The proposed study brings together the applicant's training in mitochondrial physiology and cardiovascular diseases with additional training in bioinformatics, biostatistics, and genetic epidemiology. To this end, a multidisciplinary team of investigators has been assembled to aid the applicant in her training and studies. Further, participation in the programs offered by the Boston University School of Medicine's Faculty Development and Diversity office under the directorship of one of the applicant's primary co-mentors will help her in her professional development and in transitioning to independence. The mechanisms underlying the association of advancing age with atrial fibrillation (AF) are unclear. Declines in mitochondrial function have long been appreciated to play a role in aging but whether alterations in mitochondrial genetics and function underlie age-related AF has not been thoroughly evaluated. The greater sensitivity afforded by whole genome sequencing provides novel opportunities to evaluate specific alterations in mtDNA and AF. We hypothesize that the accumulation of mitochondrial DNA (mtDNA) mutations with advancing age corresponds with a decline in mitochondrial function that promotes the development of AF.
For Aim 1, the applicant will describe the mitochondrial genetic diversity within a multiethnic population of >65,000 participants within the NHLBI's Trans-Omics for Precision Medicine (TOPMed) using bioinformatics annotations and functional predictions of mtDNA mutations (PolyPhen-2, PredictSNP, MFold). We will assess the relations of mtDNA mutations and copy number with advancing age and AF in TOPMed (Aim 2).
In Aim 3, oxidative phosphorylation complex activities will be measured in TOPMed biobanked samples from sex- and comorbidity-matched participants with and without the variants associated with AF from Aim 2 (N=150/group), using immunocapture, spectrophotometric assays. A greater understanding of the contribution of mtDNA mutations in AF will provide insights that could be utilized in precision medicine to identify individuals for specific pharmaceutical targets and lifestyle changes aimed at altering mitochondrial metabolism and downstream signaling processes. The additional training and protected time afforded by the K01 will aid the applicant in making her transition to an independent investigator studying the intersections of mtDNA, mitochondrial physiology, and cardiovascular disease.
Aging is a driver for atrial fibrillation (AF) but the underlying mechanisms are unclear. We propose to use novel whole genome sequencing in >65,000 individuals with the NHLBI's Trans-Omics for Precision Medicine to determine the relations of mitochondrial genetic mutations and function with AF. A greater understanding of the genetic mutations associated with AF may provide support for use of mitochondrial targeted therapeutics or dietary changes aimed at improving mitochondrial function.
