AKAP10 (I646V) functional polymorphism predicts heart rate and heart rate variability in apparently healthy, middle-aged European-Americans.

Cardiovascular disease is a leading cause of death in the U.S. with sudden cardiac death (SCD) taking an estimated 300,000 to 460,000 adult lives each year in the U.S (Zheng et al., 2001; de Vreede-Swagemakers et al., 1997; 2007). Unfortunately, SCD is often the first sign of cardiac illness (Weaver & Peberdy, 2002), hence posing a significant challenge for researchers to identify premorbid indicators of SCD. The heritable contribution to cardiovascular disease and SCD is complex (Nabel, 2003). Such complexity has led researchers to investigate genes regulating pathophysiologic pathways thought to enhance susceptibility to these conditions (e.g., autonomic cardiac dysregulation). Higher resting heart rate (HR) and lower tonic measures of autonomic-cardiac function (e.g., heart rate variability or HRV), are significant predictors of SCD related endpoints in apparently healthy individuals (Jouven et al., 2005; Levine, 1997; Liao et al., 1997; Tsuji et al., 1996). Autonomic nervous system dysregulation, particularly low parasympathetic (vagal/cholinergic) activity, is also associated with psychosocial risk factors for coronary heart disease (e.g., hostility and depression), coronary atherosclerosis, and risk of clinical cardiac events (e.g., 1–7). Biometric family and twin studies report significant genetic influence on parasympathetic HRV phenotypes with heritability estimates of up to 65% (Busjahn et al., 1998; Singh et al., 2001; Sinnreich et al., 1999; Snieder et al., 1997; Snieder et al., 2007; Riese et al., 2007; Uusitalo et al., 2007; Kupper et al., 2004; Kupper et al., 2005; de Geus et al., 2007). A large-scale, age-stratified association study comparing 6,500 single nucleotide polymorphisms (SNP’s) located in about 5,000 genes discovered that a SNP resulting in an amino acid change from Ile to Val at position 646 in the dual-specific A kinase-anchoring protein 2 (AKAP10, also called d-AKAP2) gene was associated significantly with a negative health prognosis in the older versus younger sample of humans which may be due, at least in part, to cardiac dysfunction (Kammerer et al., 2003). In this regard, the minor Val variant had a higher affinity to protein kinase A and greater atrioventricular node conduction than the Ile variant (Kammerer et al., 2003). Very recent molecular work suggests that this AKAP10 (I646V) genetic variant is associated with markers that predict an increased risk of SCD (Tingley et al., 2007). Specifically, in mouse embryonic stem cells, heterozygous gene trap disruption of the AKAP10 gene increases the responses of cultured cardiac cells in reaction to cholinergic signals (determined via cells treated with cholinergic and adrenergic agonists). Similar results for HR and square root of the mean squared differences of successive normal-to-normal interbeat intervals (RMSSD) were found in both heterozygous and homozygous mutant mice derived from these mouse embryonic stem cells, suggesting a dominant effect of the AKAP10 gene trap allele. The mutant mice eventually had cardiac arrhythmias and died prematurely. Additionally, a common variant of AKAP10 (646V, 40% of alleles) in a small sample of humans (N=122) with known coronary heart disease was associated with increased resting HR and decreased overall HRV (i.e., standard deviation of normal-to-normal interbeat intervals or SDNN) (Tingley et al., 2007). These findings suggest that AKAP10 regulates HR by modulating the sensitivity of cardiac pacemaker cells to cholinergic vagal inputs in humans possibly conferring risk for SCD. Although the previous evidence suggests that AKAP10 I646V influences cholinergic-autonomic activity in mice and in a small sample humans with established cardiovascular disease, it is not yet known whether this genetic variant is related to cholinergic-autonomic function in a healthy (no apparent cardiovascular disease) large community sample of European ancestry. In the present study, we aimed to investigate whether the same AKAP10 (I646V) genetic variant is related to both resting HR and time and frequency domain HRV phenotypes in a larger (N=1033), more representative U.S. community sample of generally healthy, middle-aged men and women of European ancestry.