Genetic Epidemiology and Aging Research: Past Projects

Pharmacokinetics of Nicotine in Twins

Principal Investigator: Gary E. Swan, Ph.D., Director, Center for Health Sciences, SRI International

Co-Principal Investigator: Neal L. Benowitz, M.D., Professor of Medicine, Psychiatry and Biopharmaceutical Sciences, University of California San Francisco

This project sought to explore the genetic influences on the disposition and kinetics of nicotine, stable characteristics of individuals that may be central to understanding of nicotine addiction and its effective treatment. Two hundred seventy eight twins and 16 siblings of twins were recruited for this study. Subjects completed a tobacco use questionnaire and underwent 8-hour in-hospital nicotine infusion tests. During the 8 hours after the 30-minute infusion, blood and urine samples were taken at regular intervals, up to 24 hours, for assay of nicotine and metabolites. The data have been subjected to both univariate and multivariate genetic analyses to determine genetic and environmental influences on each pharmacokinetic parameter individually and in combination with other biologically meaningful indices of nicotine metabolism, including variation in the CYP2A6 gene, which codes for the primary nicotine metabolism enzyme. This investigation contributes to novel information on the impact of genetic influences on nicotine metabolism; it refines of the metabolic phenotype associated most strongly with the genetic predisposition to nicotine addiction; and it combines biometric analysis with measured genetic factors. Ultimately, this knowledge may lead to more informed and more finely targeted treatment of individuals who are either susceptible to nicotine addiction or are already addicted to this substance.

Analysis of Patterns of Tobacco Use in Families

Principal Investigator: Gary E. Swan, Ph.D., Director, Center for Health Sciences, SRI International

This study sought to provide evidence in favor of or against genetic involvement in a number of smoking and nicotine addiction phenotypes and the extent to which genetic factors operate jointly or independently of environmental factors to determine eventual regular smoking in young adults. The data were derived from 763 adolescents, their parents, and siblings all of whom were assessed as part of the SMOFAM study, a prospective investigation of psychosocial and environmental predictors of adolescent substance use now in its 15th year of follow-up and based at the Oregon Research Institute (ORI). Additional data incorporated into the analytic plan of this study included information pertinent to nicotine addiction as assessed by newly developed questionnaires and genotypic status on 425 nuclear family biological triads. A third source of data was derived from the assay of cotinine metabolic data in 250 familial triads. After reorganizing the existing ORI data into a family structure and incorporating newly collected in depth nicotine dependence data, cotinine clearance data, and genotypic status, the analytic strategy has taken the following steps: 1) use of multivariate data reduction methods to determine independent and composite descriptions of nicotine dependence (ND) in young smokers and their families; 2) use of complex segregation analysis to determine whether each of the ND phenotypes defined above have parent-offspring transmission patterns suggestive of genetic influence; 3) use of the Transmission/Disequilibrium Test (TDT) to determine the presence of genotype-phenotype associations in ever smoking probands; 4) use of a conditional logistic regression extension of the TDT to examine the data for evidence of gene-environment interactions in determining susceptibility to tobacco use; 5) use of latent growth curve modeling to identify independent and joint genetic and environmental factors that predict the speed with which young people transition from experimentation with tobacco to regular use; 6) use of tree-structured survival analysis to identify subgroups of young people based on unique combinations of genetic and environmental risk factor profiles and who differ with respect to the age at which they experimented with tobacco and then began to smoke on a regular basis. This plan has taken full advantage of psychosocial, environmental, behavioral, pharmacokinetic, genetic, and prospective smoking outcome data from adolescents (at inception of SMOFAM) who are now young adults.

CVD Risk Factors and Brain Morphology in NHLBI Twins

Principal Investigator: Dorit Carmelli, Ph.D., Senior Biostatistician and Epidemiologist, SRI International

The purpose of this study was to extend the NHLBI Twin study of the etiology of individual differences in cardiovascular disease. The proposed study represented a fourth longitudinal follow-up 30 years after the first in-person examination done on these twins. At the time of this study, there were three waves of follow-up to the original assessment (years 10, 16, and 25), including two waves of in-person neuropsychological testing, an assessment of brain MR volumes, and a plethora of other variables to use in analyses. The proposed additional wave of testing allowed investigation of the contributions of genetic and environmental influences on individual differences in brain morphology (including changes in brain volumes, CSF, and white-matter hyperintensities), in cognitive functioning (including tests of verbal and visual memory, visuospatial processing and cognitive flexibility), in physical functioning (including performance-based measures of lower-extremity function) and in cardiovascular and physical health. The specific issues addressed by this study included: 1) the extent to which genetic and environmental factors contribute to continuity or change in brain structure and function in later life (e.g., do MR infarcts or large amounts of white-matter hyperintensity (WMH) lesions affect twins' progress to clinical disease); 2) identifying which vascular and nonvascular risk factors predict progression of brain aging as measured by reductions in brain volume, increase in WMHs, decrease in frontal brain volume, and decline in cognitive and physical functioning; 3) assessing whether cognitive decline continues to be associated with changes in brain structure, and the extent to which these relationships reflect overlapping genetic influences, the cumulative effect of individual environmental influences, or a combination of both; and, 4) identifying the role that the ApoE4 allele plays in both cardiovascular disease and cognitive decline.

Sleep Apnea in Elderly Male Twins

Principal Investigator: Dorit Carmelli, Ph.D., Senior Biostatistician and Epidemiologist, SRI International

The contribution of genetic factors to sleep disorders has been demonstrated in twin and family studies, and further understanding of the genetic underpinning of sleep disorders is considered an important area of research. Many of the suggested risk factors for sleep apnea (e.g., craniofacial morphology, obesity) have genetic determinants. However, a formal genetic analysis of these anatomical risk factors with sleep-recorded physiological measurements has not so far been conducted. The objective of this study was to conduct such an analysis in a well-characterized U.S. population-based registry of elderly male twins who have been successfully followed for the past 30 years. Specifically, it was proposed: (1) to recruit a subsample of 150 pairs from the NAS-NRC World War II Twin Registry in which at least one of the twin brothers reported sleep apnea symptoms and a subsample of 30 control pairs in which both twins reported no symptoms; (2) monitor the subgroup of 180 twin pairs with overnight sleep recording; (3) collect on these subjects anthropometric measurements of weight, height, neck circumference, and craniofacial morphology; and (4) collect blood samples for determination of zygosity and DNA extraction for future molecular studies. The twin design is most powerful for estimating the genetic and/or environmental overlap between physiological measurements such as sleep-recorded disordered breathing, obesity, and craniofacial morphology. We chose to focus on an elderly male twin sample for which a wealth of data relevant to this study has been previously collected. Twin pair concordance or discordance for monitored sleep-disordered breathing will allow the full characterization of genetic/familial and individual environmental factors associated with the expression and severity of this condition.

Ambulatory Blood Pressure and Cognition in the Elderly

Principal Investigator: Gary E. Swan, Ph.D., Director, Center for Health Sciences, SRI International

In the previous 4 years of this study, the primary objective had been to determine the relationship of cardiovascular (CVD) risk factors to cognitive decline in the elderly. A total of 733 surviving male members (mean age=76.1 years) of the Western Collaborative Group Study were assessed on several global and specific measures of neuropsychological functioning. Since the role of CVD risk factors for abnormal cognitive aging in women is generally understudied, we added 558 older women to our study (277 examined and 281 by questionnaire; mean age=71.2 years). A number of analyses of the data support the conclusion of both cross-sectional and longitudinal associations between higher levels of blood pressure and lower levels of neuropsychological performance. These findings, however, and those of others in the literature, are based on the measurement of single-point resting blood pressures and do not take into account other aspects of blood pressure measured continuously over the course of a typical day. Since these characteristics have a stronger relationship to both cardiovascular and cerebrovascular end organ damage than do resting levels, this application proposed to continue examination of the BP-cognition association with the use of noninvasive ambulatory blood pressure monitoring over the course of 16 hours. The major objective was to characterize both BP levels and variability during the day and night in 450 male and female subjects (age range=74 to 90 years) examined previously in the last round of examinations. Given that sleep-disordered breathing increases in prevalence with age and may result in both elevated nighttime blood pressure levels and variability as well as lower levels of neuropsychological performance, it was also of interest to characterize the presence or absence of significant apneic events (by noninvasive ambulatory in-home assessments) and test its mediating effect on the blood pressure-cognition association. A secondary set of analyses utilize data collected in the previous round of examinations (a total of 1,010 male and female subjects) will be used to determine prospective relationships of blood pressure, neuropsychological functioning, and symptoms of sleep apnea with subsequent 5-year mortality. Accounting for the multifactorial nature of influences such as sleep apnea on both blood pressure and neuropsychological functioning in the elderly represents a unique and important advance of our study, suggesting new avenues to prevent or slow the rate of neuropsychological decline and premature mortality in the elderly.

Contact Us

For more information contact Gary Swan, director of the Center for Health Sciences.