Biomedical subjects

Kaare Christensen

Publications and source records attributed to Kaare Christensen.

At least 37 records · Page 2Linked to original sources

PubMed2006

Genetic and environmental correlates of semen quality: a twin study.

BACKGROUND: The influences of environmental factors on the male reproductive system have been much debated over the last 3 decades. We studied the impact of genes and environment on semen quality, sex hormone levels, and sperm chromatin stability by using a twin design. METHODS: The study population consisted of monozygotic and dizygotic twins from the population-based Danish Twin Registry and a random selection of pairs of singleton brothers from the Danish Civil Registration System. All men were 20 to 45 years of age. The study population comprised 100 monozygotic twin brothers (50 pairs), 102 dizygotic twins (51 pairs), and 102 single-born brothers (51 pairs). A semen sample and blood sample were collected from all participants. RESULTS: Heritability was estimated to account for 20% (95% confidence interval = 0% to 68%) of the variation in sperm density. A higher heritability was found for the hormones reflecting Sertoli cell function (inhibin B, 76% [36% to 84%] and follicle-stimulating hormone, 81% [40% to 88%]) and for percent morphologic normal cells (41% [0% to 60%] and sperm chromatin parameters (mean alphaT, 68% [34% to 81%] and COMP alphaT, 72% [25% to 82%], respectively). CONCLUSION: Our study indicates a substantial hereditary component in plasma levels of hormones reflecting Sertoli cell function and in sperm cell chromatin stability and morphology. The environmental contribution (including the prenatal environment) appeared to be largest for sperm count.

Adult↗

PubMed2006

Bio-social determinants of fertility.

This paper reviews several studies that investigated the potential role of genetic factors in determining fertility outcomes. Our review demonstrates convincingly that fertility contains genetic variance; that is, differences between humans in their genetic make-up affects their fertility outcomes and fertility-related behaviours. This finding is robust using both heritabilities and coefficients of genetic variation, and using both direct measures of fertility outcomes and also fertility precursors like fecundity, marriage, fertility expectations and attempts to get pregnant (proception). Moreover, genetic variance can change over short periods of time or across educational levels, specifically for females, and the relevance of genetic variance seems to increase during times of increasing reproductive choice.

Demography↗

PubMed2006

Apolipoprotein e genotypes: relationship to cognitive functioning, cognitive decline, and survival in nonagenarians.

OBJECTIVES: To evaluate the extent to which relationships between apolipoprotein E, cognitive functioning, and survival in people aged 60 to 80 persist into advanced old age. DESIGN: Examine the effect of apolipoprotein E genotypes on baseline cognitive functioning, cognitive decline over 5 years, and survival in a cohort of 1,551 nonagenarians. SETTING: The Danish 1905 birth cohort. PARTICIPANTS: One thousand five hundred fifty-one nonagenarians from the Danish 1905 birth cohort. MEASUREMENTS: Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) and five brief cognitive tests (cognitive composite). RESULTS: The subjects were stratified into four groups by occurrence of a protective (epsilon2) or a risk (epsilon4) apo E allele (epsilon22 and epsilon23, epsilon33, epsilon24 and epsilon34, epsilon44). At intake, the mean scores for the three genotype groups were 22.1, 21.8, 21.4, and 21.0 for MMSE and 0.10, 0.07, -0.02, and 0.30 for the cognitive composite, respectively. Growth-curve analyses showed that, although individuals carrying at least one epsilon4 allele had slightly lower MMSE scores and declined slightly more rapidly over time, this effect was not statistically significant and was not apparent in scores on the cognitive composite. In subjects whose functioning was relatively well preserved (those still living and able to participate in the assessment, and whose cognitive functioning had declined less than 4 points on the MMSE), epsilon4 frequencies tended to decline at subsequent waves (P=.03, chi-square test for trend), but epsilon4 had no significant survival disadvantage (hazard ratio=1.11 (95% confidence interval=0.99-1.25; P=.07). CONCLUSION: Apo E genotype has a small effect on the probability of remaining a well-functioning nonagenarian but no separately detectable effect on cognitive functioning, cognitive decline, or survival.

Aged, 80 and over↗

PubMed2006

Heat-shock protein 70 genes and human longevity: a view from Denmark.

We have studied the association of three single nucleotide polymorphisms (SNPs) present in the three HSP70 (heat-shock protein) genes on 6p21 with human longevity. The availability of biological samples from various population cohorts in Denmark has given us the opportunity to try novel methods of gene association with human longevity. A significant association of one haplotype with male longevity was observed. Furthermore, a significant difference in the survival of the carriers of the different genotypes in females was observed. We also found an age-dependant decline in the ability of peripheral blood mononuclear cells to respond to heat stress in terms of Hsp70 induction.

Adult↗

PubMed2006

Possible associations between successful aging and polymorphic markers in the Werner gene region.

Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by mutations in the Werner (WRN) gene leading to the early onset of many (but not all) aspects of normal aging. To investigate whether the WRN gene affects the course of aging in non-Werner syndrome individuals, we performed association studies analyzing several single nucleotide polymorphisms (SNPs) in the WRN locus. We found certain close-set SNPs in the 5' flanking region and 5' UTR to be significantly associated with the cognitive functioning level in old age.

5' Flanking Region↗

PubMed2006

Twins and their health cost: consequences of multiple births on parental health and mortality in Denmark and England and Wales.

The rapid increase in twinning rates in developed countries has increased interest in the question as to whether twin mothers have higher mortality and more health problems than mothers of singletons. Here we use a national survey, the Office for National Statistics Longitudinal Study of England & Wales, and a linkage between the Danish Twin Registry and the Danish population register to examine mortality patterns after age 45 (50 for fathers) for twin parents and the whole population born from 1911 to 1950. For England and Wales, presence of limiting long-term illnesses and self-rated health status was also investigated. Overall similar health and mortality was found for twin parents and the whole population although both life table methods and survival analysis suggested a slight excess mortality among older cohorts of twin mothers in England and Wales.

Adolescent↗

PubMed2005

Genetic association analysis of human longevity in cohort studies of elderly subjects: an example of the PON1 gene in the Danish 1905 birth cohort.

Although the case-control or the cross-sectional design has been popular in genetic association studies of human longevity, such a design is prone to false positive results due to sampling bias and a potential secular trend in gene-environment interactions. To avoid these problems, the cohort or follow-up study design has been recommended. With the observed individual survival information, the Cox regression model has been used for single-locus data analysis. In this article, we present a novel survival analysis model that combines population survival with individual genotype and phenotype information in assessing the genetic association with human longevity in cohort studies. By monitoring the changes in the observed genotype frequencies over the follow-up period in a birth cohort, we are able to assess the effects of the genotypes and/or haplotypes on individual survival. With the estimated parameters, genotype- and/or haplotype-specific survival and hazard functions can be calculated without any parametric assumption on the survival distribution. In addition, our model estimates haplotype frequencies in a birth cohort over the follow-up time, which is not observable in the multilocus genotype data. A computer simulation study was conducted to specifically assess the performance and power of our haplotype-based approach for given risk and frequency parameters under different sample sizes. Application of our method to paraoxonase 1 genotype data detected a haplotype that significantly reduces carriers' hazard of death and thus reveals and stresses the important role of genetic variation in maintaining human survival at advanced ages.

Age Factors↗

PubMed2005

Design and analysis in genetic studies of human ageing and longevity.

With the success of the Human Genome Project and taking advantage of the recent developments in high-throughput genotyping techniques as well as in functional genomics, it is now feasible to collect vast quantities of genetic data with the aim of deciphering the genetics of human complex traits. As a result, the amount of research on human ageing and longevity has been growing rapidly in recent years. The situation raises questions concerning efficient choice of study population, sampling schemes, and methods of data analysis. In this article, we summarize the key issues in genetic studies of human ageing and longevity ranging from research design to statistical analyses. We discuss the virtues and drawbacks of the multidisciplinary approaches including the population-based cross-sectional and cohort studies, family-based linkage analysis, and functional genomics studies. Different analytical approaches are illustrated with their performances compared. In addition, important research topics are highlighted together with experiment design and data analyzing issues to serve as references for future studies.

Aging↗

PubMed2005

Back and neck pain in seniors-prevalence and impact.

Neck pain (NP) and back pain (BP) are common complaints in seniors yet specific information on these complaints is lacking in the scientific literature. We present cross-sectional interview data from the 2003 data collection within the population based Longitudinal Study of Aging Danish Twins dealing with the 1-month prevalence of NP and BP and the intensity of possible pain. Further, we present the 1-year prevalence of NP and BP, duration of pain, influence of NP and BP on daily activities and care seeking for NP and BP. 84.4% of invited twins aged 70-102 years participated in the study. The 1-month prevalence of NP and BP was similar to previously reported results. 7% of men and 13% of women reported moderate or severe NP and 12% of men and 19% of women reported moderate or severe BP on a monthly basis. 10% of men and 12% of women reported more than 30 days of NP within the past year and 13% of men and 21% of women reported more than 30 days of BP within the past year. 5% of men and 8% of women had altered or diminished their physical activities due to NP and 9% of men and 16% of women had diminished their physical activities due to BP within the past year. 10% of men and 12% of women had had treatment for NP within the past year and 13% of men and 19% of women had had treatment for BP within the past year, most commonly from general medical practitioners and physical therapists. Altering or diminishing physical activities and care seeking were associated with both pain intensity and duration of pain. NP and BP of longer duration were associated with significantly lower physical performance scores when compared to no NP or BP during the past year. NP and BP in seniors are probably associated with difficulty but not inability to perform daily activities.

Activities of Daily Living↗

PubMed2005

Twins with implanted pacemakers: Is there an increased mortality risk for the co-twin? A follow-up study based on the Danish Twin Registry and the Danish Pacemaker Register.

BACKGROUND: The main indications for implanting a cardiac pacemaker are either acquired atrio-ventricular block (AVB) or sick sinus syndrome (SSS). In general, the exact aetiology of these conditions is unknown. Genetic factors may play a role. Untreated AVB is associated with increased mortality but SSS seems to have a good prognosis. The present study was designed to assess whether first-degree relatives of these patients have an increased mortality risk. METHODS: We investigated the survival pattern of the co-twins of twins who have had a cardiac pacemaker implanted, by linking two nationwide registries in Denmark: the Danish Pacemaker Register and the Danish Twin Registry. For each "pacemaker-twin" four control-twins matched with respect to age, sex, and zygosity were selected among the twins who were alive at the time of the pacemaker implantation. A total of 159 twins with a pacemaker treated bradycardia of unknown aetiology were identified of which 73 had AVB and 64 had SSS. A total of 622 matched control-twins could be identified. The survival from age six of the co-twins of the "pacemaker-twins" was compared with that of the co-twins of the control-twins. The follow-up period ended January 1st, 2000. FINDINGS: The survival curves for the co-twins of the "pacemaker-twins" were virtually identical to those of the co-twins of the control-twins. This finding was consistent for both AVB and SSS and for monozygotic as well as dizygotic twins. CONCLUSION: No increased mortality risk could be demonstrated for first-degree relatives--including monozygotic twins--of patients with a cardiac pacemaker implanted due to either acquired AVB or SSS.

Aged↗

PubMed2005

Cancer risk in persons with oral cleft--a population-based study of 8,093 cases.

The authors conducted a nationwide study of the occurrence of cancer among 8,093 Danish oral cleft cases born in 1936 through 1998 and followed in the Danish Cancer Registry from 1968 through 1998, a total of 175,863 person-years, to assess a possible association between cancer and oral clefts. Observed and expected numbers of cancers among oral cleft cases were summarized as the overall and as 52 site-specific standardized incidence ratios. The expected overall number of all cancers was 131, but 140 incident cancers were found, corresponding to a standardized incidence ratio of 1.07 (95% confidence interval (CI): 0.90, 1.26). Analyses of the 52 sites for all oral cleft cases and analyses stratified for three cleft subgroups and the two sexes revealed only a few significant associations: an increased occurrence of breast cancer among females born with cleft lip and/or cleft palate (standardized incidence ratio (SIR) = 1.52, 95% CI: 1.05, 2.14), primary brain cancer among females born with cleft palate (SIR = 3.11, 95% CI: 1.14, 6.78), and primary lung cancer among males born with both cleft lip and cleft palate (SIR = 2.49, 95% CI: 1.00, 5.14). The results do not provide evidence for an increased overall cancer risk for individuals born with oral clefts.

Adolescent↗

PubMed2005

Genetic dissection of gene expression observed in whole blood samples of elderly Danish twins.

The microarray technique is an important tool in gene expression analysis to study the activities of thousands of genes measured by their transcript levels under disease or laboratory controlled experimental conditions. Recent studies have suggested a genetic component in the variations of gene expression thus indicating the important role of genetic control over gene activities. In this study, we analyze and report the twin correlation on gene expression in whole blood samples of six female Danish twin pairs aged from 81 to 85 years. We studied the expression phenotype by treating the measured gene expression as a quantitative trait and introducing analytical approaches including the traditional twin methods in population genetics and the multivariate statistical methods. Using this combinatory approach, we were able to estimate and compare the twin correlation on the expression phenotype while accounting for systematic influence in microarray experiments. Analyses on our twin data detected a significant correlation on the expression levels of the actively regulated genes in both monozygotic and dizygotic twins, which is more pronounced in monozygotic twins. Gene ontology analysis has shown that these actively regulated genes are predominantly involved in defense and immune responses against antigenic stimulus. In conclusion, the correlation patterns revealed in our twin data provide evidence of the existence of a heritable mechanism in gene expression regulation persistently functioning even in aged subjects.

Aged↗

PubMed2005

Estimating haplotype relative risks on human survival in population-based association studies.

Association-based linkage disequilibrium (LD) mapping is an increasingly important tool for localizing genes that show potential influence on human aging and longevity. As haplotypes contain more LD information than single markers, a haplotype-based LD approach can have increased power in detecting associations as well as increased robustness in statistical testing. In this paper, we develop a new statistical model to estimate haplotype relative risks (HRRs) on human survival using unphased multilocus genotype data from unrelated individuals in cross-sectional studies. Based on the proportional hazard assumption, the model can estimate haplotype risk and frequency parameters, incorporate observed covariates, assess interactions between haplotypes and the covariates, and investigate the modes of gene function. By introducing population survival information available from population statistics, we are able to develop a procedure that carries out the parameter estimation using a nonparametric baseline hazard function and estimates sex-specific HRRs to infer gene-sex interaction. We also evaluate the haplotype effects on human survival while taking into account individual heterogeneity in the unobserved genetic and nongenetic factors or frailty by introducing the gamma-distributed frailty into the survival function. After model validation by computer simulation, we apply our method to an empirical data set to measure haplotype effects on human survival and to estimate haplotype frequencies at birth and over the observed ages. Results from both simulation and model application indicate that our survival analysis model is an efficient method for inferring haplotype effects on human survival in population-based association studies.

Aged↗

PubMed2005

Small effect of genetic factors on neck pain in old age: a study of 2,108 Danish twins 70 years of age and older.

STUDY DESIGN: Classic twin study. OBJECTIVES: To determine the heritability of neck pain in persons 70 years of age and older. SUMMARY OF BACKGROUND DATA: Previous studies have shown a moderate effect of genetic factors on back pain in the elderly. Genetic influence on neck pain in old age is unknown. METHODS: Data on the 1-month prevalence of neck pain from twin pairs participating in the population based Longitudinal Study of Aging Danish Twins formed the basis of this analysis. To assess twin similarity, probandwise concordance rates, odds ratios, and tetrachoric correlations were calculated and compared for monozygotic and dizygotic twins. Further, heritability estimates were calculated using bivariate probit estimation. RESULTS: A total of 2,108 twin individuals, including 1,054 complete twin pairs, answered the question related to neck pain at intake into the Longitudinal Study of Aging Danish Twins study. Low and nonsignificant probandwise concordance rates, odds ratios, and tetrachoric correlations were found for both men and women in monozygotic and dizygotic twin pairs, indicating small or negligible genetic effects. Heritability estimates adjusted for age and significant environmental risk factors (rheumatoid arthritis, osteoarthritis, disc prolapse, and coronary heart disease) showed no significant additive genetic, dominant genetic, or common environmental effects. CONCLUSION: Genetic factors do not play an important role in the liability to neck pain in persons 70 years of age or older.

Aged↗

PubMed2005

Time trends in waiting time to pregnancy among Danish twins.

BACKGROUND: Little is known about time trends in fecundity because few population-based data are available. In a survey among female twins born from 1953 to 1976, their time to pregnancy did not differ from singletons and can be considered to represent the fecundity of the general population. METHODS: Information was collected by interview about waiting time to first pregnancy (TTP) and any periods of subfecundity among both male and female twins born between 1931 and 1952. Trends were analysed by considering the year of birth of the index person (birth cohort effect) or year at which the first attempt started (period effect). RESULTS: Eighty-five percent of male and 81.3% of female eligible twins participated. A total of 1598 male twins and 1653 female twins reported a TTP value and 1671 men and 1715 women had a value for their first attempt to conceive including unsuccessful attempts. No overall trends in either male or female TTP were observed with increasing year of birth or of starting time, after adjustment for confounders, but for attempts fecundity increased among female twins by year of birth or of starting the attempt. A decreasing risk of severe infertility with increasing year of birth or year for start of the attempt was observed among male twins, but this observation was based on only 81 men and was not seen among female twins. CONCLUSION: No decreasing trend in fecundity was observed among Danish twins born between 1931 and 1952 who had completed their reproduction. Female twins had a slight increase in fecundity, and men a decrease in severe infertility. In addition, TTP was apparently well reported and recalled for up to 50 years among both male and female twins.

Adult↗

PubMed2005

Evaluation of two methods for assessing gene-environment interactions using data from the Danish case-control study of facial clefts.

BACKGROUND: Epidemiological investigations have begun to consider gene-environment (GE) interactions as potential risk factors for many diseases, including several different birth defects. However, traditional methodological approaches for the analysis of case-control data tend to have low power for detection of interaction effects. A log-linear approach that can impose the assumption that the genotype and exposure of interest occur independently in the population has been proposed as a potentially more powerful method for assessing GE interactions but has not been widely applied in the published literature. METHODS: The present analyses were undertaken to compare the results obtained when stratified analyses and a log-linear approach were used to assess potential GE interactions. The analyses were conducted using data from a population-based, case-control study conducted in Denmark and considered associations between nonsyndromic cleft lip with or without cleft palate (CL+/-P), infant genotype for variants of RAR-alpha, TGF-alpha, TGF-beta3, and MSX1, and maternal exposure to smoking, alcohol, and multivitamins. RESULTS: Neither the stratified nor the log-linear analyses provided evidence that that risk of CL+/-P is influenced by any of the GE interactions that were evaluated, despite the potential increase in power offered by the latter approach. Further, the analyses highlight concerns regarding the power to reject the assumption of independence of the genetic and environmental factor of interest in the controls and related concerns regarding the validity of results obtained using the log-linear approach when the underlying assumption is violated. CONCLUSIONS: The potential increase in power offered by the log-linear approach is offset by concerns regarding the validity of this approach when the independence assumption is violated.

Abnormalities, Drug-Induced↗

PubMed2005

What are the effects of maternal and pre-adult environments on ageing in humans, and are there lessons from animal models?

An open issue in research on ageing is the extent to which responses to the environment during development can influence variability in life span in animals, and the health profile of the elderly in human populations. Both affluence and adversity in human societies have profound impacts on survivorship curves, and some of this effect may be traceable to effects in utero or in infancy. The Barker Hypothesis that links caloric restriction in very early life to disruptions of glucose-insulin metabolism in later life has attracted much attention, as well as some controversy, in medical circles. It is only rarely considered by evolutionary biologists working on phenotypic plasticity, or by biogerontologists studying model organisms such as C. elegans or Drosophila. One crucial mechanism by which animals can respond in an adaptive manner to adverse conditions, for example in nutrition or infection, during development is phenotypic plasticity. Here we begin with a discussion of adaptive plasticity in animals before asking what such phenomena may reveal of relevance to rates of ageing in animals, and in humans. We survey the evidence for effects on adult ageing of environmental conditions during development across mammalian and invertebrate model organisms, and ask whether evolutionary conserved mechanisms might be involved. We conclude that the Barker Hypothesis is poorly supported and argue that more work in human populations should be integrated with multi-disciplinary studies of ageing-related phenomena in experimental populations of different model species that are subjected to nutritional challenges or infections during pre-adult development.

Adaptation, Physiological↗

PubMed2005

Haplotype association analysis of human disease traits using genotype data of unrelated individuals.

Haplotype inference has become an important part of human genetic data analysis due to its functional and statistical advantages over the single-locus approach in linkage disequilibrium mapping. Different statistical methods have been proposed for detecting haplotype - disease associations using unphased multi-locus genotype data, ranging from the early approach by the simple gene-counting method to the recent work using the generalized linear model. However, these methods are either confined to case - control design or unable to yield unbiased point and interval estimates of haplotype effects. Based on the popular logistic regression model, we present a new approach for haplotype association analysis of human disease traits. Using haplotype-based parameterization, our model infers the effects of specific haplotypes (point estimation) and constructs confidence interval for the risks of haplotypes (interval estimation). Based on the estimated parameters, the model calculates haplotype frequency conditional on the trait value for both discrete and continuous traits. Moreover, our model provides an overall significance level for the association between the disease trait and a group or all of the haplotypes. Featured by the direct maximization in haplotype estimation, our method also facilitates a computer simulation approach for correcting the significance level of individual haplotype to adjust for multiple testing. We show, by applying the model to an empirical data set, that our method based on the well-known logistic regression model is a useful tool for haplotype association analysis of human disease traits.

Computer Simulation↗