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May 31, 2026Cardiovascular Research

Multiple 4q25 risk variants impair calcium homeostasis and compromise left atrial function

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Why the study?

Do distinct 4q25 risk variants (rs1448818, rs2200733, rs10033464) differentially affect calcium homeostasis and left atrial function to increase the risk of atrial fibrillation?

Population

391,008 individuals from the UK biobank, human atrial myocytes from 66 patients without AF, 119 patients…

Comparison

Presence of 4q25 risk variants vs Non-carriers of the respective risk alleles

Design

Cohort

Follow-up

10-year period

Authors

VJVerónica Jiménez-SábadoCTCarmen TarifaOVO B Vad

Discussion

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Overview

May inform SNP-guided AF risk models; leaves open whether tailored strategies improve outcomes.

Key Points

  • This research investigates how specific genetic variants in the 4q25 region affect calcium homeostasis and atrial function.
  • Analyzed data from 391,008 individuals in the UK Biobank over 10 years.
  • Conducted patch-clamp analyses on human atrial myocytes from 66 patients without AF.
  • Performed linear regression analyses of cardiac MRI data from 39,391 individuals.
  • Three risk alleles increased incident atrial fibrillation (AF) in a dose-dependent manner.
  • Carriers of the rs1448818 allele had reduced L-type calcium current, while rs2200733 and rs10033464 showed differential calcium dynamics.
  • Left atrial volume was increased and ejection fraction decreased in rs1448818 or rs2200733 carriers, while rs10033464 carriers exhibited preserved function.

Structured PICO

Do distinct 4q25 risk variants (rs1448818, rs2200733, rs10033464) differentially affect calcium homeostasis and left atrial function to increase the risk of atrial fibrillation?

P
Population
391,008 individuals from the UK biobank (for incident AF analysis), human atrial myocytes from 66 patients without AF (for patch-clamp), 119 patients (for RyR2 phosphorylation), and 39,391 individuals without AF from the UK biobank (for cardiac MRI).
I
Intervention
Presence of 4q25 risk variants (rs1448818, rs2200733, rs10033464)
C
Comparator
Non-carriers of the respective risk alleles
O
Outcome
Incident AF over 10 years, PITX2C mRNA expression, L-type calcium current (ICaL), transient inward current (ITI) frequency, sarcoplasmic reticulum calcium load, RyR2 phosphorylation, and left atrial volume and active ejection fraction (LAAEF)surrogate

Distinct 4q25 risk variants for atrial fibrillation produce specific alterations in intracellular calcium homeostasis and left atrial function, suggesting genotype-tailored therapeutic strategies may be possible.

Cite This Study

Jiménez-Sábado et al. (2026) studied this question.

synapsesocial.com/papers/6a1bd12d5783ba022b6fcbc7https://doi.org/10.1093/cvr/cvag122
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1A titin missense variant drives atrial electrical remodeling and is associated with atrial fibrillation2026
  2. 2Novel TBX20 Variations Susceptible to Sporadic Atrial Fibrillation2026
  3. 3Investigation the Impact of 2025
  4. 4<i>CAV1</i> —A Susceptibility Gene for Atrial Fibrillation: The Impact of Coding and Noncoding Variants2026
  5. 5Early onset atrial fibrillation as a marker of inherited cardiomyopathy: lessons from combined imaging and genetic assessment2026