Jul 17, 2019
Jane Ferguson: Hi everyone. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson and this is episode 30 from July 2019.
First up we have a paper, the Subtype Specificity of Genetic Loci Associated With Stroke in 16664 cases and 32792 Controls, from Matthew Trailer and colleagues on behalf of the NINDS Stroke Genetics Network and the International Stroke Genetics Consortium.
They were interested in understanding whether genetic loci previously found to be associated with stroke have distinct associations with stroke subtypes, specifically ischemic and hemorrhagic stroke. They compiled data sets through an international consortium to analyze 16664 stroke cases and 32792 controls, all of European ancestry. The cases were subtyped using two different stroke classification systems: the Trial of ORG 10172 in Acute Stroke Treatment, or TOAST system, and the Causative Classification of Stroke, or CCS system.
They selected genetic loci for consideration based on previous association with stroke in general or stroke subtypes in the MEGASTROKE consortium, which had included a large number of the subjects included in the present study. They used a Bayesian multinomial logistic regression approach to evaluate the association of snips at each locus with stroke subtypes identified under the TOAST and CCS classifications, giving five different case groups compared with a set of controls.
16 loci were taken forward for further analysis. There were seven loci which associated with both ischemic and hemorrhagic strokes subtypes, four which clearly associated with either ischemic or hemorrhagic stroke, with the rest showing less consistent effects. One locus, EDNRA, showed opposite affects for ischemic and hemorrhagic stroke. Overall, the findings indicate a large degree of genetic heterogeneity, but some overlap, suggesting common underlying pathophysiological pathways in different stroke subtypes, potentially related to small vessel disease. More detailed phenotyping and further analysis in large samples is required to fully understand genetic mechanisms underlying the risk of different stroke subtypes.
And, just to add, this paper was previously submitted to the pre-print server Bio Archive. We support open science and are always happy to consider papers that have been submitted to pre-print servers. So, if you have a particularly cool paper on Bio Archive that fits our scope, do feel free to send it our way.
Next up, we have a paper from Fabiola del Greco, Cristian Pattaro, Peter Pramstaller, Alessandera Rossini, and colleagues, from Eurac Research Institute for Biomedicine. This paper, entitled Lipidomics, Atrial Conduction, and Body Mass Index, Evidence from Association, Mediation, and Mendelian Randomization Models, aims to investigate the mechanisms underlying associations between circulating lipids and atrial conduction. They used mass spectrometry measurement of 151 sphingo- and phospholipids in plasma or serum from individuals who had undergone electrocardiogram measurements to ascertain P-wave duration.
They first looked for associations in 839 individuals from the micro islets in South Tyrol, or MICROS study, based in Italy, and replicated in 951 participants of the Orkney Complex Disease Study, ORCADES, based in Scotland. They identified and replicated an association between levels of phosphatidylcholine 38-3 and P-wave duration, which was independent of cholesterol, triglycerides, and glucose levels.
However, the association was mediated by BMI, and suggested that increased BMI may cause both increased levels of PC38-3 and longer P-wave duration, suggesting a role for body mass in altered lipids in atrial electrical activity.
The next paper is a research letter from Hana Bangash, Iftikhar Kullo, and colleagues from the Mayo Clinic on Use of Twitter to Promote Awareness of Familial Hypercholesterolemia.
Scientists and health professionals are increasingly using Twitter to communicate. This team wondered whether organized awareness campaigns, including Twitter events like Tweetathons, really make a different. They analyzed Twitter activity related to familial hypercholesterolemia in September 2018, during national cholesterol education month, which included an international familial hypercholesterolemia awareness day and Tweetathon. They also analyzed tweets from August and October 2018, where there was no formal awareness campaign and compared the FH Twitter activity with that of colorectal cancer, which did not have any formal awareness campaigns at that time.
In September, FH-related tweets increased by 152.9% compared to August, and then declined by over 58% in October. The topic reach for familial hypercholesterolemia was 11.1 million in August, and increased over 250% in September to 37.7 million. The reach declined by over 71% in October to just over 10 million. In comparison, the reach for colorectal cancer declined from 453 million in August to 300 million in September and then increased to 677 million in October, which happened to be breast cancer awareness month.
These data suggest that awareness campaigns like national cholesterol education month do lead to an increase in Twitter activity. However, this increase isn't necessarily sustained during the following month, and it remains unclear whether Twitter activity actually translates into a wider awareness amongst providers or patients, which could translate into clinical benefits. Nonetheless, as the use of Twitter increases, this may be a promising avenue to promote awareness and to disseminate knowledge.
And, of course, I have to take this opportunity to mention that Circulation: Genomic and Precision Medicine is on Twitter and you can follow us @Circ_Gen to keep up with what's going on at the journal.
Next up, we have a letter entitled B-iallelic Mutations in NUP205 and NUP210 Are Associated with Abnormal Cardiac Left-Right Patterning from WeiCheng Chen, Yuan Zhang, Sunhu Yang, Xiangyu Zhou, and colleagues from Tongji University.
They set out to understand the genetic underpinnings of cardiac left-right patterning and to probe why individuals with situs inversus totalis, or SIT, where the chest organs are in a complete mirror image to typical, have almost no symptoms or complications, while individuals with heterotaxy, who have abnormal organ arrangement that is not a mirror image, typically have severe phenotypes including congenital heart disease.
They performed whole exome and whole genome sequencing in 61 family trios with SIT or heterotaxy and identified ballielic missense mutations in nucleoporins NUP205 and NUP210. Nucleoporins comprise the main components of the nuclear pore complex in eukaryotic cells. The team generated induced pluripotent sense cells from peripheral blood cells of an affected patient and a healthy control, and found that there were impairments in protein interactions in the variant cells, particularly interactions with another crucial nucleoporin, NUP93.
In zebra fish, NUP205 knockdown resulted in left-right assymetry and defects in heart looping formation in a subset of fish embryos. Knockdown of both NUP205 and NUP93 resulted in impairments in cilia and human retinal pigment epithelial cells. Gene expression analysis revealed affects in known cilia genes NEC2 and NEC3.
Overall, this study provides evidence that mutations in nucleoporins NUP205 and NUP210 may cause defects in cardiac left/right patterning, potentially through effects on ciliary function.
This issue closes with a letter and response conversation around a recent article on missense mutations in the FLNC gene, causing familial restrictive cardiomyopathy. Hisham Ahamed and Muthiah Subramanian from Amrita Institute of Medical Scientists write to share a case of a woman presenting with features of heart failure and muscular weakness consistent with distal myopathy who was found to carry a deletion in exome 37 of the FLNC gene. This case adds to the previous evidence published by Alvaro Roldan Sofia and Julian Palomino-Doza in March 2019 in our journal, Highlighting Mutations in the FLNC Gene in Cardiomyopathy.
That's all for this month. Come back in August for your roundup of the next issue. Thanks for listening!
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.