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Heart Failure Study at Lund University to Use Arrays, NGS, Mass Spec

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NEW YORK (GenomeWeb) – The European Commission has awarded researchers at Lund University in Sweden €1.5 million ($1.7 million) to probe the mechanics of heart failure using proteomic, genomic, and epidemiological approaches.

The project, called "Integrative omics of heart failure to inform discovery of novel drug targets and clinical biomarkers," or inHForm, recently commenced and is slated to run through March 2021. The EC's Horizon 2020 research and innovation program is funding the effort and Lund is inHForm's sole participant.

Gustav Smith, a molecular epidemiologist at Lund, is the principal investigator on the project. Smith, who is also a cardiologist at Skåne University Hospital in the same city, told GenomeWeb that he decided to create the inHForm project to address the "major unmet clinical need" of heart failure by applying a suite of molecular biology tools in large population cohorts to better understand the condition.

"My belief is that such studies could identify both new therapeutic targets and biomarkers to guide clinical decision making," Smith said.

Smith has spent his career studying the epidemiology of heart disease, particularly the genetic epidemiology of myocardial and valvular phenotypes. In the past 18 months, he has co-authored a dozen papers on the topic, and taken part in several consortia focused on the condition, including the Cohorts for Heart and Aging Research in Genetic Epidemiology, or CHARGE, consortium. Smith was lead author on the project's paper in PLoS Genetics that showcased the use of a combination of genotyping, expression, and methylation array data to identify a genetic variant with an increased risk of death from heart failure.

Smith called the CHARGE results "initial proof of concept" that the method of combining a variety of omics platforms could be used to identify novel pathways in human heart failure.

The preliminary success of CHARGE encouraged Smith to move ahead with inHForm, which will see his research team use a variety of tools, including protein microarrays, SNP genotyping chips, and mass spectrometry to hunt for variants associated with heart failure in sizable cohorts.

The new project will also benefit from access to the detailed phenotypic information contained in Swedish nation-wide disease registers, meaning that Smith and colleagues may be able to link variants of interest with specific phenotypes.

Smith breaks inHForm down into five, distinct work packages. The first package includes using aptamer-based protein arrays from Somalogic and mass spectrometry to profile proteins in blood samples drawn from a cohort of 6,000 subjects and clinical cases to identify subjects at risk for heart disease. Smith said the group will then employ affinity reagents and targeted mass spec to measure "thousands of circulating factors" in a subset of the same samples and relate those to heart failure and genetic variation.

As part of the second package, Smith's team will assess heritable components to outcomes in heart disease using Swedish disease registers. According to Smith, the use of the registers will enable inHForm to study the epidemiology of heart failure across Sweden, allowing the scientists to identify individuals from the population cohorts who developed heart failure during follow-up, and to relate that information to genetic factors and other biomarkers at baseline.

Smith and colleagues will also discover variants associated with heart disease by using Illumina SNP arrays to genotype large cohorts, including 70,000 subjects from three generations based in the city of Malmö in southern Sweden. "We are also undertaking resequencing of selected cases and controls on both the exome and whole-genome scale to further characterize less common variants and to generate local imputation panels," Smith noted. He said that his team will use Illumina instruments to carry out the resequencing.

To improve statistical power, inHForm may integrate data from the UK Biobank, a British biorepository of 500,000 genotyped samples, as well as a variety of consortia, including the HERMES Consortium and Myocardial Genetics Consortium.

In addition to plasma protein profiling, genotyping, and resequencing, inHForm aims to profile expression in human heart tissue samples using Illumina chips, and will also use a custom human cardiomyocyte strain assay to translate genomic and proteomic findings from the first packages of the study into an understanding of pathophysiological mechanisms. He said the latter assay, developed in his lab, is based on the isolation of human cardiomyocytes, which are stretched uniaxially.

As its fifth work package, inHForm will evaluate the importance of plasma proteins and genetic variants in another 3,000 cases.

"I have established clinical collections of blood and heart tissue from patients with heart failure where I can further study the mechanisms and clinical utility of identified biomarkers," said Smith. "My research group is currently performing comprehensive molecular characterization of these samples, using various omics tools."

Data analysis will be carried out at Lund, using  "in-house scripts and various freewares," Smith added. "We have a good computational infrastructure here," he said.

According to Smith, the ultimate goal is to deliver therapeutic targets and clinical biomarkers that can be used to tailor therapies to prevent heart failure in the future. Smith said he retains a "broad network of clinical contacts at other institutions" to move potential targets and markers into clinical use. "We'll see what we find and take it one step at a time," he said.

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