Clinical OMICS

SEP-OCT 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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32 Clinical OMICs September/October 2018 a key protein involved in muscle contraction. During fetal heart development, cells switch on the fetal myosin heavy chain gene to produce the fetal form of the protein. The fetal gene is subsequently switched off, and the adult gene switched on to produce the adult form of the myosin heavy chain protein. The identified link between fetal heart genes and AF hints at two potential mechanisms, Willer explained. "It is pos- sible that variations in fetal cardiac protein-coding genes could impact directly on heart structure or function during cardiac development, which then predisposes to AF later in life. Alternatively, genetic variation occurring in regulatory elements might trigger the undesirable reactivation of fetal genes in the adult heart, which might alter electrical signal- ling, for example, and lead to AF." This second hypothesis was supported by studies in a rabbit model of induced AF, which showed that at least one of the fetal genes identified through the GWAS was reacti- vated in rabbit hearts in parallel with the induction of AF. Effectively, one of the genetic variants acted as a molecu- lar switch that turned off production of adult myosin heavy chain and switched production of the fetal form of myosin heavy chain back on. This switch altered the contractile properties of the heart muscle, which can trigger AF. "If we can demonstrate that turning off the fetal genes in the stressed adult heart can relieve AF, this may represent a potential future therapeutic approach," Willer suggested. AF-Linked Genes Key to Future Treatments The team separately identified known drug compounds that interact with 32 of the 151 AF-linked functional genes. Some of these drugs are already known to be able to either control or trigger cardiac arrhythmias, but other compounds were originally developed to treat completely unrelated diseases, including neuro- psychiatric or inflamma- tory disorders. "Whether the highlighted drugs can be used to treat or prevent atrial fibrillation requires further evaluation, but the findings can be used as a foundation for directing future functional experi- ments and clinical trials," the authors stated in their published paper. "These findings need confirmation but provide a foundation for directing future functional experiments to better understand the biol- ogy underlying atrial fibrillation." Just a couple of weeks before the UM team's paper was released in Nature Genetics, the journal published a meta-analysis of existing AF GWAS. This study, carried out by a large international research group headed by Patrick Ellinor, Ph.D., and scientists at the Broad Institute of MIT and Harvard, included 65,446 cases with AF. The poten- tial now exists to pool data from both studies, to generate an even more detailed list of genetic variants, and a more accurate polygenic risk score, Willer explained to Clinical OMICS. "The Ellinor study gives us a major opportunity to collaborate and increase scientific knowledge even further. One of our next steps will be to see if we can work with the group to put all the data together. Combining the two datasets will increase the sample size significantly,"—to more than 93,000 AF cases—"and will almost certainly lead to the identification of additional genes as potential targets, as well as providing even greater detailed insights into the (continued from previous page) "Each one of the genetic variants and genes that we have identified represents a clue to the underlying pathways and processes that cause AF." —Cristen Willer, Ph.D., University of Michigan Cristen Willer, Ph.D., University of Michigan Department of Internal Medicine tolokonov / Getty Images

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