medRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Фев. 14, 2023
Abstract
Background
Calcium
channel
blockers
(CCBs)
are
common
antihypertensive
medications.
Pharmacogenetic
variants
affect
CCB
clinical
outcomes,
although
effect
sizes
modest
in
community
samples.
Variation
patient
characteristics
may
also
predict
and
variation
attributable
to
relevant
polygenic
scores
is
less
prone
confounding.
We
aimed
test
associations
between
genetically
predicted
plus
pharmacogenetic
with
outcomes
a
large
cohort.
Methods
extended
our
analysis
of
32,000
UK
Biobank
dihydropiridine
CCBs
treated
participants
(mean
duration
5.9
years)
testing
23
variants,
where
NUMA1
rs10898815
RYR3
rs877087
showed
the
most
robust
(for
discontinuation
heart
failure,
respectively).
calculated
for
systolic
diastolic
blood
pressures
(SBP
DBP),
body
fat
mass,
waist
hip
ratio,
lean
serum
calcium,
eGFR,
lipoprotein
A,
urinary
sodium,
liver
fibrosis.
Outcomes
were
discontinuation,
coronary
disease
chronic
kidney
disease.
Results
For
highest
risk
20%
mass
A
associated
increased
risks
(Hazard-Ratio
(HR)Fat-mass
1.46,
95%
CI
1.25-1.70,
p=1*10-6;
HRLean-mass
1.20,
95%CI
1.04-1.38,
p=0.01;
HRLipoproteinA
1.29,
1.12
1.48,
p=
4*10-4),
versus
lowest
each
score
respectively.
Across
cohort,
T-allele
modestly
failure
(HR
1.13:
1.02-1.25)
non-carriers,
but
subsets
high
scores,
estimates
substantially
larger,
e.g.,
females
aged
65-70
Relative
Risk
was
4.4
(95%
1.54-12.4)
no
T-alleles
low
scores.
20%,
whereas
SBP
DBP
decreased
risks.
Hazard
ratios
A-allele
(overall
HR
1.07:
1.02-1.12)
higher
1.17:
1.05-1.29)
those
mass.
Conclusion
Polygenic
affecting
adiposity
levels
add
known
predicting
key
treatment.
Combining
individual
characteristic
help
personalizing
prescribing.
What
needed,
what
do
we
add?
previously
that
patients,
modest.
Various
reportedly
outcomes.
therefore
tested
effects
using
They
minimize
unmeasured
confounders
as
genotypes
invariant
since
conception
reflect
lifetime
exposure
factor.
combining
improved
outcome
prediction.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Июнь 2, 2023
Abstract
We
assess
performance
and
limitations
of
polygenic
risk
scores
(PRSs)
for
multiple
blood
pressure
(BP)
phenotypes
in
diverse
population
groups.
compare
“clumping-and-thresholding”
(PRSice2)
LD-based
(LDPred2)
methods
to
construct
PRSs
from
each
GWAS,
as
well
multi-PRS
approaches
that
sum
with
without
weights,
including
PRS-CSx.
use
datasets
the
MGB
Biobank,
TOPMed
study,
UK
biobank,
All
Us
train,
assess,
validate
groups
defined
by
self-reported
race/ethnic
background
(Asian,
Black,
Hispanic/Latino,
White).
For
both
SBP
DBP,
PRS-CSx
based
PRS,
constructed
a
weighted
developed
independent
perform
best
across
all
backgrounds.
Stratified
analysis
shows
are
better
predictive
BP
females
compared
males,
individuals
obesity,
middle-aged
(40-60
years)
older
younger
individuals.
Abstract
Atherosclerotic
cardiovascular
disease
(ASCVD)
remains
the
leading
cause
of
death
in
world.
However,
advances
genetics,
omics
research,
machine
learning
(ML),
and
precision
medicine
have
inspired
revolutionary
new
tools
ASCVD
risk
stratification.
Together,
polygenic
scores
(PRS)
composite
ML-based
algorithms
help
shift
paradigm
away
from
binary
predictions
towards
more
comprehensive
continuum
models.
Continued
efforts
are
needed
to
address
socioeconomic
racial
disparities
PRS
space.
Journal of Infection and Public Health,
Год журнала:
2025,
Номер
unknown, С. 102686 - 102686
Опубликована: Янв. 1, 2025
Tuberculosis
(TB)
is
a
widespread
infectious
disease
and
associated
with
high
mortality
if
not
effectively
treated.
We
studied
the
influence
of
sodium-glucose
cotransporter
2
inhibitors
(SGLT2-i)
on
in
patients
TB.
retrospectively
recruited
new-onset
TB
from
National
Health
Insurance
database
2017
to
2020.
The
association
between
one-year
use
SGLT2-i
was
analyzed
by
using
Cox
proportional
hazard
regression.
A
total
34,820
were
identified
period
studied.
classified
those
(n
=
345)
matched
4-fold
cohort
1380
without
1380)
propensity
score
method.
Times
death
averaged
6.2
4.6
months
group
non-SGLT2-i
group,
respectively
(p
0.0150).
Mortality
within
1
year
higher
(17.5
%
vs.
8.1
%,
p
<
0.0001)
than
group.
adjusted
ratio
(AHR)
significantly
lower
(0.42
[0.28-0.63])
high-dose
(0.10
[0.03-0.33])
might
improve
outcomes
for
dose
response.
Although
further
prospective
clinical
trials
validate
this
possibility
are
needed,
be
considered
absence
contraindication.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Фев. 6, 2025
Genome-wide
association
studies
have
identified
thousands
of
genetic
variants
associated
with
non-small
cell
lung
cancer
(NSCLC),
however,
it
is
still
challenging
to
determine
the
causal
and
improve
disease
risk
prediction.
Here,
we
applied
massively
parallel
reporter
assays
perform
NSCLC
variant-to-function
mapping
at
scale.
A
total
1249
candidate
were
evaluated,
30
potential
within
12
loci
identified.
Accordingly,
proposed
three
architectures
underlying
susceptibility:
multiple
in
a
single
haplotype
block
(e.g.
4q22.1),
blocks
5p15.33),
variant
20q11.23).
We
developed
modified
polygenic
score
using
from
Chinese
populations,
improving
performance
prediction
450,821
Europeans
UK
Biobank.
Our
findings
not
only
augment
understanding
architecture
susceptibility
but
also
provide
strategy
advance
stratification.
Determining
GWAS
crucial
for
mechanisms.
authors
apply
MPRA
(NSCLC)
scale
propose
distinct
susceptibility.
BACKGROUND:
Cardiovascular
disease
(CVD)
risk
differs
across
Asian
subgroups,
possibly
due
to
differences
in
hypertension
burden.
We
characterized
lifetime
blood
pressure
(BP)
trajectories
for
East
and
South
individuals
compared
their
associations
with
CVD
risk.
METHODS:
Among
148
872
UK
Biobank
participants
primary
care
utilization
data,
life
course
BP
were
fitted
as
a
function
of
age
by
sex
according
self-identified
ethnicity.
determined
time-averaged
young
adulthood
(18–39
years),
middle
(40–64
later
(≥65
years)
systolic
(SBP)
diastolic
incident
atherosclerotic
RESULTS:
The
predicted
SBP/diastolic
(95%
CI)
at
30
years
was
108
(103–114)/68
(65–71)
mm
Hg
114
(110–118)/72
(71–73)
individuals.
By
40,
projected
reach
an
SBP
130.0
Hg,
whereas
reached
the
equivalent
49
years.
individuals,
each
SD
increase
associated
higher
odds
ratio
1.41
(1.12–1.75),
but
not
among
Asians
(
P
interaction
=0.01).
Midlife
peripheral
artery
(odds
ratio,
2.08
[95%
CI,
1.51–2.88])
ischemic
stroke
3.84
1.08–5.07]).
Later-life
myocardial
infarction
1.52
(1.15–1.92)-fold
2.50
(1.06–3.80)-fold
CONCLUSIONS:
exhibit
distinct
that
age-differentially
associate
CVD.
Disaggregating
subgroups
may
inform
tailored
screening
management.
The Pharmacogenomics Journal,
Год журнала:
2024,
Номер
24(3)
Опубликована: Апрель 17, 2024
Abstract
Pharmacogenetic
variants
are
associated
with
clinical
outcomes
during
Calcium
Channel
Blocker
(CCB)
treatment,
yet
whether
the
effects
modified
by
genetically
predicted
risk
factors
is
unknown.
We
analyzed
32,000
UK
Biobank
participants
treated
dihydropiridine
CCBs
(mean
5.9
years),
including
23
pharmacogenetic
variants,
and
calculated
polygenic
scores
for
systolic
diastolic
blood
pressures,
body
fat
mass,
other
patient
characteristics.
Outcomes
included
treatment
discontinuation
heart
failure.
variant
rs10898815-A
(
NUMA1
)
increased
rates,
highest
in
those
high
mass.
The
RYR3
rs877087
T-allele
alone
modestly
failure
risks
versus
non-carriers
(HR:1.13,
p
=
0.02);
patients
lean
lipoprotein
A,
were
substantially
elevated
(HR:1.55,
4
×
10
−5
).
Incorporating
adiposity
A
may
improve
estimates
of
key
CCB
such
as
failure,
compared
to
alone.
