10 Feb Two Frequent Genetic Variants Lower Risk for Heart Attack
MedicalResearch.com Interview with:
Wolfgang Sadee, Dr.rer.nat.
Felts Mercer Professor of Medicine and Chair, Pharmacology Director
and Elizabeth S Barrie, PhD
Center for Pharmacogenomics
The Ohio State University Columbus OH
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Sadee and Dr. Barrie: We have determined that two frequent genetic variants can interact in a way that lowers the carrier’s risk for a heart attack. These genetic variants are single nucleotide polymorphisms (SNPs) – single base changes in the DNA sequence – of the dopamine-beta hydroxylase gene (DBH), which converts dopamine to norepinephrine. Both act as hormones in the periphery and as neurotransmitters vital to the brain’s activity central nervous system. Numerous studies had tested genetic variants in DBH for effects on brain functions. In contrast to expectations, however, our work demonstrates that our two genetic variants lower DBH activity primarily in the periphery, in tissues with sympathetic innervation mediated by norepinephrine, such as the heart, lung, and liver. As a result, we searched for genetic influence on risk of various diseases of the cardiovascular system and the lung, metabolic disorders, and more. Each of the two DBH variants alone was associated with a number of disease states; however, when considering both variants in combination, a strong protective effect on the risk for heart attacks was discovered in several clinical trials. Such combined effects arising from interactions between two genetic variants may be more common than currently realized, possibly providing a path towards effective biomarker panels for personalized medicine.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Sadee and Dr. Barrie: The sympathetic tone of peripheral organs is critical to well being and disease risk. The hormone norepinephrine can over-stimulate the heart when it circulates in the bloodstream or is released within the heart. The DBH variants lower DBH expression in turn norepinephrine production in target organs. Testing for the presence of both genetic variants can indicate reduced activity of DBH and reduced norepinephrine (sympathetic tone) in multiple organs. Beta-blockers are mainstream medications for treatment of heart failure, and beta-agonists for treatment of asthma, for example. Patients carrying the DBH SNPs conveying reduced sympathetic activity may be less likely to benefit from beta blockers, but could be more responsive to beta-agonists.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Sadee and Dr. Barrie: Norepinephrine has a pervasive impact on the body on all levels. Because the DBH SNPs robustly influence the local production and release of norepinephrine in sympathetically innervated organs, we anticipate a spectrum of potential effects on disorders and therapies. With the knowledge of how the two DBH SNPs exert their effect, we can exploit the vast databases consisting of clinical studies with genomic information available (genome-wide association studies) to determine where and how the genetic effect alters disease risk or treatment outcomes. Preliminary evidence suggests, that reduced DBH expression could have metabolic effects and represent a risk factor for asthma because lungs need norepinephrine to open constricted airways. The finding that both DBH SNPs combined afford protection against heart attacks further signals the relevance of sympathetic tone and therapeutic options. Prospective trials need to address how this information can be exploited for individualized therapies and disease prevention.
Barrie ES, Weinshenker D, Verma A, Pendergrass SA, Lange LA, Ritchie MD, Wilson JG, Kuivaniemi H, Tromp G, Carey DJ, Gerhard GS, Brilliant MH, Hebbring SJ, Cubells JF, Pinsonneault JK, Norman GJ, Sadee W. Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity. Circ.Res. 115: 1017-1025 (2014). PMID: 25326128
MedicalResearch.com Interview with:, & Wolfgang Sadee, Dr.rer.nat. (2015). Two Frequent Genetic Variants Lower Risk for Heart Attack MedicalResearch.com