ex
p
er
im
en
tal
v
alid
atio
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an
d
p
o
p
u
latio
n
-
s
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ec
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ic
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ies to
co
n
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ir
m
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io
lo
g
ical
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d
p
u
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h
ea
lth
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elev
an
ce
[
2
7
]
,
[
2
8
]
.
2
.
2
.
9
.
Sta
t
is
t
ica
l
a
na
ly
s
is
T
o
ass
ess
th
e
r
o
b
u
s
tn
ess
o
f
th
e
p
r
io
r
itizatio
n
r
esu
lts
,
a
s
en
s
itiv
ity
an
aly
s
is
was
co
n
d
u
cted
b
y
ev
alu
atin
g
g
en
e
r
a
n
k
in
g
s
u
n
d
er
alter
n
ativ
e
s
co
r
in
g
s
ce
n
ar
io
s
,
in
clu
d
in
g
p
ar
tial
ex
cl
u
s
io
n
o
f
in
d
iv
id
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al
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n
o
tatio
n
lay
e
r
s
.
C
o
r
e
p
r
io
r
it
ized
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en
es
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em
ain
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n
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is
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tly
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k
ed
a
m
o
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g
th
e
h
ig
h
est
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s
co
r
in
g
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i
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ates,
in
d
icatin
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t
h
at
th
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lts
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e
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o
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d
r
i
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ata
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t
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ef
lecte
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r
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ig
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als.
T
h
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tatis
t
ical
an
aly
s
is
ca
n
b
e
s
ee
n
in
Fig
u
r
e
2
.
Fig
u
r
e
2
.
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l
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d
atab
ase
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ativ
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in
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o
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atics wo
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k
f
lo
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o
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d
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RE
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I
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a
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p
r
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s
e
n
t
a
t
i
o
n
.
3
.
1
.
Resul
t
s
3
.
1
.
1
.
SNPs
s
cr
ee
nin
g
a
nd
m
is
s
en
s
e
v
a
ria
nt
identif
ica
t
io
n
A
t
o
ta
l
o
f
3
,
1
4
5
SNPs
s
ig
n
i
f
i
c
an
t
ly
ass
o
c
iat
e
d
wi
th
R
A
(
p
<
5
×
1
0
⁻⁸
)
we
r
e
id
e
n
ti
f
ie
d
f
r
o
m
t
h
e
GW
AS
C
atal
o
g
.
Ne
x
t
,
L
D
s
c
r
e
en
in
g
was
p
e
r
f
o
r
m
e
d
u
s
i
n
g
Ha
p
l
o
R
e
g
v
4
.
2
wit
h
a
t
h
r
esh
o
l
d
o
f
r
²
>
0
.
8
t
o
r
e
d
u
c
e
g
e
n
e
tic
s
ig
n
al
r
ed
u
n
d
a
n
c
y
.
T
h
is
s
t
ep
p
r
o
d
u
ce
d
a
n
u
m
b
e
r
o
f
r
e
p
r
ese
n
ta
ti
v
e
v
a
r
ia
n
ts
th
at
w
er
e
t
h
e
n
f
u
n
cti
o
n
al
ly
an
n
o
ta
te
d
.
F
u
n
cti
o
n
a
l
an
n
o
ta
ti
o
n
i
d
e
n
t
if
ie
d
5
8
m
is
s
en
s
e
S
NP
s
t
h
at
c
o
u
l
d
p
o
te
n
t
ial
ly
c
au
s
e
a
m
i
n
o
a
ci
d
ch
a
n
g
es
in
t
ar
g
e
t
p
r
o
te
in
s
.
T
h
ese
m
i
s
s
en
s
e
v
ar
ia
n
ts
we
r
e
d
is
tr
ib
u
ted
ac
r
o
s
s
v
ar
io
u
s
c
an
d
i
d
ate
g
e
n
es
co
m
m
o
n
l
y
ass
o
cia
te
d
w
it
h
im
m
u
n
e
f
u
n
ct
io
n
,
i
n
f
la
m
m
ati
o
n
,
a
n
d
ce
ll
u
la
r
r
es
p
o
n
s
e
r
eg
u
l
ati
o
n
.
Al
l
g
e
n
es
c
o
n
t
ai
n
i
n
g
t
h
es
e
m
is
s
e
n
s
e
SNPs
w
er
e
co
m
p
il
ed
as
a
b
asis
f
o
r
f
u
r
th
er
a
n
al
y
s
is
an
d
s
y
s
t
e
m
ati
ca
ll
y
s
u
m
m
ar
i
ze
d
in
T
a
b
le
1
.
3
.
1
.
2
.
I
nte
g
ra
t
io
n o
f
cis
-
eQ
T
L
a
nd
ca
nd
ida
t
e
g
ene
identif
ica
t
io
n
I
n
t
eg
r
atio
n
o
f
v
a
r
ian
t
d
ata
wi
th
cis
-
eQT
L
was
p
e
r
f
o
r
m
ed
u
s
in
g
Hap
lo
R
eg
v
4
.
2
t
o
s
tr
e
n
g
th
en
th
e
b
io
lo
g
ical
r
elev
an
ce
o
f
ca
n
d
id
ate
g
en
es.
T
h
is
ap
p
r
o
ac
h
e
n
ab
led
th
e
id
en
tific
atio
n
o
f
SNPs
with
th
e
p
o
ten
tial
to
alter
p
r
o
tein
s
an
d
g
en
e
r
e
g
u
lato
r
s
.
T
h
e
r
esu
lts
s
h
o
we
d
th
at
5
2
ca
n
d
id
ate
g
en
es
ac
h
i
ev
ed
an
in
teg
r
ativ
e
s
co
r
e
≥
2
,
in
d
icatin
g
s
u
p
p
o
r
t
f
r
o
m
m
u
ltip
le
la
y
er
s
o
f
f
u
n
cti
o
n
al
ev
i
d
en
ce
.
A
s
m
all
n
u
m
b
er
o
f
g
e
n
es
s
h
o
wed
lo
wer
s
co
r
es
d
u
e
to
lim
ited
an
n
o
tatio
n
s
u
p
p
o
r
t.
T
h
e
d
is
tr
ib
u
tio
n
o
f
s
co
r
es
a
n
d
f
u
n
ctio
n
al
an
n
o
tatio
n
s
ar
e
p
r
esen
ted
in
d
etail
in
T
ab
le
1
.
Alth
o
u
g
h
a
s
u
b
s
tan
tial
n
u
m
b
er
o
f
g
en
es
wer
e
id
en
tifie
d
t
h
r
o
u
g
h
m
is
s
en
s
e
v
ar
ian
t
an
aly
s
is
alo
n
e,
in
teg
r
atio
n
with
cis
-
eQT
L
d
at
a
r
ev
ea
led
th
at
g
e
n
es
s
u
p
p
o
r
te
d
b
y
b
o
th
s
tr
u
ctu
r
al
v
a
r
iatio
n
an
d
tr
an
s
cr
ip
tio
n
al
r
eg
u
latio
n
e
v
i
d
en
ce
ac
h
iev
e
d
h
ig
h
er
p
r
io
r
itizatio
n
s
co
r
es.
T
h
is
f
in
d
in
g
in
d
icate
s
th
at
v
ar
ia
n
ts
in
f
lu
en
cin
g
b
o
th
p
r
o
tein
s
tr
u
ctu
r
e
a
n
d
g
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n
e
e
x
p
r
ess
io
n
h
av
e
g
r
ea
ter
b
io
lo
g
ical
s
ig
n
if
ican
ce
in
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A.
C
o
m
p
ar
ed
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o
g
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s
u
p
p
o
r
ted
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y
o
n
ly
a
s
in
g
le
a
n
n
o
tatio
n
lay
e
r
,
th
ese
v
ar
i
an
ts
ar
e
m
o
r
e
co
n
s
is
ten
tly
ass
o
ciate
d
with
R
A
-
r
elate
d
b
io
lo
g
ical
r
elev
a
n
ce
.
3
.
1
.
3
.
F
un
ct
io
na
l
cla
s
s
if
ica
t
io
n ba
s
ed
o
n G
O
Gen
e
o
n
to
l
o
g
y
an
aly
s
is
was
p
er
f
o
r
m
ed
to
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if
y
th
e
f
u
n
ctio
n
s
o
f
ca
n
d
id
ate
b
io
lo
g
ical
g
en
es
in
to
th
r
ee
m
ain
ca
teg
o
r
ies,
n
am
el
y
b
io
lo
g
ical
p
r
o
ce
s
s
es,
ce
llu
lar
co
m
p
o
n
e
n
ts
,
an
d
m
o
lecu
lar
f
u
n
ctio
n
s
.
T
h
e
an
n
o
tatio
n
r
esu
lts
s
h
o
w
th
at
s
o
m
e
ca
n
d
id
ate
g
en
es
ar
e
in
v
o
lv
ed
i
n
p
r
o
ce
s
s
es
r
elate
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to
im
m
u
n
e
r
esp
o
n
s
e
r
eg
u
latio
n
,
s
ig
n
al
tr
a
n
s
d
u
ctio
n
,
an
d
in
te
r
ce
llu
lar
c
o
m
m
u
n
icatio
n
.
At
th
is
s
tag
e,
GO
an
n
o
tatio
n
is
u
s
ed
as
a
d
escr
ip
tiv
e
f
u
n
ctio
n
al
class
if
icatio
n
with
o
u
t
m
ec
h
a
n
is
tic
in
ter
p
r
etatio
n
.
All
GO
an
n
o
tatio
n
r
esu
lts
ar
e
s
u
m
m
ar
ized
as p
ar
t
o
f
th
e
in
te
g
r
ativ
e
g
en
e
s
co
r
e
an
d
ar
e
s
h
o
wn
in
T
ab
le
1
.
3
.
1
.
4
.
M
o
lecula
r
pa
t
hwa
y
ma
pp
ing
us
i
ng
K
E
G
G
Mo
lecu
lar
p
ath
way
m
ap
p
in
g
was
p
er
f
o
r
m
ed
b
y
lin
k
in
g
ca
n
d
id
ate
g
en
es
to
th
e
KE
GG
d
atab
ase
v
ia
Un
iPro
tKB
.
T
h
is
an
aly
s
is
id
en
tifie
d
th
e
in
v
o
l
v
em
en
t
o
f
a
n
u
m
b
er
o
f
g
en
es
i
n
m
o
lecu
lar
p
ath
way
s
r
elate
d
t
o
cy
to
k
in
e
s
ig
n
alin
g
,
i
n
n
ate
im
m
u
n
e
r
esp
o
n
s
e,
im
m
u
n
e
ce
ll
ac
tiv
atio
n
,
a
n
d
an
tig
e
n
p
r
esen
tatio
n
.
T
h
e
KE
GG
m
ap
p
in
g
r
esu
lts
in
th
is
s
ec
tio
n
ar
e
p
r
esen
ted
d
escr
ip
tiv
ely
as
p
ar
t
o
f
th
e
in
teg
r
ativ
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s
co
r
e
a
s
s
es
s
m
en
t,
with
o
u
t
f
u
r
th
er
b
io
l
o
g
ical
in
ter
p
r
etati
o
n
.
C
o
m
p
lete
in
f
o
r
m
atio
n
r
e
g
ar
d
in
g
th
e
in
v
o
lv
em
en
t
o
f
ca
n
d
id
ate
g
en
es
in
KE
GG
p
ath
way
s
is
p
r
esen
ted
in
T
ab
le
1
.
3
.
1
.
5
.
I
dentif
ica
t
io
n o
f
p
rio
ri
t
y
RA
risk
g
enes
B
a
s
e
d
o
n
t
h
e
r
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s
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l
t
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o
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a
l
l
p
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m
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t
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l
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c
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n
d
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t
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e
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r
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k
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w
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m
o
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c
o
n
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t
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n
v
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l
v
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m
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t
.
T
h
e
r
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n
k
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g
r
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l
t
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s
h
o
w
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d
t
h
a
t
T
Y
K
2
,
I
R
A
K
1
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n
d
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L
2
3
R
h
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d
t
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e
h
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g
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s
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g
r
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t
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v
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s
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o
r
e
s
(
s
c
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r
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=
4
)
,
r
e
p
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e
s
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t
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n
v
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l
v
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m
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t
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o
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l
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Dis
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T
h
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s
tu
d
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ap
p
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a
m
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lti
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ased
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io
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atics
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n
n
o
tatio
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d
KE
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p
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ap
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ly
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ciate
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u
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f
u
n
ct
io
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al
in
v
o
l
v
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en
t
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n
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l
o
g
ical
p
ath
way
s
o
f
th
e
im
m
u
n
e
s
y
s
tem
.
B
ased
o
n
th
e
h
ig
h
est
in
teg
r
ativ
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s
co
r
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TY
K
2
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L2
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,
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s
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.
Evaluation Warning : The document was created with Spire.PDF for Python.
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T
ab
le
1
.
Mu
ltil
ay
er
f
u
n
ctio
n
al
an
n
o
tatio
n
an
d
i
n
teg
r
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s
co
r
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R
A
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M
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Q
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M
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l
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r
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t
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G
To
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l
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r
e
1
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L
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58
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T
ab
le
2
.
Fu
n
ctio
n
al
s
u
m
m
ar
y
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f
p
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r
itized
R
A
r
is
k
g
en
es
No
G
e
n
e
G
e
n
e
f
u
n
c
t
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o
n
M
o
l
e
c
u
l
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ter
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Activ
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lls
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th
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ch
r
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ic
in
f
lam
m
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th
at
c
h
ar
ac
ter
izes
R
A
[
3
8
]
-
[
4
0
]
.
T
h
is
in
teg
r
ativ
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r
esu
lt
is
co
n
s
is
ten
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with
p
r
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I
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4
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7
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lam
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d
jo
in
t
tis
s
u
e
d
am
ag
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in
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[
4
3
]
-
[
4
5
]
.
T
h
e
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io
r
itizatio
n
o
f
I
L2
3
R
in
th
is
in
teg
r
ativ
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io
in
f
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r
m
atics
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aly
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is
is
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n
s
is
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t
with
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ev
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s
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ter
n
ati
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em
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n
s
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atin
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th
at
d
y
s
r
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latio
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f
th
e
I
L
-
2
3
/Th
1
7
p
ath
way
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r
esen
ts
o
n
e
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f
th
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d
o
m
in
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t
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m
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n
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h
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is
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s
s
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s
tain
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g
ch
r
o
n
ic
s
y
n
o
v
ial
in
f
lam
m
atio
n
in
R
A
[
4
6
]
.
I
n
ad
d
itio
n
,
r
ec
e
n
t
g
en
o
m
ic
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im
m
u
n
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g
ical
s
tu
d
ies
h
av
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ted
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if
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R
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th
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le
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L2
3
R
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m
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ig
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alin
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in
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ea
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ath
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en
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r
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s
s
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if
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t
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o
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latio
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s
[
4
7
]
.
T
h
u
s
,
th
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id
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tific
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L2
3
R
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T
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7
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to
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d
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ased
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Me
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I
R
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ten
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T
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I
R
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1
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ase
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T
L
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r
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to
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ter
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1
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r
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ep
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tr
an
s
d
u
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wh
ich
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n
tr
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f
in
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Activ
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f
th
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ath
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ig
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wn
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lex
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v
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s
p
r
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in
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ato
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m
ed
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s
.
Dy
s
r
eg
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latio
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o
f
th
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T
L
R
–
NF
-
κ
B
p
ath
way
h
as
b
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n
s
h
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wn
to
co
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tr
ib
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te
to
th
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am
p
l
if
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o
f
c
h
r
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n
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a
n
d
tis
s
u
e
d
am
ag
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in
R
A.
Pre
v
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e
s
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wn
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at
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en
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a
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s
an
d
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n
cr
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ed
I
R
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ac
tiv
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e
ass
o
ciate
d
with
in
cr
ea
s
ed
in
f
lam
m
ato
r
y
r
esp
o
n
s
es
an
d
d
is
ea
s
e
s
ev
er
ity
in
R
A
[
4
8
]
,
[
4
9
]
.
T
h
e
p
r
io
r
itizatio
n
o
f
I
R
A
K
1
in
th
is
i
n
teg
r
ativ
e
an
aly
s
is
is
co
n
s
is
ten
t
with
p
r
ev
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u
s
s
tu
d
ies
r
ep
o
r
tin
g
ass
o
ciatio
n
s
b
etwe
en
I
R
A
K
1
g
en
etic
v
ar
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n
ts
an
d
h
eig
h
ten
ed
in
f
lam
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ato
r
y
r
esp
o
n
s
es
as
well
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in
cr
ea
s
ed
d
is
ea
s
e
s
ev
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ity
in
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in
clu
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in
g
f
in
d
in
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s
f
r
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m
p
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ased
r
esear
ch
an
d
m
o
lecu
la
r
in
v
esti
g
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n
s
[
5
0
]
,
[
5
1
]
.
T
h
u
s
,
th
e
id
en
tific
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n
o
f
I
R
A
K
1
in
th
is
s
tu
d
y
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n
d
er
s
co
r
es
th
e
im
p
o
r
tan
ce
o
f
in
n
at
e
im
m
u
n
e
s
ig
n
alin
g
in
R
A
p
ath
o
g
e
n
esis
an
d
s
u
p
p
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r
ts
I
R
A
K
1
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m
ed
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p
ath
way
s
as
r
ele
v
an
t
tar
g
ets
f
o
r
in
f
lam
m
atio
n
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f
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c
u
s
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m
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ti
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DG
M
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h
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t
h
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wo
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lik
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to
th
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k
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Ah
m
ad
Da
h
lan
f
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its
in
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titu
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u
p
p
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t,
as
well
as
th
e
s
u
p
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v
is
in
g
lectu
r
er
s
wh
o
p
r
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ce
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in
p
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p
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ly
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ield
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f
b
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f
o
r
m
atics,
d
o
es
th
at
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co
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s
m
o
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ly
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UNDING
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m
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it secto
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CO
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B
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NS ST
A
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M
E
N
T
T
h
is
jo
u
r
n
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ad
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ts
th
e
C
o
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tr
i
b
u
to
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R
o
les
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ax
o
n
o
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y
(
C
R
ed
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to
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th
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ac
h
au
th
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h
as
m
ad
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s
u
b
s
tan
tial
co
n
tr
ib
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tio
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s
to
th
e
wo
r
k
an
d
m
ee
ts
th
e
au
th
o
r
s
h
ip
c
r
iter
ia.
Na
m
e
o
f
Aut
ho
r
C
M
So
Va
Fo
I
R
D
O
E
Vi
Su
P
Fu
Mu
h
am
m
ad
N
u
h
✓
✓
✓
✓
✓
✓
✓
✓
L
o
lita
✓
✓
✓
✓
✓
✓
✓
C
:
C
o
n
c
e
p
t
u
a
l
i
z
a
t
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o
n
M
:
M
e
t
h
o
d
o
l
o
g
y
So
:
So
f
t
w
a
r
e
Va
:
Va
l
i
d
a
t
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o
n
Fo
:
Fo
r
mal
a
n
a
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y
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i
s
I
:
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n
v
e
s
t
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g
a
t
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o
n
R
:
R
e
so
u
r
c
e
s
D
:
D
a
t
a
C
u
r
a
t
i
o
n
O
:
W
r
i
t
i
n
g
-
O
r
i
g
i
n
a
l
D
r
a
f
t
E
:
W
r
i
t
i
n
g
-
R
e
v
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e
w
&
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d
i
t
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n
g
Vi
:
Vi
su
a
l
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z
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t
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p
e
r
v
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s
i
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P
:
P
r
o
j
e
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a
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mi
n
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Fu
:
Fu
n
d
i
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g
a
c
q
u
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si
t
i
o
n
CO
NF
L
I
C
T
O
F
I
N
T
E
R
E
S
T
ST
A
T
E
M
E
NT
Au
th
o
r
s
s
tate
n
o
co
n
f
lict o
f
in
t
er
est.
I
NF
O
RM
E
D
CO
NS
E
N
T
T
h
is
s
tu
d
y
d
id
n
o
t
in
v
o
lv
e
d
ir
ec
t
in
ter
ac
tio
n
with
h
u
m
a
n
p
a
r
ticip
an
ts
.
All
an
aly
s
es
wer
e
co
n
d
u
cte
d
u
s
in
g
an
o
n
y
m
ized
a
n
d
p
u
b
licl
y
av
ailab
le
d
atasets
.
T
h
er
ef
o
r
e
,
in
f
o
r
m
ed
co
n
s
en
t w
as n
o
t r
e
q
u
ir
ed
.
E
T
H
I
CAL AP
P
RO
V
AL
T
h
is
s
tu
d
y
was
co
n
d
u
cted
in
ac
co
r
d
an
ce
with
th
e
p
r
in
cip
le
s
o
f
th
e
Dec
lar
atio
n
o
f
Helsin
k
i.
E
th
ical
ap
p
r
o
v
al
was
n
o
t
r
eq
u
ir
ed
b
e
ca
u
s
e
th
e
s
tu
d
y
u
s
ed
an
o
n
y
m
ized
,
p
u
b
licly
a
v
ailab
le
d
ata
an
d
d
id
n
o
t
in
v
o
lv
e
d
ir
ec
t in
ter
ac
tio
n
with
h
u
m
an
p
ar
ticip
an
ts
.
DATA AV
AI
L
AB
I
L
I
T
Y
Th
e
m
ain
d
ata
an
aly
ze
d
in
th
i
s
s
tu
d
y
wer
e
o
b
tain
ed
f
r
o
m
p
u
b
lic
d
atab
ases
,
n
am
ely
GW
AS
C
a
talo
g
,
Hap
lo
R
eg
v
.
4
.
2
,
W
eb
Gestalt,
an
d
KE
GG
-
Un
iPro
t
.
T
h
e
p
r
o
ce
s
s
ed
d
ata
r
esu
ltin
g
f
r
o
m
th
is
an
aly
s
is
ar
e
av
ailab
le
f
r
o
m
th
e
co
r
r
esp
o
n
d
in
g
au
th
o
r
u
p
o
n
r
ea
s
o
n
ab
le
r
eq
u
est.
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