Evidence for a gene influencing heart rate on chromosome 4 among hypertensives

Abstract

While mechanisms are poorly understood, resting heart rate has been shown to be a strong predictor of the risk of cardiovascular disease, cancer, and all-cause mortality. We performed a genome scan for quantitative trait loci influencing the resting heart rate among 962 Caucasians and 1,124 African-Americans in the Hypertension Genetic Epidemiology Network (HyperGEN), a multi-center study of genetic and environmental factors related to hypertension. The NHLBI Mammalian Genotyping Service typed a total of 391 anonymous microsatellite markers, spaced roughly equally throughout the genome. Within each race and sex, heart rate was adjusted for covariates, including age, age(2), study center, body mass index, beta-blocker use, alcohol consumption, smoking, number of city blocks walked per day, and number of hours watching television. Genome scans were performed using variance component linkage analysis as implemented by GENEHUNTER (version 2) for each race, using race-specific marker allele frequencies derived from random samples. The highest lod score detected in Caucasians was 2.14 on chromosome 4 (at 195.06 cM); a lod score of 1.14 was found at the same locus among the African-Americans, and a lod score of 3.18 resulted when the two racial groups were combined. Evidence was also found on chromosome 10 to support a recent report of an association between heart rate and the beta1 adrenergic receptor. The suggestive evidence for linkage found on chromosome 4 in both Caucasian and African-American hypertensive sib pairs indicates that further investigation on that region may be warranted to locate a gene influencing variability in resting heart rate.

Adrenergic Receptor Polymorphisms Associated with Resting Heart Rate: The HyperGEN Study

“…In the race specific models of heart rate the characteristics with the largest effects on heart rate were hypertension status, beta blocker use and gender. Beta-blocker medication was significantly associated with a lower resting heart rate among hypertensives, but other hypertensive medications were not strongly related to resting heart rate, which is consistent with our prior report for this cohort (Wilk et al 2002) and the findings of Ranade et al (2002). Since hypertension status and beta blocker use may be effect modifiers of the association between AR polymorphisms and heart rate, we controlled for these factors in analysis by stratification.…”

“…The mean value of six heart rate measures was the dependant variable in a GEE model with all four SNPs and covariates. The covariates included in the model were the same as those used previously to create an adjusted phenotype for genome-wide linkage analyses (Wilk et al 2002), which included age, BMI, sex, alcohol drinking, current smoking, former smoking, blocks walked per day, and hours of TV watched per weekday.…”

“…Greenland et al (1999) evaluated heart rate in a prospective cohort study, and demonstrated that a 12 beat per minute higher heart rate was significantly associated with increased risk of coronary heart disease and cardiovascular disease mortality in middle-aged men and women. Previously, we reported heritability estimates and a genome-wide scan for rest-ing heart rate in the hypertensive subjects of the Hypertension Genetic Epidemiology Network (HyperGEN) (Wilk et al 2002). The estimate of the proportion of variance in resting heart rate explained by genetic factors was 24% for African-Americans and 27% for whites.…”

Linkage of serum leptin levels in families with sleep apnea

“…31 A genome scan for resting heart rate in 513 African Americans from the Hypergen study found a peak at this same location on chromosome 3 (124 cM) for resting heart rate, after adjusting for a series of covariates including BMI (LOD 1.35). 32 Evidence suggests that increased sympathetic nervous system activity, measured by a resting heart rate, is related to aspects of insulin resistance syndrome. 33,34 A linkage analysis for adiponectin in Pima Indians, not treated pharmacologically for diabetes, demonstrated a peak (LOD ¼ 1.8-1.9) at the same location (124 cM) with and without adjusting for BMI.…”

“…It is worth noting, however, that the main finding of the 41 genome scan for resting heart rate is a linkage peak in both Caucasians and African Americans at 195 cM located on chromosome 4.…”