Expressive

rs10261575 (PHF14): Heart Diastolic Function Variant

Key takeaways

  • rs10261575 sits near PHF14 (Plant Homeodomain Finger protein 14) and was linked to heart diastolic function - how well the heart relaxes between beats - in a large cardiac MRI study of nearly 40,000 people.
  • The locus is among 9 genome-wide significant variants found near genes involved in heart muscle contractile function and cardiomyopathy.
  • The ALT allele reduces PHF14 expression in at least seven tissues including pancreas, fat, and skin.
  • Age, sex, and diabetes were independent predictors of diastolic function in the same study.
  • Evidence comes from a single large study with internal replication; external replication has not yet been reported.

Key takeaways

  • rs10261575 sits near PHF14 (Plant Homeodomain Finger protein 14) and was linked to heart diastolic function - how well the heart relaxes between beats - in a large cardiac MRI study of nearly 40,000 people.
  • The locus is among 9 genome-wide significant variants found near genes involved in heart muscle contractile function and cardiomyopathy.
  • The ALT allele reduces PHF14 expression in at least seven tissues including pancreas, fat, and skin.
  • Age, sex, and diabetes were independent predictors of diastolic function in the same study.
  • Evidence comes from a single large study with internal replication; external replication has not yet been reported.

What the research says A genome-wide association study (GWAS) of 39,559 UK Biobank participants used cardiac magnetic resonance imaging (MRI) with machine learning motion tracking to measure three validated diastolic function traits: radial peak early diastolic strain rate (PDSRrr), longitudinal peak early diastolic strain rate (PDSRll), and maximum body surface area-indexed left atrial volume (LAVmaxi). Nine significant independent loci were identified, including the PHF14 - NPM1P11 locus, near genes described as involved in sarcomeric function (the contractile units of heart muscle cells) under biomechanical stress and in cardiomyopathy (disease of the heart muscle). A Mendelian randomisation analysis - a method that uses genetic variants as natural experiments to test causal effects - found evidence of a causal relationship between genetically-determined ventricular stiffness and incident heart failure.

Reported associations

  • Diastolic function (cardiac imaging): rs10261575 was identified as one of 9 genome-wide significant independent loci in a GWAS of diastolic function traits - radial and longitudinal peak early diastolic strain rates and maximum left atrial volume - measured by cardiac MRI in 39,559 UK Biobank participants.

Evidence quality Evidence for rs10261575 rests on a single large GWAS of 39,559 UK Biobank participants using cardiac MRI phenotypes derived by machine learning. The study partitioned participants into discovery and validation sets using sequential data release tranches, providing internal but not independent external replication. Nine loci reached genome-wide significance across three diastolic imaging phenotypes. Specific p-values or effect sizes for this variant were not reported in the provided study text. Age, sex, and diabetes were significant independent covariates accounted for in the multivariable analysis. Machine learning-derived cardiac imaging phenotypes are a relatively new approach, and findings await confirmation in independent cohorts. The Mendelian randomisation link between ventricular stiffness and heart failure supports biological plausibility but does not confirm the clinical significance of this specific variant.

Tissue-specific expression effects

  • PHF14: The ALT allele is associated with reduced PHF14 expression across seven tissues - pancreas, visceral abdominal fat (omentum), cultured fibroblasts, esophagus mucosa, subcutaneous fat, testis, and sun-exposed lower leg skin. GTEx Portal
  • ENSG00000230333: The ALT allele is associated with reduced expression of this gene in tibial artery tissue. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs10261575?

rs10261575 is a genetic variant near the PHF14 gene that was linked to diastolic function - how well the heart relaxes and fills with blood between beats - in a genome-wide study of nearly 40,000 participants using cardiac MRI.

What is PHF14 and what does it do in the heart?

PHF14 (Plant Homeodomain Finger protein 14) sits at a locus identified in a genome-wide study of diastolic heart function. The genes at these identified loci were described as involved in sarcomeric function (the contractile machinery of heart muscle cells) under mechanical stress and in cardiomyopathy development, though the specific mechanistic role of PHF14 was not detailed in the study.

Is rs10261575 linked to heart failure?

The study found a causal relationship between genetically-determined ventricular stiffness - a measure this locus contributes to - and incident heart failure using Mendelian randomisation analysis. This is a statistical inference about population-level biology, not a direct clinical prediction for any individual.

What is diastolic function and why does it matter?

Diastolic function describes how well the heart muscle relaxes and chambers refill with blood between beats. It depends on myocardial relaxation, stiffness, and recoil. Abnormal diastolic function is associated with many cardiovascular conditions and can predict health outcomes.

How reliable is the evidence for this variant?

Evidence comes from one large study of 39,559 UK Biobank participants with internal discovery and validation phases. The variant reached genome-wide significance, but independent external replication in separate cohorts has not yet been reported.