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A polymorphism predisposing to sick sinus syndrome identified
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Utilizing genome-wide association studies, the deCODE group has identified a single nucleotide polymorphism in the alpha-myosin heavy chain — MYH6 — that predisposes to sick sinus syndrome. Carriers of this polymorphism have a 50% increased risk for developing sick sinus syndrome as compared with noncarriers, who have only a 6% increased risk.
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Sick sinus syndrome, also known as SSS, was first described in 1968. It is a syndrome due to primary degenerative disease of the sinus node and the specialized conduction tissue. It is characterized by bradycardia; prolonged sinus pauses from the failure of sinus impulse formation (sinus arrest); block of conduction of sinus impulses to surrounding atrial tissue (sinus exit block); or inability of the sinus rate to accelerate in response to exercise or fever (chronotrophic incompetence). The atrial bradycardia and sinoatrial exit block are also commonly associated with a junctional escape rhythm. Another electrocardiogram manifestation of the syndrome is prolonged atrial asystole.
Symptoms of SSS include dizziness, syncope, confusion, fatigue and HF. These symptoms may be associated with palpitations from persistent or episodic atrial bradycardia. Although SSS can affect any age group with structural cardiac disease, it predominates in the elderly who often have concommitant atrial tachycardia in the form of atrial fibrillation. The syncope associated with SSS is believed to result from atrioventricular and intraventricular conduction defects, as well as ventricular tachyarrhythmias from structural damage. Currently, SSS remains the most common indication for a permanent pacemaker.
Link between the syndrome and mutation
The genome-wide association study was performed utilizing 7.2 million single nucleotide polymorphisms as DNA markers in 792 Icelandic patients diagnosed with SSS who were compared with 37,592 controls. Of note, 627 of the patients had undergone pacemaker implantation.
A significant association was observed between SSS and three of the single nucleotide polymorphisms located on chromosome 14q11. Sequencing in this region uncovered a missense mutation in the MYH6 gene in four carriers; this was absent in noncarriers. The mutation induced the substitution of cytosine for thymidine (c.2161T) in exon 18 of MYH6 at nucleotide position 22,936,019. In the alpha-myosin protein, this mutation substitutes arginine to tryptophan at amino acid 721. This was validated in several independent Icelandic populations. The increased risk for SSS as expressed by the OR is 12.53 (95% CI, 8.08-19.44). The frequency of the mutation is 38% in the Icelandic population, as determined from the 38,384 genotyped. The lifetime risk for diagnosis of SSS is 50% for carriers of the c.2161C>T. In families in which this mutation is present, the risk for a sibling developing SSS is approximately 50%. It is of note that a retrospective analysis of 916 patients diagnosed with syncope showed that 50% were carriers of the c.2161C>T polymorphism.
Although this polymorphism is extremely common in the Icelandic population, it may indeed be restricted to the Icelandic population through a founder effect. Genotyping in other populations, including 184 Danish, 94 Dutch and 1,498 US controls, as well 136 US SSS patients, did not detect a single individual with c.2161C>T. Furthermore, this particular polymorphism or mutation is not present in the HapMap catalog of polymorphisms or that of the recent 15 million polymorphisms identified and annotated by the 1,000 Genomes Project. The mutation is estimated to have occurred 29 generations ago — or approximately 870 years ago. Thus, this polymorphism until further evidence must be regarded as restricted to the Icelandic population.
Unusual features
There are several unusual features of this finding. The finding of a mutation in the alpha-myosin heavy chain (MYH6) that affects conduction is unexpected. Thirty-eight percent of the weight of the human adult heart is due to myosin, primarily beta-myosin heavy chain (MYH7); however, alpha-myosin heavy chain is the predominant myosin in the atrium. Myosin is the contractile engine of the heart and numerous mutations have been identified to be responsible for cardiomyopathies. These abnormalities, as expected, are associated with contractile alterations. Direct involvement of MYH6 in conduction abnormalities would not be anticipated.
However, there may already be an identified connection between the MYH6 gene and conduction because MYH6 encodes a cardiac-specific microRNA — miR-208 — in intron 27 in both mice and humans. This microRNA is claimed to be required for expression of connexin40 (Cx40). The Cx40 encodes for the connexion protein that is involved in conduction and has been shown to be associated with AF in humans. Mice models lacking Cx40 showed abnormalities in both sinus node impulse formation and atrial propagation.
Frequency of the mutation
The other peculiarity of the MYH6 mutation is its frequency. Rare mutations and common polymorphisms are both due to a DNA mutation. However, we commonly refer to those alterations that are rare (ie, occurring less than 1% of the population) as “mutations” and refer to those that are common (ie, occurring in 1% or more of the population) as “polymorphisms.” The 38% frequency of this alteration makes it a common polymorphism. The risk associated with this polymorphism is 12-fold more than that of controls, which are much greater than other common polymorphisms predisposing to disease.
Future insight
SSS is a very common disorder, particularly in the elderly. The discovery of this polymorphism in MYH6 will undoubtedly shed new biological insight into mechanisms controlling cardiac conduction. The idea that a contractile protein also directly involves itself in the regulation of conduction is a novel concept.
The role of this polymorphism, in screening for this disorder, may at present be restricted to the Icelandic population. Further studies are required to determine whether this polymorphism exists outside of the founder population in Iceland. However, that founder may have originated in a European population.
Robert Roberts, MD, is president and CEO of the University of Ottawa Heart Institute and director of the Ruddy Canadian Cardiovascular Genetics Centre at the University of Ottawa Heart Institute. He is also a member of the Cardiology Today Editorial Board. Brandon A. Roberts, MD, MSc, is a resident in internal medicine at Louisana State University.
Holm H. Nat Genet. 2011;43:316-320.
Disclosure: Dr. Roberts and Roberts report no relevant financial disclosures.