For more than a decade, Mark Keating, a Howard Hughes Medical Institute investigator at Children's Hospital, and colleagues have produced a string of critical advances in the study of cardiac arrhythmias, identifying a handful of genes that are mutated in an inherited condition called Long QT syndrome (LQT), which is often associated with sudden heart attacks. But these hereditary conditions are quite rare, and can only account for a small percentage of the 450,000 fatal heart attacks suffered by Americans each year.
In 1995, Keating's group documented some LQT mutations in the gene coding for the alpha subunit of the cardiac sodium channel, SCN5A. This serpentine protein snakes through the membrane of heart muscle cells, providing a passage for the flow of sodium ions that initiate the cardiac action potential and heart contraction. Some of these mutations make the channel leaky, allowing current to pass when it should be closed, and increasing the chances of a potentially fatal arrhythmia. But could other variants in genes such as SCN5A contribute to other cases of sudden heart attack that do not appear to be hereditary?
As reported in the August 23, 2002, issue of Science, Keating's group became interested in an African-American woman with a slightly abnormal EKG but no family history of heart disease. She had a curious single base change in the SCN5A gene, not previously associated with arrhythmia. This variant — the substitution of a C to A — changes the 1102nd amino acid in the SCN5A protein from a serine to a tyrosine (S1102Y).
Heart of the Matter
This Y1102 variant, or allele, turns out to be far more common in people of African descent than in other populations. Specifically, it is found in about 20 percent of West Africans and Caribbean individuals, as well as in 13 percent of African Americans. In contrast, the mutation occurs in less than 1 percent of Hispanics, and was not detected in more than 1,000 Caucasians and Asians tested.
Keating's team found that the variant is highly over-represented in African-Americans with
|I. Splawski, K.W. Timothy, M. Tatoyama, C.E. Clancy, A. Malhotra, A.H. Beggs, F. P. Cappuccio, G.A. Sagnella, R.S. Kass, & M.T. Keating. "Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia." Science 297, 1333-1336 (2002).
M.T. Keating & M.C. Sanguinetti. "Molecular and cellular mechanisms of cardiac arrhythmias." [Review]. Cell, 104, 569-580 (2001).
arrhythmia — more than 50 percent of patients carried either one or two copies of the Y1102 variant. Not all carriers, however, exhibit symptoms of arrhythmia, indicating that the variant alone is not sufficient to cause heart problems. So what is the effect of Y1102?
By purifying the mutant channel protein and studying its biophysical properties, Keating recorded subtle, but reproducible, differences with the normal variant. The presence of the Y1102 residue subtly alters the gating properties of the channel, causing it to remain open slightly longer than normal. This in turn prolongs the duration of the action potential duration, which subsequently can cause transient conduction abnormalities between heart cells, contributing to arrhythmia risk. The researchers also studied a computer simulation of the effects of the Y1102 substitution. Comparisons with clinical findings of drug effects on arrhythmias revealed that the polymorphism did produce the predicted sensitivity.
What are the clinical consequences of this mutation? Some 4.6 million African-Americans carry the Y1102 allele, but although most will likely never experience heart problems, carrying this variant could exacerbate the risk of arrhythmia. This is particularly true if, for example, individuals are taking certain medications such as antihistamines, antibiotics, blood pressure medication, or suffer from a deficit of potassium. "The key to therapy is prevention," the authors conclude, to which Keating adds, "It is worth knowing if you have the variant, because there are simple things you can do to prevent arrhythmias." Smart moves include avoiding certain medications, maintaining normal levels of electrolytes, and possibly beta-blocker therapy. Maintaining electrolyte levels, particularly potassium, is well-known to be important to counter the risk of heart attacks — too much salt, for example, can block another important cardiac channel, the potassium channel HERG.
Studies showing increased genetic predisposition among certain racial or ethnic groups have often proven a sensitive issue, prone to misunderstanding. Concern has been expressed about the apparent prevalence of certain cancer-causing mutations among Ashkenazi Jews, while the incidence of cystic fibrosis and hemochromatosis is much higher in northern European populations than other groups. While Keating does not believe routine genetic testing for the SCN5A variant is justified, it is certainly feasible, and might be worthwhile depending on the existence of other risk factors. In time, tests such as for Y1102 will likely be part of a systematic screening procedure, allowing individuals to make lifestyle decisions based on their unique genetic profile.