Biomedical subjects

Nancy L Pedersen

Publications and source records attributed to Nancy L Pedersen.

At least 73 records · Page 4Linked to original sources

PubMed2004

Variants of CYP46A1 may interact with age and APOE to influence CSF Abeta42 levels in Alzheimer's disease.

Recent studies have suggested that variants of CYP46A1, encoding cholesterol 24-hydroxylase (CYP46), confer risk for Alzheimer's disease (AD), a prospect substantiated by evidence of genetic association from several quantitative traits related to AD pathology, including cerebrospinal fluid (CSF) levels of the 42 amino-acid cleavage product of beta-amyloid (Abeta42) and the tau protein. In the present study, these claims have been explored by the genotyping of previously associated markers in CYP46A1 in three independent northern European case-control series encompassing 1323 individuals and including approximately 400 patients with measurements of CSF Abeta42 and phospho-tau protein levels. Tests of association in case-control models revealed limited evidence that CYP46A1 variants contributed to AD risk across these samples. However, models testing for potential effects upon CSF measures suggested a possible interaction of an intronic marker (rs754203) with age and APOE genotype. In stratified analyses, significant effects were evident that were restricted to elderly APOE epsilon4 carriers for both CSF Abeta42 ( P=0.0009) and phospho-tau ( P=0.046). Computational analyses indicate that the rs754203 marker probably does not impact the binding of regulatory factors, suggesting that other polymorphic sites underlie the observed associations. Our results provide an important independent replication of previous findings, supporting the existence of CYP46A1 sequence variants that contribute to variability in beta-amyloid metabolism.

Age Factors↗

PubMed2004

Birth order, sibship size, and housing density in relation to tooth loss and periodontal disease: a cohort study among Swedish twins.

For diseases with an infectious etiology, birth order may dictate the age of exposure to childhood infection, while sibship size may be a proxy for the probability of exposure. The authors examined whether birth order, sibship size, and childhood housing density affect risk of tooth loss and periodontal disease. The study included 28,690 adults aged > or = 42 years who were participating in a 1998-2002 follow-up of persons listed in the Swedish Twin Registry. Logistic regression was used to calculate odds ratios and 95% confidence intervals, with adjustment for age, sex, education, and smoking and mutual adjustment for family composition (sibship size and/or birth order). Tooth loss and periodontal disease affected 8% and 19% of the twins, respectively. Each additional sibling increased the odds of tooth loss by 10% (95% confidence interval (CI): 1.06, 1.15) and the odds of periodontal disease by 5% (95% CI: 1.02, 1.08). Later birth order was associated with lower odds of periodontal disease. Each additional person per room in the childhood home increased the odds of tooth loss (odds ratio = 1.28, 95% CI: 1.03, 1.60) but lowered the odds of periodontal disease (odds ratio = 0.65, 95% CI: 0.48, 0.89). These findings are compatible with the hypotheses that adult oral diseases are associated with the probability of exposure in childhood and that earlier age at exposure lowers risk.

Adult↗

PubMed2004

Common variants of ACE contribute to variable age-at-onset of Alzheimer's disease.

Studies on the role that genetic variation may play in a complex human disease can be empowered by an assessment of both disease risk in case-control or family models and of quantitative traits that reflect elements of disease etiology. An excellent example of this can be found for the epsilon4 allele of APOE in relation to Alzheimer's disease (AD) for which association with both risk and age-at-onset (AAO) is evident. Following a recent demonstration that variants of the gene encoding angiotensin I converting enzyme ( ACE) contribute to AD risk, we have explored the potential influence of ACE upon AAO in AD. A total of 2861 individuals from three European populations, including six independent AD samples, have been examined in this study. Three single nucleotide polymorphisms (SNPs) previously demonstrated to have maximum effects upon ACE plasma levels and that span the ACE locus were genotyped in these materials. A strong effect upon AAO was observed for marker rs4343 in exon 17 ( P<0.0001), but evidence was also obtained indicating a possible independent effect of marker rs4291 ( P=0.0095) located in the ACE promoter. Effects were consistent with data from previous studies suggesting association with AD in case-control models, whereby alleles demonstrated to confer risk to disease also appear to reduce AAO. Equivalent effects were evident regardless of APOE epsilon4 carrier status and in both males and females. These results provide an important complement to existing AD risk data, confirming that ACE harbors sequence variants that contribute to aspects of AD pathology.

Age of Onset↗

PubMed2004

Effect of low doses of ionising radiation in infancy on cognitive function in adulthood: Swedish population based cohort study.

OBJECTIVE: To determine whether exposure to low doses of ionising radiation in infancy affects cognitive function in adulthood. DESIGN: Population based cohort study. SETTING: Sweden. PARTICIPANTS: 3094 men who had received radiation for cutaneous haemangioma before age 18 months during 1930-59. MAIN OUTCOME MEASURES: Radiation dose to frontal and posterior parts of the brain, and association between dose and intellectual capacity at age 18 or 19 years based on cognitive tests (learning ability, logical reasoning, spatial recognition) and high school attendance. RESULTS: The proportion of boys who attended high school decreased with increasing doses of radiation to both the frontal and the posterior parts of the brain from about 32% among those not exposed to around 17% in those who received > 250 mGy. For the frontal dose, the multivariate odds ratio was 0.47 (95% confidence interval 0.26 to 0.85, P for trend 0.0003) and for the posterior dose it was 0.59 (0.23 to 1.47, 0.0005). A negative dose-response relation was also evident for the three cognitive tests for learning ability and logical reasoning but not for the test of spatial recognition. CONCLUSIONS: Low doses of ionising radiation to the brain in infancy influence cognitive abilities in adulthood.

Adolescent↗

PubMed2004

How heritable is Alzheimer's disease late in life? Findings from Swedish twins.

Although genetic effects are known to be important for early onset Alzheimer's disease, little is known about the importance of genetic effects for late-onset disease. Furthermore, previous studies are based on prevalent cases. Our purpose was to characterize the relative importance of genetic and environmental factors for incident Alzheimer's disease late in life, and to test for differences in the importance of genetic effects at different ages. A cohort of 662 pairs of Swedish twins 52 to 98 years of age who were without symptoms of dementia was followed up for an average of 5 years. Incident dementia cases were detected through follow-up at 2 to 3-year intervals using either cognitive testing or telephone screening followed by dementia workups. A physician, psychologist, and nurse gave consensus diagnoses. During the follow-up period, 5.8% of the sample was diagnosed with Alzheimer's disease. Average age of onset was 83.9 years (standard deviation, 6.3). Of the 26 monozygotic pairs in which at least one twin developed Alzheimer's disease, 5 were concordant (probandwise concordance, 32.2%). The concordance rate for dizygotic pairs was 8.7% (2 of 44 pairs). Structural model fitting indicated that 48% of the variation in liability to Alzheimer's disease could be attributed to genetic variation. Estimates did not differ significantly between twins younger than age 80 years and those older than age 80 years at baseline. Although these genetic estimates for incident disease are lower than those for prevalent disease, the importance of genetic factors for liability to Alzheimer's disease is considerable even late in life.

Age Factors↗

PubMed2004

Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism.

Linkage studies have provided evidence that one or more loci on chromosome 9q influence Alzheimer disease (AD). The gene encoding the ATP-binding cassette A1 transporter (ABCA1) resides within proximity of previously identified linkage peaks and represents a plausible biological candidate for AD due to its central role in cellular lipid homeostasis. Several single nucleotide polymorphisms (SNPs) spanning ABCA1 have been genotyped and haplotype-based association analyses performed in four independent case-control samples, consisting of over 1,750 individuals from three European populations representing both early and late-onset AD. Prominent effects were observed for a common (H2) and rarer haplotype (H5) that were enriched in AD cases across studied populations (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.36-1.82; P<0.00001 and OR 2.90; 95% CI 2.54-3.27; P<0.00001, respectively). Two other common haplotypes in the studied region (H1 and H3) were significantly under-represented in AD cases, suggesting that they may harbor alleles that decrease disease risk (OR 0.79, 95% CI 0.64-0.94; P=0.0065 and OR 0.70, 95% CI 0.46-0.93; P=0.011, respectively). While findings were significant in both early and late-onset samples, haplotype effects were more distinct in early-onset materials. For late-onset samples, ancillary evidence was obtained that both single marker alleles and haplotypes of ABCA1 contribute to variable cerebrospinal fluid tau and beta amyloid (Abeta42) protein levels, and brain Abeta load. Results indicate that variants of ABCA1 may affect the risk of AD, providing further support for a genetic link between AD and cholesterol metabolism.

ATP Binding Cassette Transporter 1↗

PubMed2004

Genetic influences on CHD-death and the impact of known risk factors: comparison of two frailty models.

The importance of some recognized risk factors on genetic influences for coronary heart disease (CHD) needs further clarification. The aim of the present study was therefore to study the impact of known risk factors on genetic influences for CHD-death. Both twin (correlated gamma-frailty) and non-twin models (univariate gamma-frailty) were utilized and compared regarding their suitability for genetic analyses. The study population consisted of twins born in Sweden between 1886 and 1925. As expected, our findings indicate that genetic influences are important for CHD-death. Inclusion of risk factors in the twin-model increased heritability estimates, primarily due to a substantial reduction in non-shared environmental variances. The genetic influences for CHD-death are only marginally mediated through the risk factors among males, but more so among females. Although the outcome phenotype used in the present study is not behavioral, the analyses demonstrate the potential of frailty models for quantitative genetic analyses of categorical phenotypes.

Body Mass Index↗

PubMed2004

Type 2 diabetes mellitus contributes to cognitive decline in old age: a longitudinal population-based study.

We examined change in neuropsychological test performance related to type 2 diabetes mellitus across a 6-year interval. A population-based sample of 274 elderly participants (36 with diabetes and 238 without diabetes) was examined at four occasions at a 2-year interval. The participants were 80-93 years of age (M = 82.8 years) and without dementia at baseline. The test battery included tests of speed, visuospatial ability, short-term memory, semantic memory, episodic memory, and the Mini Mental Status Examination. Several models, taking into account diabetes and demographic data, were analyzed using SAS Proc Mixed multilevel modeling. At baseline, there were no significant differences in the neuropsychological tests related to diabetes. The longitudinal analyses, however, showed that diabetes was a significant predictor of decline for many of the tests. These findings points to the conclusion that type 2 diabetes is associated with accelerated cognitive decline in old age that may result in dementia.

Age Factors↗

PubMed2004

Genetic and environmental influences on mothering of adolescents: a comparison of two samples.

This study examined 2 samples of adolescents and mothers using a child-based design (Nonshared Environment in Adolescent Development [NEAD] project, N = 395 families) and a parent-based design (Twin Moms [TM] project, N = 236 twin family pairs) to compare genetic and environmental influences on mothering. For both samples, the same measures of positivity, negativity, control, and monitoring were used. The use of matched child-based and parent-based samples enabled passive and nonpassive genotype-environment (GE) correlations to be approximated, providing information about process. Passive GE correlations were suggested for mother's positivity and monitoring. For mother's negativity and control, primarily nonpassive GE correlations were suggested. In several cases, both types of GE correlation were indicated. Finally, observer ratings of negativity and monitoring were influenced only by environmental factors.

Adolescent↗

PubMed2004

Change in cognitive capabilities in the oldest old: the effects of proximity to death in genetically related individuals over a 6-year period.

Change in cognitive abilities was assessed over a 6-year period in a sample of monozygotic and same-sex dizygotic twin pairs (N = 507 individuals), aged 80 and older (mean age = 83.3 years: SD = 3.1). who remained nondemented over the course of the study. Latent growth models (LGMs) show that chronological age and time to death are consistent predictors of decline in measures of memory, reasoning, speed, and verbal abilities. Multivariate LGM analysis resulted in weak and often negative correlations among rates of change between individuals within twin pairs, indicating greater differential change within twin pairs than occurs on average across twin pairs. These findings highlight several challenges for estimating genetic sources of variance in the context of compromised health and mortality-related change.

Aged↗

PubMed2004

The genetics of middle-age spread in middle-class males.

This study provides findings to assist in identifying factors that contribute to the current clinical and public health debate of the obesity epidemic. The study examined the genetics of adult-onset weight change in middle-aged male-male twins controlling for weight in early adulthood, lifetime history of tobacco use and alcohol dependence, and aimed to estimate the proportion of genetic factors that influence weight change between early adulthood and middle age in white middle-class males. The study was a classic longitudinal twin design and used Body Mass Index (BMI) for three waves of data collection from the Vietnam Era Twin Registry--induction physicals (approximately 1968), 1987 and 1990--or periods corresponding between young adulthood and middle age. Univariate heritability estimates for BMI at all three data periods were conducted as well as a Cholesky longitudinal genetic analysis for weight change controlling for BMI at military induction, smoking and alcohol use. Frequency data indicated that the sample was on average classified as normal BMI in their 20s; but BMI gradually increased during the next twenty years. Univariate data for each data period indicated that additive genetic factors accounted for between 63% and 69% of total variance in BMI. The Cholesky longitudinal genetic analysis of BMI87 and BMI90, controlling for BMI at military induction, indicated that more than half of the change in BMI from early adulthood to middle age remains heritable. No shared environmental factors were identified, thus the remainder of the variance was accounted for by nonshared, or unique, environmental factors and error. The data analysis suggests that treatments and public health interventions need to recognize the magnitude of genetic factors if short-term and long-term interventions are to be effective.

Aged↗

PubMed2004

The epidemiology and genetics of smoking initiation and persistence: crosscultural comparisons of twin study results.

We examined whether there are crosscultural differences in the magnitude of genetic and environmental contributions to risk of becoming a regular smoker and of persistence in smoking in men and women. Standard methods of epidemiologic and genetic analysis were applied to questionnaire data on history of cigarette use obtained from large samples of male and female like-sex twins from three different countries: Australia (N = 2284 pairs), Sweden (N = 8651 pairs), and Finland (N = 10,948 pairs). Samples were subdivided into three age groups (AG), 18-25 years, 26-35 years, and 36-46 years of age. The magnitude of genetic influence for lifetime smoking was found to be consistent across country and AG for women (46%) and men (57%), and estimates of the contribution from environmental influences shared by twin and co-twin could be equated across all countries by AG for the women (from youngest to oldest AG: 45%, 35%, and 26%), but not for men, with separate estimates obtained for the Scandinavian (33%, 29%, and 19%) and the Australian men (26%, 9%, and 11%). There was no evidence for an important role for shared environmental influences on persistent smoking, and the genetic contribution was found to be consistent in magnitude in men and women, and the same across country and AG (52%). There are strong genetic influences on smoking behavior, and that risk of becoming a smoker (but not persistence in smoking) may be modified by experiences shared by twins that differ by AG and, at least for men, cultural background.

Adolescent↗

PubMed2003

Obesity and hormone-dependent tumors: cohort and co-twin control studies based on the Swedish Twin Registry.

Obesity increases the risk of certain cancer types, e.g., cancer of the endometrium, colon and gallbladder. For some other cancer forms, e.g., prostate cancer, the association is less clear. We examined the association between body mass index (BMI) and hormone-dependent tumors, utilizing a cohort of 21,884 Swedish twins born during 1886-1925. Information about BMI at different ages and potential confounding factors was collected prospectively. The Swedish Cancer Registry was used to identify cases of cancer in the prostate (n = 666), breast (n = 607), corpus uteri (n = 150) and ovary (n = 118) during 1969-1997. The material was analyzed as a traditional cohort and with co-twin control analyses that allow for control of genetic influences. Obesity (BMI >/=30 kg/m(2)) at baseline was positively associated with cancer in the corpus uteri [relative risk (RR) = 3.03, 95% confidence interval (CI) 1.82-5.03], as was BMI at age 25, independently of BMI at baseline. Increased risk was also found for breast cancer but only in older women (>/=70 years). Overweight at age 25 was associated with decreased risk of breast cancer (RR = 0.51, 95% CI 0.33-0.78). No association was found for prostate cancer. We conclude that age is an important effect modifier of cancer risk associated with obesity and that obesity and overweight in young adult life may affect cancer risk also later in life.

Adult↗

PubMed2003

Three-state frailty model for age at onset of dementia and death in Swedish twins.

We present a frailty model to estimate the relative importance of genetic and environmental factors on age at onset of dementia in a twin design. We use modern survival methodology to define a model that accounts simultaneously for longitudinal aspects, e.g., left truncation and right censoring in data, and the multivariate nature of twin data. Additionally, we present a novel three-state frailty model, with nondemented, demented, and dead states, describing variation in the onset of disease and mortality simultaneously in one model, while accounting for possible dependence for the two competing events. The frailty structure, i.e., the latent random effects structure, mimics the traditional twin model for continuous variables used in quantitative genetics, and as such describes within-pair dependence. This in turn leads to estimates for intrapair correlations, as well as for additive genetic, and shared and nonshared environmental components of variance. A hierarchical Bayesian model formulation and Gibbs sampling are used to estimate posterior distributions of the parameters. The models are applied to Swedish Twin Registry data on the onset of dementia in elderly twins. Based on the three-state frailty model, we estimate the intrapair correlations for dementia to be 0.87 [90% credible interval: 0.61,0.98] and 0.68[0.18,0.91] for MZ and DZ twins, respectively. Based on our model, we estimate that genetic effects account for about one third, and shared environmental effects for almost a half, of the variation in dementia hazards between individuals. More data, however, are needed to gain precision in these estimates.

Age of Onset↗

PubMed2003

Cross-national determinants of quality of life from six longitudinal studies on aging: the CLESA project.

BACKGROUND AND AIMS: The Comparison of Longitudinal European Studies on Aging (CLESA) Project, here presented for the first time, is a collaborative study involving five European and one Israeli longitudinal study on aging. The aim of this paper is to describe the methodology developed for the harmonization of data and the creation of a Common Data Base (CDB), and to investigate the distribution of some selected common variables among the six countries. The design of each study is briefly introduced and the methodology leading to the harmonization of the common variables is described. METHODS: The study base includes data from five European countries (Finland, Italy, the Netherlands, Spain, Sweden) and Israel, for older people aged 65-89 living both in the community and in institutions (total, 11557 subjects). For two age classes (65-74 and 75-84), the prevalence ratios or the mean values of the following selected variables are provided: a) sociodemographic variables; b) health habits; c) health status; d) physical functioning; e) social networks and support; and f) health and social services utilization. RESULTS: Statistically significant differences were found between most of the investigated characteristics across the CLESA countries, with very few exceptions. While some of the differences found may be due to cultural variations, others require further investigation and should be encompassed in the main framework of the Project, which is to identify predictors of hospitalization, mortality, institutionalization and functional decline. CONCLUSIONS: A common data base is available for the study of the aging process in five European and one Israeli population. These data provide a unique opportunity to identify common risk factors for mortality and functional decline and increase our understanding of country-specific exposures and vulnerability.

Aged↗

PubMed2003

The influence of mortality on twin models of change: addressing missingness through multiple imputation.

Twin analyses of phenotypes that are associated with mortality may provide biased heritability estimates if the models require that data from both members of a pair are available. This is particularly true when longitudinal analyses are applied to measures of cognition or biomarkers of aging. The effect of applying imputational techniques that include information on age at death was tested on longitudinal data from two twin studies of aging, each with up to four occasions of measurement. Measures of twin similarity for intercepts and slopes from three latent growth curve models were compared: without imputed data, including imputed data but without information on age at death, and including imputed data with information on age at death. Results indicated that twin similarity for slopes decreases when mortality is accounted for, but that considerable age-related covariation remains.

Humans↗

PubMed2003

Genetic and environmental influences on decline in biobehavioral markers of aging.

Latent growth models were applied to longitudinal twin data on markers of aging to investigate genetic and environmental influences on the processes of change with age. The sample included 1957 participants aged 50 to 96 years. Five markers were assessed: forced expiratory volume, mean arterial pressure, grip strength, motor functioning, and well-being. Data were gathered at up to three follow-up occasions at intervals of 3 years. Results indicated monotonic changes with age for all but two variables. Performance on motor functioning and well-being was stable until age 65 or 70, followed by significant decline. Genetic influences on the level of performance were indicated for all five markers of aging. Genetic influences on the slope were found for only three of the variables: motor functioning, mean arterial pressure, and forced expiratory volume. Investigations of the aging process will differ depending on whether the focus is on static performance or change.

Aged↗

PubMed2003

Sex differences in genetic risk for dementia.

We used two Swedish twin samples to test whether women are at greater risk than men of developing dementia and whether there are sex differences in mechanisms underlying dementia and cognitive dysfunction. Dementia analyses found no sex differences in incidence of dementia or Alzheimer's disease among initially intact participants followed longitudinally. Twin analyses indicated a substantial genetic influence on liability to incident dementia. Although sex differences in model parameters were not statistically significant, for women but not men an equally attractive model included genetic influence due to both additive effects and dominance or epistasis. In the cognitive dysfunction analyses, results from a sex limitation model raise the possibility that either different genes or different environments have a role for men and women. We conclude that women are not at higher risk of developing dementia, but there is a hint that different genetic processes may be involved for women than for men.

Alzheimer Disease↗