Nina Kupper

Familial influences on basal salivary cortisol in an adult population

To understand the underlying genetic and environmental sources of individual variation in basal cortisol levels, we collected salivary cortisol at awakening and at six fixed time points during the day in adult twins and their singleton siblings. Reported time of awakening was verified with heart rate and body movement recordings. Cortisol data were available for 199 MZ twins, 272 DZ twins and 229 singleton siblings from 309 twin families. No differences in cortisol means and variances were found between twins and singleton siblings. Additionally, the correlations for DZ twins and siblings were not significantly different, indicating generalizability of twin study results to the general population. Genetic model fitting showed heritability for cortisol levels during the awakening period (34% for cortisol level at awakening and 32% for cortisol level at 30 min after awakening) but not for cortisol levels later during the day. The current study shows that, while cortisol levels in the awakening period are influenced by genetic factors, cortisol levels throughout most of the day are not heritable, indicating that future gene finding studies for basal cortisol should focus on the first hour post-awakening.

Heritability of Ambulatory Heart Rate Variability

Background—Reduced heart rate variability (HRV) is a prognostic factor for cardiac disease and cardiac mortality. Understanding the sources of individual differences in HRV may increase its diagnostic use and provide new angles for preventive therapy. To date, the contribution of genetic and environmental factors to the variance in HRV has not been investigated during prolonged periods of ambulatory monitoring in a naturalistic setting. Methods and Results—In 772 healthy twins and singleton siblings, ambulatory ECG was recorded during 24 hours. Two time domain measures of HRV were used: the standard deviations of all normal-to-normal intervals across 5-minute segments (SDNN index) and the root mean square of successive differences between adjacent normal RR intervals (RMSSD). Multivariate genetic analyses across 4 periods of day (morning, afternoon, evening, night) yielded significant estimates for genetic contribution to the mean ambulatory SDNN index (ranging from 35% to 47%) and the mean ambulatory RMSSD (ranging from 40% to 48%). Conclusions—Ambulatory HRV measures are highly heritable traits that can be used to support genetic association and linkage studies in their search for genetic variation influencing cardiovascular disease risk.

Large-scale ensemble averaging of ambulatory impedance cardiograms

Impedance cardiography has been used increasingly to measure human physiological responses to emotional and mentally engaging stimuli. The validity of large-scale ensemble averaging of ambulatory impedance cardiograms was evaluated for preejection period (PEP), interbeat interval, and dZ/dt(min) amplitude. We tested whether the average of “classical” 60-sec ensemble averages across periods with fixed activity, posture, physical load, social situation, and location could be accurately estimated from a single large-scale ensemble average spanning these entire periods. Impedance and electrocardiograms were recorded for about 24-h from 21 subjects. Recordings were scored by seven raters, using both methods for each subject. Good agreement (average intraclass correlation coefficient was .91) between both ensemble averaging methods was found for all three cardiac function measures. The results indicate that for unambiguous ambulatory impedance cardiograms, large-scale ensemble averaging is valid, which makes measuring prolonged changes in cardiac sympathetic activity by measuring ambulatory PEP feasible even in large epidemiological samples.

Temporal stability of ambulatory stroke volume and cardiac output measured by impedance cardiography.

UNLABELLEDnRecently, devices have become available that allow non-invasive measurement of stroke volume and cardiac output through ambulatory thorax impedance recording. If such recordings have adequate temporal stability, they offer great potential to further our understanding of how repeated or chronic cardiovascular activation in response to naturalistic events may contribute to cardiovascular disease. In this study, 24 h ambulatory impedance-derived systolic time intervals, stroke volume and cardiac output were measured in 65 healthy subjects across an average time span of 3 years and 4 months. Stability was computed separately for sleep and daytime recordings. To avoid confounding by differences in posture and physical activity across measurement days, temporal stability was computed using sitting activities only. During the day intraclass correlations were moderate for stroke volume (.29-.46) and cardiac output (.33-.46) and good for systolic time intervals (.55-.81). When test-retest comparison was limited to two comparable days (two work days or two leisure days), correlations for both SV (.42-.46) and CO (.43-.50) improved.nnnCONCLUSIONnModerate long-term temporal stability is found for individual differences in ambulatory stroke volume and cardiac output measured by impedance cardiography.

A whole-genome scan for 24-hour respiration rate: a major locus at 10q26 influences respiration during sleep.

Identification of genes causing variation in daytime and nighttime respiration rates could advance our understanding of the basic molecular processes of human respiratory rhythmogenesis. This could also serve an important clinical purpose, because dysfunction of such processes has been identified as critically important in sleep disorders. We performed a sib-pair-based linkage analysis on ambulatory respiration rate, using the data from 270 sibling pairs who were genotyped at 374 markers on the autosomes, with an average distance of 9.65 cM. Uni- and multivariate variance-components-based multipoint linkage analyses were performed for respiration rate during three daytime periods (morning, afternoon, and evening) and during nighttime sleep. Evidence of linkage was found at chromosomal locations 3q27, 7p22, 10q26, and 22q12. The strongest evidence of linkage was found for respiration rate during sleep, with LOD scores of 2.36 at 3q27, 3.86 at 10q26, and 1.59 at 22q12. In a simultaneous analysis of these three loci, >50% of the variance in sleep respiration rate could be attributed to a quantitative-trait loci near marker D10S1248 at 10q. Genes in this area (GFRA1, ADORA2L, FGR2, EMX2, and HMX2) can be considered promising positional candidates for genetic association studies of respiratory control during sleep.

Twins and the fetal origins hypothesis: an application to growth data

The Barker hypothesis states that size at birth is negatively associated with disease risk later in life. Numerous studies have tested and confirmed this hypothesis in singletons. Using twin (or sibling) data, several extensions of the Barker hypothesis may be considered: n n1. n nWithin pairs, is the smallest twin also the one with the highest disease risk later in life? Since twins (or siblings) come from the same family, this test controls for any shared family effects, such as maternal nutrition, parental education or socio-economic status. n n n n n2. n nA second extension compares associations of differences in size at birth with differences in disease risk in monozygotic (MZ) and dizygotic (DZ) twin pairs. If associations of difference scores are larger in DZ than in MZ twin pairs, this is taken as evidence that the association is mediated by genetic factors. n n n n n3. n nThese two methods can be considered as alternative approaches to the full bivariate analysis of MZ and DZ twin data. Using a bivariate structural equation model, the correlation between two traits can be decomposed into genetic and environmental correlations.