Approved Research

Identification, Characterization and Structural Elucidation of Significant Exome Variations in Population of Asian Ancestry with Heart Failure

Lay summary

Heart failure (HF) affects over 64 million people worldwide, and HF with preserved ejection fraction (HFpEF) accounts for at least 50% of HF cases, with its prevalence increasing. Despite advances in HF therapy, outcomes remain relatively poor. Asians constitute a significant proportion of the global burden of heart disease but are underrepresented in many global HF trials. Limited data suggest that Asians may have a higher risks for cardiovascular disease, and have similar outcomes (whether they live within or outsides Asia) in cardiovascular deaths and HF worsening that improved similarly with treatment. The molecular pathogenesis of HF specific to the Asian population is not well understood, and genetic variants may contribute to differences in HF presentation in this population.

HF genome-wide association studies (GWAS) have limitations in identifying the exact genes and molecular pathways for the disease. While GWAS identify gene regions associated with HF, they cannot pinpoint the specific molecular pathways and proteins involved in the disease. GWAS does not determine the specific gene and variant causing HF. Thus, it remains challenging to identify the actual causal gene, establishing clear genotype-phenotype correlations and translating genetic advances into improved patient care.

Whole exome sequencing (WES) studies have been conducted to help understand genetic abnormalities associated with HF, with a focus on protein-coding regions. This may lead to the identification of biomarkers and drug targets and offer a clearer path toward therapeutic insights. Although some WES studies have studied ancestral diversities, they have only focused on certain phenotypes. As different ancestral populations have unique genetic characteristics, there is a need to explore the genetic factors specific to Asian ancestry. This may help identify some genetic predispositions and potential therapeutic targets for HF.

This project will be conducted over 3 years based on the hypothesis:

1. There maybe novel genetic variant(s) involved in the pathogenesis of HF, which is predisposed in the Asian population;
2. The examination of identified novel variant(s) will lead to a better understanding of the molecular pathogenesis of HF in the Asian population.

The research will focus on examining specific genetic variants and use that information to better understand the biology of HF, and identify potential biomarkers and therapeutic targets for HF in Asian population. The ultimate goal of this research is to identify potentially clinically actionable biomarkers unique to the Asian HF population, which can help in disease prevention, early diagnosis, and HF hospitalization and mortality reduction.