Health and death have genetic risk factors. International research has linked ten gene variations to sudden cardiac death (SCD). What is SCD? It is death resulting from an abrupt loss of heart function -- cardiac arrest. Was this perhaps what the first famous poly-marathoner suffered?
Recent - The American Heart Association (AHA) says about 850 Americans die each day without being hospitalized or admitted to an emergency room. Most are sudden deaths caused by cardiac arrest. Death occurs within minutes after symptoms appear. Yet this health problem has received much less publicity than heart attack.
A. Selcuk Adabag and colleagues studied 2,997 people (59% men) who had a heart attack in Olmsted County (Minnesota) between 1979 and 2005. Patient medical records were followed up through 29 February 2008. The risk of sudden cardiac death was the highest during the first month after heart attack and quadruple of the rate in the general population. Each following year saw a constant but lower rate in comparison with the general population. "Sudden cardiac death is independently associated with heart failure but not with recurrent ischemia" concluded the researchers.[1]
Across the globe, in Germany for example, SCD kills about 274 people per day. S. Kauferstein and team studied the causes of sudden cardiac deaths. Their conclusion: "identifiable cardiac ion channel disorders are responsible for a third of cases of sudden cardiac death for which no cause is detectable at postmortem."[2]
In this review of potentially lethal ion channel disorders (channelopathies) such as the long QT syndrome (LQTS), they mentioned more than known 200 mutations in the 5 potassium channel genes KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2; in the sodium channel gene SCN5A, and in the adapter protein ankyrin-B. (The QT interval represents the time for electrical activation and inactivation of the ventricles, the lower chambers of the heart.) (Note genes in bold letters.)
Only in recent years, a further arrhythmia has been associated with sudden cardiac death: the short QT syndrome (SQTS). The ECG of patients with this syndrome shows a shortened QT interval and tall and narrow T waves. Five mutations of the potassium channel genes KCNH2 (SQTS1), KCNQ1 (SQTS2), and KCNJ2 (SQTS3) — which are also associated with the long QT syndrome — have been confirmed as the molecular basis of the SQT syndrome.
Genetic Risk Factors - Earlier this year, at Johns Hopkins, genetic variants in gene NOS1AP, associated with QT interval was identified to increase risk for SCD.[3] The same group's members along with other researchers in USA, Germany, and Italy reported jointly in March two studies, QTGEN and QTSCD, that confirmed these five genes written in bold letters, KCNQ1, KCNH2, KCNE1, SCN5A, and NOS1AP, and identified five additional. [4][5]
The QTGEN researchers performed a meta-analysis of three genome-wide association (GWA) studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study, and the Cardiovascular Health Study. The QTSCD study analyzed genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA, and HNR) with a total of 15,842 individuals of European ancestry. In comparison, Johns Hopkins had conducted the first GWA study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. They validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. About 60% of subjects of European ancestry did carry at least one minor allele of the NOS1AP genetic variant, which explained up to 1.5% of QT interval variation.[3]
QTGEN observed associations at P < 5 x 10-8 with variants in NOS1AP, KCNQ1, KCNE1, KCNH2, and SCN5A, known to be involved in myocardial repolarization and long-QT syndromes. Additional associations were identified at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. The 14 independent variants at these 10 loci explained collectively 5.4–6.5% of the variation in QT interval.
QTSCD confirmed the NOS1AP association and identified nine additional loci at P < 5 x 10-8. Four loci mapped near the long-QT syndrome genes KCNQ1, KCNH2, SCN5A, and KCNJ2; two loci included ATP1B1 and PLN, genes with established electrophysiological function, and three mapped to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively.
Both QTGEN and QTSCD have stated in their publications that their results, together with the "accompanying" paper, offer insights into myocardial repolarization and identify five new candidate genes for ventricular arrhythmias and SCD.
Implications - Most GWA studies have been so far designed to identify single-nucleotide polymorphisms (SNPs) associated with common diseases. This technique has been extended to identify genetic variants related to quantitative traits such as electrocardiographic QT interval as I have described here. The Johns Hopkins study appears to be the first to identify NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization.[3]
This phenotype, which is a risk factor for sudden cardiac death, was evaluated in multiple association studies carried out as part of the QTGEN and QTSCD studies. The study of 15,842 people demonstrated the more of these 10 variants, the greater the chances of having a prolonged QT interval.
A heart attack can also raise the risk of having this type of abnormal heart rhythm, but people who inherit this genetic risk are often unaware. The studies were not about a search for rare variants carried by only a few of us. The primary interest was in common gene variants, which can influence the length of the QT interval. These variants increase an individual's disease risk, not as single genes, but in combination of genetic factors and with other risk factors such as medications or ischemia.
Genes are largely responsible for why some people suffer heart attacks early in life despite a seemingly healthy lifestyle. Those at risk might be offered drugs to mitigate damage. Especially, the young with the highest genetic risk might benefit the most from early intervention.
Clearly, this is an advancement to lead further to new treatment at least for SCD. Surprised?
Folklore Comment - We are told "you can't control your family health history." Not so fast, we can say today. The next research is underway to identify what role each of these known ten genes play in raising risks. These findings might offer a target for new drugs even today.
Do we know what happened to the famous ancient Athenian herald aka Pheidippides? He had run about a twelve-marathon distance in total just to solicit aid on behalf of his city-state from neighboring Sparta. He probably did not die at that point contrary to the poem Pheidippides -- written by Robert Browning some 18 centuries later.
We wonder aloud today if there is a second chance in case of cardiac arrest. "Quick action" is recommended by AHA as delineated below. We can hope to help more than just the poet and the marathoner in our lives. Disease: eat your heart out!
Quick Action - The American Heart Association says cardiac arrest strikes immediately and without warning. These are the warning signs:[6]
If these signs of cardiac arrest are present, tell someone to call 9-1-1 and get an AED (if one is available) and you begin CPR immediately.
If you are alone with an adult who has these signs of cardiac arrest, call 9-1-1 and get an AED (if one is available) before you begin CPR.
Use an AED as soon as it arrives.
Lexicon:
AED: Automated External Defibrillator
CPR: Cardiopulmonary Resuscitation
P: Probability of the observed association arising by chance alone
ECG: lectrocardiogram
References:
[1] A. Selcuk Adabag, Terry M. Therneau, Bernard J. Gersh, and Susan A. Weston, Veronique L. Roger. Sudden Death After Myocardial Infarction. JAMA, 2008; 300 (17): 2022-2029
[2] S. Kauferstein, N. Kiehne, T. Neumann, H. Pitschner, and H. Bratzke. Cardiac Gene Defects Can Cause Sudden Cardiac Death in Young People. Deutsches Ärzteblatt International, 2009; 106(4): 41-7; doi: 10.3238/arztebl.2009.0041
[3] [4] Christopher Newton-Cheh, Mark Eijgelsheim, Kenneth M Rice, Paul I W de Bakker, Xiaoyan Yin, Karol Estrada, Joshua C Bis, Kristin Marciante, Fernando Rivadeneira, Peter A Noseworthy, Nona Sotoodehnia, Nicholas L Smith, Jerome I Rotter, Jan A Kors, Jacqueline C M Witteman, Albert Hofman, Susan R Heckbert, Christopher J O'Donnell, André G Uitterlinden, Bruce M Psaty, Thomas Lumley, Martin G Larson, and Bruno H Ch Stricker. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nature Genetics 41, 399 - 406 (2009): | doi :10.1038/ng.364
[5] Arne Pfeufer, Serena Sanna, Dan E Arking, Martina Müller, Vesela Gateva, Christian Fuchsberger, Georg B Ehret, Marco Orrú, Cristian Pattaro, Anna Köttgen, Siegfried Perz, Gianluca Usala, Maja Barbalic, Man Li, Benno Pütz, Angelo Scuteri, Ronald J Prineas, Moritz F Sinner, Christian Gieger, Samer S Najjar, W H Linda Kao, Thomas W. Mühleisen, Mariano Dei, Christine Happle, Stefan Möhlenkamp, Laura Crisponi, Raimund Erbel, Karl-Heinz Jöckel, Silvia Naitza, Gerhard Steinbeck, Fabio Marroni, Andrew A Hicks, Edward Lakatta, Bertram Müller-Myhsok, Peter P Pramstaller, H-Erich Wichmann, David Schlessinger, Eric Boerwinkle, Thomas Meitinger, Manuela Uda, Josef Coresh, Stefan Kääb, Gonçalo R Abecasis, and Aravinda Chakravarti. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nature Genetics 41, 407 - 414 (2009): | doi :10.1038/ng.362
[6] http://www.americanheart.org
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