25 February 2019

Getting Personal: Omics of the Heart

Jane Ferguson: Hi everybody. Welcome to Episode 25. I'm Jane Ferguson. This is Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine, and it is February 2019. Let's get started.

The first paper this issue is a concurrent publication and comes to us from 29 different editors-in-chief of 27 major cardiovascular journals, led by Joseph Hill, editor-in-chief of Circulation. This editorial, entitled Medical Misinformation: Vet the Message! gives a pointed reminder of the real life risks of misinformation that spreads rapidly through social media and influences people who are making crucial decisions about healthcare for themselves and their families. Quoting directly from the paper they say, "We, the editors-in-chief of the major cardiovascular scientific journals around the globe, sound the alarm that human lives are at stake. People who decline to use a statin when recommended by their doctor, or parents who withhold vaccines from their children, put lives in harm’s way."

In this editorial they call on those in the media to do a better job of taking responsibility for the information they disseminate. In particular, in evaluating content before disseminating it, and avoiding false equivalencies where overwhelming scientific evidence favors one side of the so called "debate." I'll add to that that those of us who are medical or scientific professionals need to do our best to take the time to explain our science to those around us. The science underlying most of medicine is complex and hard to explain and sometimes incomplete, but we do a disservice to people if we don't at least try. Let's all join the editors in calling everyone to vet information and hold those with power in the media accountable for the spread of misinformation they enable.

Next up this issue, a paper from Jody Ingles, Birgit Funke, and co-authors from the University of Sydney, Harvard Medical School and others, entitled Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. As panels for clinical genetic testing expands to include more genes, there are more and more variants that are detected and reported to patients, but do not necessarily have underlying evidence to support or disprove pathogenicity. This group aimed to systematically assess the validity of potential gene disease associations with hypertrophic cardiomyopathy and left ventricular hypertrophy by curating variants based on multiple lines of genetic and experimental evidence.

They categorized genes based on the strength of evidence of disease causation and reviewed HCM variant classification in the ClinVar variant and phenotype repository. They selected 57 genes to study based on those which were frequently included on test panels or had previous reports of association with HCM. Of HCM genes, only 24% were characterized as having definitive evidence for disease causation, 10% of the genes had moderate evidence, while 66% had limited or no evidence for disease causation. Of syndromic genes, 50% were definitively associated with left ventricular hypertrophy. Of over 4,000 HCM variants in ClinVar, 31% were in genes that, on review, had limited or no evidence for association with disease.

What this study shows is that many genes that are included on panels for diagnostic testing for HCM actually have little evidence for any relationship to disease. Systematic curation is required to improve the accuracy of information being acquired and reported to patients and families with HCM.

Moving on to the next paper. This manuscript describes the international Triadin Knockout Syndrome Registry: The Clinical Phenotype and Treatment Outcomes of Patients with Triadin Knockout Syndrome. It comes from Daniel Clemens, Michael Ackerman and colleagues from the Mayo Clinic. So, Triadin Knockout Syndrome is a rare inherited arrhythmia syndrome and it is caused by recessive null mutations in the cardiac triadin gene. To improve the ability to study this rare syndrome, this group established the International Triadin Knockout Syndrome Registry, with the goal of including patients across the world with homozygous or compound heterozygous triadin null mutations. The registry currently includes 21 patients from 16 families who have been carefully phenotyped and many of whom exhibit T wave inversions and have transient QTC prolongation.

The average age for first presentation with cardiac arrest or syncope was three years of age. Despite a variety of treatments, the majority still have recurrent breakthrough cardiac events. These data highlight the importance of conducting testing for triadin mutations in patients, particularly young children presenting with cardiac arrest, and as this registry grows it will enable a better understanding of the disease and hopefully pave the way for future triadin gene therapy trials.

The next paper comes from Daiane Hemerich, Folkert Asselbergs and colleagues from Utrecht University, and is entitled Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes. They were interested in whether variants that have been associated with myocardial mass may exert their influence through regulatory elements. They analyze the hearts of hypertrophic cardiomyopathy patients and non-disease controls and ran ChIP-seq in 14 patients and 4 controls and RNA-seq in 11 patients and 11 controls.

They selected 52 loci that have been associated with electric cardiogram defined abnormalities in amplitude and duration of the QRS complex and looked specifically at these gene regions. They found differential expression of over 2,700 different genes between HCM and control. They further found differential acetylation over 7,000 regions. They identified over 1000 super enhancers that were unique to the HCM samples. They found significant enrichment for differential regulation between disease and control hearts within the loci previously associated with HCM, compared with loci not associated with HCM. They analyzed regions where putative causal SNPs overlapped regulatory regions, and identified 74 co-localized variants within 20 loci, with particular enrichment for SNPs in differentially expressed promoters. They confirmed associations with 18 previously implicated genes, as well as identifying 14 new genes. Overall, what this study demonstrates is that by looking at regulatory features that differ in affected tissues between disease and healthy individuals, we can learn more about the underlying mechanisms of disease.

Moving on, we have a paper entitled Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates from Ellie Paige, Marc Clément, Daniel Freitag, Dirk Paul, Ziad Mallatt and colleagues from the University of Cambridge. They aimed to investigate a specific SNP in the Interleukin-6 receptor rs2228145, which has been associated with abdominal aortic aneurysms. Inflammation is thought to be a contributor to aneurism progression. The authors hypothesized that the IL-6 receptor's SNP may affect aneurysm growth. They use data from over 2,800 subjects from nine different prospective cohorts and examine the effect of genotype on annual change in aneurysm diameter. Although there was a significant association between genotype and baseline aneurysm size, there was no statistically significant association with growth over time. It appeared that growth was less in minor allele carriers, but the effect if true, was small and the analyses were not powered for small effect sizes.

Sample sizes are limited for cohorts with abdominal aortic aneurysms and the authors already used all available worldwide data. In complimentary experiments in mice, they examined the effect of blocking the IL-6 receptor pathway. They found that selective blockage of the IL-6 trans-signaling pathway mediated by soluble IL-6 receptor was associated with improved survival in two different mouse models. However, blocking the classical membrane-bound IL-6 signaling pathway in addition to the trans-signaling pathway did not lead to improved survival. Although the severe lack of enough subjects for well powered genetic analyses is a major limitation for the study of abdominal aortic aneurism and humans, this paper demonstrates the potential relevance of the IL-6 trans-signaling pathway and aneurysm growth, and suggests that further interrogation of this pathway may be informative in figuring out new ways to prevent aneurysm progression and rupture.

Next, we have the first of two research letters this issue. The letter on Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation comes to us from Marcus Dorr, Renate Schnabel and co-authors from several institutions including University Heart Center in Hamburg. They were interested in gaining a better understanding of the genetics underlying vascular function. They ran a meta-analysis of brachial artery diameter, maximum brachial artery diameter adjusted for baseline diameter, and flow-mediated dilation in over 17,000 individuals of European ancestry from six different GWA studies. They sought to replicate findings in over 9,500 newly genotyped individuals. They identified two novel SNPs for baseline brachial artery diameter, but no SNPs reached significance or replication from maximum brachial artery diameter or flow-mediated dilation. One of the significant SNPs was located in the insulin-like growth factor binding protein 3, or IGFBP-3 gene. They analyzed plasma IGFBP-3 protein levels in 1,400 individuals and found a significant association with brachial artery diameter.

The second SNP they identified is located within the AS3MT gene for arsenite methyltransferase, and this SNP appears to be an eQTL for AS3MT expression in monocytes and arterial tissue. Along with identifying these two genes with potential involvement in baseline brachial artery diameter, this study also supports a low genetic component to flow-mediated dilation, indicating that environmental factors may be or more influential in FMD.

The final research letter comes from Alexis Williams, Craig Lee and colleagues from the University of North Carolina and is entitled CYP2C19 Genotype-Guided Antiplatelet Therapy and 30-Day Outcomes After Percutaneous Coronary Intervention. It is known that loss of function variants in CYP2C19 effect bioactivation of clopidogrel, and CYP2C19 genotyping is increasingly used to guide antiplatelet therapies. The authors were interested in whether genotype-guided therapy is effective in reducing major adverse cardiovascular events in the short term, specifically in the 30 days following percutaneous coronary intervention, when most MACE occurs. They followed over a thousand individuals undergoing PCI and CYP2C19 testing and looked at atherothrombotic and bleeding outcomes. Consistent with implementation of genotype-guided therapy, individuals carrying loss of function alleles were less likely to be prescribed clopidogrel.

However, out of loss of function carriers, those who did take clopidogrel had significantly higher risk of MACE with no difference in bleeding risk. There was no difference by therapy in individuals without a loss of function allele. What this study shows us is that even in the 30 days following PCI, genotype-guided therapy can be effective in protecting individuals carrying loss of function CYP2C19 variants.

And that's it from us for February. Go online to ahajournals.org/journal/circgen to read the full papers, access videos and more, and of course to delve into the podcast archives. Thank you for listening and I look forward to bringing you more next month. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.