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UAB Researcher Receives Grant to Look for Rare Variants Linked to Cardiac Hypertrophy


NEW YORK (GenomeWeb) – Building on data generated through the Family Blood Pressure Program (FBPP), a research team from the University of Alabama at Birmingham has kicked off a project that aims to identify rare variants associated with left ventricular (LV) hypertrophy, the thickening of the left ventricle that is closely associated with heart attack, stroke, and heart failure and is particularly prevalent among African Americans.

The work is being supported by a one-year, $1.5 million grant from the National Heart, Lung, and Blood Institute (NHLBI).

The FBPP is a multicenter network of investigators exploring the genetics of blood pressure and hypertension established by the NHLBI in 1995. As part of the program, UAB's Donna Arnett and others undertook two family-based studies — dubbed HyperGEN for hypertension genetic epidemiology, and GENOA for genetic epidemiology network of arteriopathy — that aimed to better understand the genetics behind hypertension and atherosclerosis, respectively.

Through related NHLBI-funded projects, Arnett and colleagues collected echocardiographic data on the studies' participants and analyzed it through linkage analyses and genome-wide association studies, revealing genetic loci contributing to LV hypertrophy.

Still, a large portion of variation in LV traits remains unaccounted for. Hypothesizing that rare variants are responsible for this, Arnett has recently begun work on a project in which whole-exome sequencing will be performed on 1,200 unrelated African Americans with hypertension from the HyperGEN study who were found to have either very high or very low LV mass as measured by echocardiography.

This effort is expected to uncover rare and low-frequency variants contributing to LV mass and related structural and functional phenotypes. Extreme phenotype-based analysis, weighted by function and conservation, will be conducted to identify high-impact coding variants. Arnett said that she and her collaborators will also try to replicate the findings in individuals from the GENOA study.

From these data, the researchers will generate a list of candidate genes and attempt to validate the most significant variants by sequencing all exons and regulatory regions in the remainder of the FBPP families and siblings not already sequenced.

"We will conduct association analysis followed by bioinformatic filtering to identify high-impact coding variants and rank the 768 most significant variants for further external replication," the team wrote in its grant abstract. "We will genotype these in 9,160 [African American] participants from population-based studies using Illumina assays. Gene-based associations will be examined within and meta-analyzed among cohorts."

The most promising variants will then be studied in induced pluripotent stem cell-derived cardiomyocytes derived from HyperGEN participants.

"In those cardiomyocytes, we're going to be knocking down variants that we identify through our exome sequencing for changes in the phenotype in response to drugs that induce hypertrophy and stretching mechanisms that induce hypertrophy," she told GenomeWeb.

Arnett said that she hopes the work may lead to both new biomarkers for early-stage LV hypertrophy, as well as novel therapeutics, which could go a long way in addressing a serious public health issue for the black community.

Though it has been decades since the Framingham Heart Study identified LV hypertrophy as measured via electrocardiogram as a primary risk factor for coronary disease, stroke, and cardiac failure, there are still no treatments available that are specific for the condition.

"We treat blood pressure, we treat obesity — two of the big contributors to hypertrophy — but there's not a unique treatment for hypertrophy," she said. "I think there could be in the future."

And while there are biomarkers for hypertrophic cardiomyopathy, none exist for earlier-stage hypertension-induced hypertrophy, she said. The identification of rare variants underlying LV hypertrophy could create opportunities to diagnose the condition early on and allow for better patient management.