Response to Letter Regarding Article, “Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study”
We thank Drs. Herring and Paterson for their thoughtful comments on our article.1 As they have pointed out, no clear mechanism for the role of the NOS1AP gene in the heart in general, or of common genetic variants specifically, is yet understood. They suggest that apart from the effect of less active NOS-I in the cardiomyocyte, it might also affect the sympathetic innervation of the heart, thus contributing to catecholamine-induced sudden cardiac death.
Although we cannot exclude this mechanism, our data cannot provide any direct support for this hypothesis, because of the limited physiological resolution of a simple genetic association. If NOS1AP variants, via altered activation of NOS-I, indeed modulate norepinephrine release from sympathetic innervation of the heart or acetylcholine release from the vagus nerve, NOS1AP alleles could be associated with different resting heart rates. However, we find no association of NOS1AP alleles with resting heart rate (P=0.54 for rs10494366, P=0.93 for rs10918594). Nor did we find a statistically significant difference in the hazard of sudden cardiac death by NOS1AP genotype, but larger samples will be required to exclude such a possibility. The relationship of NOS1AP variation and Long-QT syndrome, if any, remains to be defined. Resequencing of affected individuals to identify rare variants and genotyping of known common variants are needed to identify causation or modification of Long-QT syndrome.
In conclusion, the finding that common genetic variation in NOS1AP is convincingly associated with QT interval duration points to the exciting potential of genome-wide association studies to identify genes and pathways not previously recognized to contribute to myocardial repolarization. The role of autonomic function in myocardial repolarization and arrhythmia triggering is well established, but our data cannot provide direct support for a role of NOS1AP in modulation of autonomic function. As Drs Herring and Paterson conclude, experimental work needs to be done to unravel the underlying mechanism by which NOS1AP variants modulate QT interval duration; a direct effect on autonomic modulation of cardiac electrogenesis is one exciting possibility.