Circulating Proteins and IgA Nephropathy
Journal of the American Society of Nephrology,
Год журнала:
2024,
Номер
35(8), С. 1045 - 1057
Опубликована: Апрель 30, 2024
Key
Points
A
multiancestry
proteome-wide
Mendelian
randomization
analysis
was
conducted
for
IgA
nephropathy.
The
findings
from
the
study
would
help
prioritize
new
drug
targets
and
drug-repurposing
opportunities.
Background
therapeutic
options
nephropathy
are
rapidly
evolving,
but
early
diagnosis
targeted
treatment
remain
challenging.
We
aimed
to
identify
circulating
plasma
proteins
associated
with
by
studies
across
multiple
ancestry
populations.
Methods
In
this
study,
we
applied
colocalization
analyses
estimate
putative
causal
effects
of
2615
on
in
Europeans
235
East
Asians.
Following
two-stage
network
randomization,
multitrait
protein-altering
variant
annotation
were
performed
strengthen
reliability
results.
protein–protein
interaction
constructed
investigate
interactions
between
identified
existing
medications.
Results
Putative
184
13
protein–disease
pairs
European
Asian
ancestries
identified,
respectively.
Two
showed
shared
them
(CFHR1
FCRL2).
Supported
evidence
analysis,
potential
prioritized
four
opportunities
suggested.
further
provided
strong
medications
pathways
that
known
be
therapeutically
important.
Conclusions
Our
a
number
several
require
investigation.
Язык: Английский
Identification of druggable targets in acute kidney injury by proteome- and transcriptome-wide Mendelian randomization and bioinformatics analysis
Biology Direct,
Год журнала:
2025,
Номер
20(1)
Опубликована: Март 27, 2025
Acute
kidney
injury
(AKI)
remains
a
critical
condition
with
limited
therapeutic
options,
predominantly
managed
by
renal
replacement
therapy.
The
challenge
of
developing
targeted
treatments
persists.
We
integrated
genetic
data
related
to
druggable
proteins
and
gene
expression
AKI
genome-wide
association
study
(GWAS)
findings.
Based
on
multi-omics
Mendelian
randomization
(MR),
we
identified
the
potential
causal
influence
5,883
unique
genes
AKI.
also
performed
using
reverse
MR
external
cohort-based
analysis
verify
robustness
this
relationship.
Expression
patterns
these
targets
were
examined
bulk
transcriptome
single-cell
data.
In
addition,
drug
repurposing
analyses
conducted
explore
existing
medications.
constructed
molecular
interaction
network
interplay
between
known
drugs.
Genetically
predicted
levels
seven
twelve
associated
an
increased
risk
Of
these,
six
(NCF1,
TNFRSF1B,
APEH,
ACADSB,
ADD1,
FAM3B)
prioritized
based
robust
evidence
validated
in
independent
cohorts.
Reverse
showed
one-way
relationship
targets.
These
are
expressed
proximal
tubular
cells,
endothelial
collecting
duct-principal
immune
cells
within
both
AKI-affected
normal
tissues.
Several
promising
opportunities
identified,
such
as
telmisartan-NCF1,
calcitriol-ACADSB,
ethinyl
estradiol-ACADSB.
mapping
pathway
integration
provided
further
insights,
suggesting
strategies
for
combinatorial
therapies.
This
extensive
investigation
several
highlighted
repurposing.
findings
offer
valuable
insights
that
could
shape
future
research
development
treatments.
Язык: Английский
Combining Genetic Proxies of Drug Targets and Time-to-event analyses From Longitudinal Observational Data To Identify Target Patient Populations
medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 5, 2024
Abstract
Background
Human
genetics
is
an
important
tool
for
identifying
genes
as
potential
drug
targets,
and
the
extensive
genetic
study
of
cardiovascular
disease
provides
opportunity
to
leverage
match
specific
patient
populations
targets
improve
prioritization
selection
clinical
studies.
Methods
We
selected
well
described
variants
in
region
PCSK9
(rs11591147
rs562556),
ADRB1
(rs7076938),
ACE
(rs4968782
rs4363)
BAG3
(rs2234962)
use
proxies
effects
drugs.
Time-to-event
analyses
were
utilized
evaluate
their
on
atrial
fibrillation
(AF)
heart
failure
(HF)
death
and/or
re-hospitalization
using
real-world
longitudinal
dataset.
To
mitigate
effect
confounding
factors
(CV)
outcomes,
we
employed
propensity
score
matching.
Results
After
matching,
a
proxy
inhibition
(rs11591147)
improved
survival
from
CV
death/heart
transplant
individuals
following
diagnosis
ischemic
(Hazard
Ratio
(HR)
0.78,
P
=0.04).
A
beta-blockade
(rs7076938)
freedom
rehospitalization
or
with
AF
(HR
0.92,
=0.001),
HF
0.84,
=0.017)
0.85,
=0.0014).
protective
variant
showed
decreased
risk
composite
outcome
within
10
years
patients
(HR=0.96,
=0.033).
Notably,
despite
smaller
cohort
sizes
after
often
observed
numerically
HRs
reduced
P,
indicating
more
pronounced
increased
statistical
association.
However,
not
all
replicated
known
treatment
effects.
Conclusions
Genetic
well-known
drugs
corroborate
findings
trials
disease.
Our
results
may
demonstrate
novel
analytical
approach
that
leverages
evidence
large
effectively
select
where
be
most
effective.
Язык: Английский
Introduction to Genomic-Driven Drug Discovery
Advances in medical technologies and clinical practice book series,
Год журнала:
2024,
Номер
unknown, С. 167 - 184
Опубликована: Дек. 13, 2024
This
chapter
provides
a
comprehensive
overview
of
the
role
genomics
in
accelerating
drug
development
process.
It
highlights
significant
advancements
large-scale
population
collections
and
whole
genome
sequencing
approaches,
which
have
significantly
influenced
multiple
stages
across
lifespan
discovery
program.
The
emphasizes
increasing
importance
genomic
data
target
identification,
prioritization,
tractability,
as
well
predicting
outcomes
from
pharmacological
perturbations.
also
discusses
integrating
technologies
with
other
omics
such
proteomics
metabolomics,
to
understand
disease
mechanisms
better
identify
potential
therapeutic
targets.
integration
bioinformatics
is
pivotal
harnessing
power
for
endeavors.
delves
into
computational
approaches
analytical
frameworks
that
enable
extracting
meaningful
insights
vast
datasets.
Furthermore,
it
examines
contributions
field
pharmacogenomics.
Язык: Английский
PNPLA3 inhibition: Replacing one Evil with the Other?
The Journal of Clinical Endocrinology & Metabolism,
Год журнала:
2024,
Номер
unknown
Опубликована: Май 30, 2024
Journal
Article
Accepted
manuscript
PNPLA3
inhibition:
Replacing
one
Evil
with
the
Other?
Get
access
Arnold
von
Eckardstein,
Eckardstein
Institute
of
Clinical
Chemistry,
University
Zurich
and
Hospital
Zurich,
Switzerland
Correspondence
to:
MD,
Raemistrasse
100,
CH
8091
ZURICH,
Switzerland,
Email:
[email protected].
https://orcid.org/0000-0002-1666-2266
Search
for
other
works
by
this
author
on:
Oxford
Academic
Google
Scholar
Mary
Julieth
Gonzalez
Melo
https://orcid.org/0000-0001-5261-0116
The
Endocrinology
&
Metabolism,
dgae377,
https://doi.org/10.1210/clinem/dgae377
Published:
31
May
2024
history
Received:
19
Revision
received:
25
Editorial
decision:
28
Accepted:
30
Язык: Английский