# Risk Alleles in Protein Quality Control Genes as Modifiers of Hypertrophic Cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $749,824

## Abstract

Patients with hypertrophic cardiomyopathy (HCM) experience a high symptomatic burden, heart failure and
lethal arrhythmias. While the HCM has been recognized as a disease of the sarcomere for >30 years, the
heterogeneity of disease expression is substantial and not fully explained by these primary genetic variants.
Recent genome wide association studies (GWAS) for HCM have uncovered common genetic variants as risk
alleles for HCM. Many of these are conversely protective alleles for dilated cardiomyopathy (DCM), supporting
the concept of polygenic regulation of contractile function. However, the mechanisms by which they exert their
effects are unknown. Here, we focus on a subset of GWAS loci that strongly implicate protein quality control as
a modifier of HCM. Three of the top 10 loci associated with HCM reside within or near genes that encode
proteins of the heat shock protein 70 (HSP70) chaperone network: BAG3, HSPB7, and DNAJC18. Prior
studies, and our own preliminary data, indicate that these cochaperones are involved in sarcomeric protein
maintenance. We hypothesize that risk alleles in BAG3, HSPB7 and DNAJC18 are strong genetic
modifiers of sarcomeric HCM, acting through distinct molecular mechanisms to coordinate sarcomere
protein dynamics and cardiac contractility. Our approach involves focused human genetic association
studies and functional studies in human model systems. In Aim 1, we will determine the impact of risk alleles in
BAG3, HSPB7, and DNAJC18 on disease expression and clinical outcomes in patients with HCM, stratified by
sarcomere genotype and genetic similarity. Combining cases and controls from several sources, including the
Sarcomeric Human Cardiomyopathy Registry (SHaRe), Penn Medicine BioBank, TOPMED and All of Us, we
will perform a case-control study to determine associations of BAG3, DNAJC18 and HSPB7 risk alleles with
HCM, a case-only analysis to determine association with clinical outcomes, and additive and epistasis
modeling to determine interaction effects. In Aim 2, the role of each co-chaperone in regulating sarcomeric
protein dynamics and contractility will be explored through genetic knockdown experiments. We will determine
effects of each variant on transcript/protein abundance and splice isoforms in cardiomyopathic human hearts.
In parallel, we will perform genome editing of each variant in human stem cell-derived cardiac myocytes
(hiPSC-CMs) and measure cellular phenotypes, including contractility. For the BAG3 coding variant,
Cys151Arg, we will use proximity labeling to determine how this variant affects BAG3 localization and its
interactome. Finally, we will use patient-derived hiPSC-CMs that have reduced levels of MyBP-C to determine
whether chaperone manipulation stabilizes wild-type MyBP-C to rescue haploinsufficiency. Successful
completion of these aims will impact the field by gaining an understanding of the clinical and biological
relevance of HSP70 risk alleles to HCM. Our team is composed of highly ...

## Key facts

- **NIH application ID:** 10824051
- **Project number:** 1R01HL168841-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sharlene M Day
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $749,824
- **Award type:** 1
- **Project period:** 2023-12-14 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824051

## Citation

> US National Institutes of Health, RePORTER application 10824051, Risk Alleles in Protein Quality Control Genes as Modifiers of Hypertrophic Cardiomyopathy (1R01HL168841-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10824051. Licensed CC0.

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