Analysis of Cardiac Mitochondrial DNA in Unique Populations and the Elucidation of Pharmacogenomic Utilization in New York State
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An individual’s genetics can impact drug therapy. Altered oxidative states seen in disorders such as Down syndrome (DS) and coronary artery disease (CAD) may serve as a source of differential drug response or as a potential therapeutic target. DS is the most survivable aneuploidy and is characterized by an additional whole or partial 21 st chromosome. This results in a massive genomic imbalance. Patients with DS are more likely to suffer a range of physical and biochemical defects including congenital heart defects, stunted growth, obesity, and hematological malignancies. These hematological malignancies include Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia, which often manifest early in life. Patients with DS that develop these malignancies are generally treated with anthracycline-based chemotherapeutic regimens that regularly include doxorubicin or daunorubicin. Individuals with DS that are treated with anthracycline-based chemotherapy regimens often display increased toxic effects from the drugs necessary to treat the cancer. These toxicities can include more severe mucositis, leukopenia, and cardiotoxicity. The cause of this increased toxicity in DS is likely multifactorial but rooted in altered protein expression caused by the additional 21 st chromosome (gene dosage effect). Patients with DS also exhibit mitochondrial dysfunction that likely results from the higher level of damaging reactive species generated in trisomic cells. Mitochondrial dysfunction is often the result of damaged or altered mitochondrial DNA (mtDNA). Anthracycline agents have the potential to damage mitochondria via generation of reactive species. The additive effect of anthracycline-related oxidative stress in DS cells with high baselines of oxidative species may be a factor contributing to increased toxicity seen in patients with DS treated with these agents. A range of studies were performed with the aim of ascertaining the status of mitochondria in individuals with DS by considering the mtDNA status. As anthracycline-related cardiotoxicity is prominent in patients with DS, heart tissue was specifically considered. A pilot study that considered the amount of mtDNA and the frequency of a diagnostic “common” mtDNA 4977 deletion was performed. Non-significant increases in the deletion, decreases in mtDNA content, and increased accumulation of the deletion with age were noted in cardiac tissue from the DS group ( p < 0.050). Subsequent studies utilized next-generation massively parallel sequencing to measure mitochondrial variation that occurs in select mtDNA copies (heteroplasmy) were performed. The results indicated that cardiac genomes of individuals with and without DS were similar in all measured endpoints. CAD is characterized by the formation of an atheroma in the arteries supplying blood to the heart. CAD progression is dependent on multiple factors, including oxidative stress. The pro-oxidative cardiovascular environment that exists in CAD can lead to mtDNA damage, resulting in a positive feedback loop of increased oxidative species production. The status of cardiac mtDNA has not been investigated in patients with CAD and compared to those without CAD. A pilot study comparing heteroplasmic mtDNA variation in subjects with and without CAD showed significantly more heteroplasmic single nucleotide variants and overall variants in the control region of the mitochondrial genome. This research represents an exploration into the fundamental factors that may enhance the understanding and development of pharmacologic approaches in patients with DS and CAD, respectively. A large gap of knowledge still exists with respect to actual implementation of pharmacogenomic understanding into clinical practice. To address this, a study using data from the New York Statewide Planning and Research System (SPARCS) was conducted in order to measure pharmacogenomic testing statewide from 2012 through 2015. Pharmacogenomic tests that establish gene expression for the purposes of guiding chemotherapy were more commonly documented in the SPARCS database. Overall, documented pharmacogenomic testing occurs in approximately 57 per 100,000 individuals in the large population represented in the SPARCS database. Women made up 90-95% of the individuals receiving documented pharmacogenomic testing in the SPARCS database in the years considered. This work contributes to the body of knowledge related to the complex genetic consequences of Down syndrome, CAD, and pharmacogenomic testing.