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An Integrated Multi-Omics Approach to Identify Genetic Underpinnings of Heart Failure and its Echocardiographic Precursors: The Framingham Heart Study.

07:00 EST 8th November 2019 | BioPortfolio

Summary of "An Integrated Multi-Omics Approach to Identify Genetic Underpinnings of Heart Failure and its Echocardiographic Precursors: The Framingham Heart Study."

Heart failure (HF) may arise from alterations in metabolic, structural, and signaling pathways, but its genetic architecture is incompletely understood. To elucidate potential genetic contributors to cardiac remodeling and HF, we integrated genome-wide single nucleotide polymorphisms (SNPs), gene expression, and DNA methylation using a transomics analytical approach. We used robust rank aggregation (where the position of a certain gene in a rank order list [based on statistical significance level] is tested against a randomly shuffled rank order list) to derive an integrative trans-omic score for each annotated gene associated with a HF trait. We evaluated up to 8372 Framingham Heart Study participants (54% women, mean age 55±17 years). Of these, 62 (0.7%) and 35 (0.4%) had prevalent HF with reduced and preserved left ventricular (LV) ejection fraction (HFrEF and HFpEF), respectively. During a mean follow-up of 8.5 years (min-max 0.005-18.6 years), 223 (2.7%) and 234 (2.8%) individuals developed incident HFrEF and HFpEF, respectively. Top genes included (matrix metalloprotease 20) and (promotes actin assembly at intercellular junctions) for LV systolic function; (receptor for ) and (complement C5) for LV remodelling; (expressed during myogenic differentiation) and (cytoskeletal protein) for diastolic function; and (involved in regulation of actin cytoskeleton) for prevalent HFrEF; and for incident HFrEF; and for prevalent HFpEF; and (close to the enzyme) and (close to , the riboflavin transporter) for incident HFpEF. We tested the HF-related top SNPs in the UK biobank, where in (MAF 0.023, odds ratio 0.83, p=0.002) remained statistically significant upon Bonferroni-correction. Our integrative transomics approach offers insights into potential molecular and genetic contributors to HF and its precursors. Although several of our candidate genes have been implicated in HF in animal models, independent replication is warranted.

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Name: Circulation. Genomic and precision medicine
ISSN: 2574-8300
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