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Lise Bathum

Publications and source records attributed to Lise Bathum.

18 recordsLinked to original sources
PubMed2006

Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.

Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment interactions. For genes identified as related to oral clefting, we studied gene-expression profiles in fetal development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish participants. In an expanded case set, NAT2 continued to show significant overtransmission of an allele to the fetus, with a final P value of .00003. There was an interaction between maternal smoking and fetal inheritance of a GSTT1-null deletion, seen in both the Danish (P=.03) and Iowan (P=.002) studies, with a Fisher's combined P value of <.001, which remained significant after correction for multiple comparisons. Gene-expression analysis demonstrated expression of GSTT1 in human embryonic craniofacial tissues during the relevant developmental interval. This study benefited from two large samples, involving independent populations, that provided substantial power and a framework for future studies that could identify a susceptible population for preventive health care.

Arylamine N-Acetyltransferase↗
PubMed2006

Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomatology in an elderly population.

BACKGROUND: Depressed mood is a major concern in the elderly, with consequences for morbidity and mortality. Previous studies have demonstrated that genetic factors in depression and subsyndromal depressive symptoms are no less important in the elderly than during other life stages. Variations in genes included in the serotonin system have been suggested as risk factors for various psychiatric disorders but may also serve as candidates for normal variations in mood. METHODS: This study included 684 elderly Danish twins to investigate the influence of 11 polymorphisms in 7 serotonin system genes on the mean level of depression symptomatology assessed over several years, reflecting individuals' underlying mood level. RESULTS: A suggestive association of sequence variations in genes responsible for the synthesis (TPH), recognition (5-HTR2A), and degradation (MAOA) of serotonin with depression symptomatology was found, although the effect was generally restricted to men. We also found that a specific haplotype in VMAT2, the gene encoding the vesicular monoamine transporter, was significantly associated with depression symptoms in men (p= .007). CONCLUSIONS: These results suggest that variations in genes encoding the components of serotonin metabolism may influence the basic mood level and that different genetic factors may apply in men and women.

Affect↗
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↗
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

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

Association between combined properdin and mannose-binding lectin deficiency and infection with Neisseria meningitidis.

BACKGROUND: Individuals genetically deficient of properdin are more susceptible to meningococcal disease. Likewise low concentration or decreased biological activity of mannose-binding lectin (MBL) is associated with higher incidence of bacterial infections during childhood. In this study we report our findings in a Danish family with a remarkably high incidence of meningococcal meningitis-in total four cases, one of them fatal. METHODS: Properdin and MBL were quantified by ELISA and the properdin gene was screened for sequence variations using denaturing high-performance liquid chromatography (DHPLC) and subsequent sequencing of abnormal patterns. The MBL gene was genotyped for the three known variant alleles (B, C and D) as well as three promoter polymorphisms (-221Y/X, -550H/L and +4P/Q). RESULTS: Two out of six males with undetectable properdin activity had meningitis. They had also low MBL serum levels or carried an MBL variant allele, whereas high MBL concentrations were measured in three out of four properdin deficient males--without meningitis. A splice site mutation in exon 10 (c.1487-2A>G) was found in the properdin gene and co segregated with biochemically measured properdin deficiency. CONCLUSION: Our results indicate that a combined deficiency of both properdin and MBL increases the risk of infection with Neisseria meningitidis and stress the importance of epistatic genetic interactions in disease susceptibility.

Adolescent↗
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↗
PubMed2005

Twin study of genetic and aging effects on X chromosome inactivation.

To investigate the genetic influence on X chromosome inactivation and on age-related skewing of X inactivation, in particular, we analysed the X inactivation pattern (XIP) in peripheral blood cells from 118 young monozygotic (MZ) twin pairs (18-53 years), 82 elderly MZ twin pairs (55-94 years), 146 young dizygotic (DZ) twin pairs (20-54 years) and 112 elderly DZ twin pairs (64-95 years). Elderly twins had a higher frequency of skewed X inactivation (34%) than young twins (15%) (P<0.001). Our data suggest that the increase in skewing occurs after age 50-60 years. The intraclass correlation was 0.61 and 0.58 in young and elderly MZ twin pairs, and 0.08 and 0.09 in young and elderly DZ twin pairs. Biometric analysis showed that dominant genetic effects accounted for 63 and 58% of the variance of XIP in the young and elderly twin pairs, respectively. The dominant genetic effect and the shared environment for monochorionic MZ twins may explain the high intraclass correlation for the MZ twin pairs compared to the DZ twin pairs. We did not observe a significant decrease in the intraclass correlation in elderly MZ twins compared to young MZ twins, which would be expected if age-related skewing were due to stochastic factors. We conclude that the increased skewing with age implies that a genetically dependent selection of blood cells take place.

Adolescent↗
PubMed2005

No evidence for an association between extreme longevity and microsomal transfer protein polymorphisms in a longitudinal study of 1651 nonagenarians.

Previous studies have reported two SNPs and a haplotype marker within the Microsomal Transfer Protein gene associated with extreme longevity. Here, we test this finding in a longitudinal study of nonagenarians and in an association study. Participants in the Danish 1905 cohort study (1651 participants aged 92-93 years) were genotyped for the two SNPs (rs2866164 and Q95H) in the Microsomal Transfer Protein gene recently reported to be associated with longevity. The 1905 Cohort has been followed for 6.5 years, during which period 83% of the cohort has died. Furthermore, a group of 575 middle-aged Danish twins (mean age 53.7 years) were tested as a younger control group. The risk haplotype had no significant survival disadvantage (P-values: 0.56, 0.31 and 0.97 in the total population of nonagenarians, males and females, respectively) after 6.5 years of follow-up. The distributions of the suggested risk alleles (rs2866164-G and Q95) and the resulting haplotypes are very similar and not statistically different between the two age cohorts. The frequency for rs2866164-G is in the middle-aged compared to the nonagenarians 25.4 and 23.6% in males and 23.0 and 26.1% in females. The frequency for the risk haplotype is in the middle-aged compared to the nonagenarians 22.7 and 19.2% in males and 18.1 and 21.8% in females. In conclusion, our longitudinal study of survival in the 10th decade of life and an association study in a genetically homogeneous population provided no support for an association between the Microsomal Transfer Protein gene and extreme longevity.

Aged↗
PubMed2004

Genetic influence on inflammation variables in the elderly.

BACKGROUND: Inflammation variables (C-reactive protein [CRP], fibrinogen, and soluble intercellular adhesion molecule-1 [sICAM-1]) have been identified as risk factors for cardiovascular disease. It is still not known how much the regulation of inflammatory risk factors is determined by genetic factors, and the aim of this study was to determine the heritability of these inflammation variables and of the acute phase regulating cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) at older ages. METHODS AND RESULTS: The heritability of CRP, fibrinogen, sICAM-1, IL-6, and TNF-alpha was determined in a twin study consisting of 129 monozygotic twin pairs and 153 dizygotic same-sex twins aged 73 to 94 years who participated in the Longitudinal Study of Aging of Danish Twins. Furthermore, we determined the influence of selected genetic polymorphisms on the plasma level variations. Genetic factors accounted for 20% to 55% of the variation in plasma levels of the inflammation variables. The highest heritability was found for sICAM-1. The genetic polymorphisms we studied explained only a small, insignificant part of the heritability. CONCLUSIONS: This study in elderly twins provides evidence for a substantial genetic component of inflammatory cardiovascular risk factors among the elderly.

Acute-Phase Proteins↗
PubMed2004

Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study.

Osteoporotic fractures are some of the major causes of morbidity and health care expenditure among the elderly. Identifying subjects at risk could be of major importance since several preventive treatments are now available. A large genetic component in the development of osteoporosis has been established. Previous studies concerning association of the common point mutation C677T in methylentetrahydrofolate reductase (MTHFR) and osteoporosis have revealed contradictory results. The aim of this study was to test the association between the MTHFR polymorphism, homocysteine, and fractures in a population-based sample of Danish twins aged 73+. In total, 689 subjects, with a mean age of 78 years, participated. Genotype and data of fractures are available from 687 subjects--144 with a previously diagnosed fracture. The genotype distribution is as follows: CC, CT, and TT genotypes, 317 (46.1%), 298 (43.3%), and 73 (10.6%), respectively. Using the proportional odds-ratio model adjusted for age, gender, and body mass Index, the odds-ratio of fracture was 1.5 per number of T alleles--meaning that fracture risk is 1.5 times higher in the CT group compared with the CC group and again 1.5 times higher in the TT group compared with the CT group. Homocysteine, smoking, and self-reported hormone use provided no significant contribution to fracture risk. Using biometrical modelling, the heritability of the liability to fractures was found to be approximately 0.10, when the effect of the MTHFR locus was included, and 0.07 when it was omitted. But both confidence intervals include zero and the estimates are therefore not significant. In conclusion, we here provide evidence for a significant impact of the MTHFR genotype on the occurrence of fractures in an elderly Danish population.

Aged↗
PubMed2004

Heritability of biochemical kidney markers and relation to survival in the elderly--results from a Danish population-based twin study.

BACKGROUND AND AIM: We performed a twin study to assess the relative contribution of genetic and environmental factors to serum levels of urea, creatinine, urate and sodium in a population of 688 elderly twins (73-95 years). Furthermore, we tested the association between these biochemical values and mortality to examine the consequence of an abnormal biochemical kidney parameter in an aging population. RESULTS: A third to a half of the variation in the biochemical kidney tests is due to genetic factors except for creatinine in males. Survival analysis show that all four parameters influence mortality and values below reference interval for urea and urate have a more pronounced impact on survival [hazard ratios (95% confidence interval): 2.32 (1.03-5.26) and 3.56 (1.46-8.69), respectively] than values above [1.20 (0.87-1.64) and 1.50 (1.11-2.02), respectively]. Increased creatinine (above 130 micromol/l) and decreased sodium (below 136 mmol/l) also have a significant impact on survival with hazard ratios on 1.83 (1.13-2.95) and 1.56 (1.22-1.99), respectively. Between 5% and 44% of the measured values are outside the established reference interval. CONCLUSION: This study provides evidence for the importance of genetic factors in determining the biochemical kidney parameters in an aging population. Furthermore, our data shows that abnormal kidney parameters are common in older adults and results in a significant increase in mortality risk.

Aged↗
PubMed2004

Apolipoprotein E genotype frequency patterns in aged Danes as revealed by logistic regression models.

Although the ApoE gene has been intensively studied in aging research, most of the studies conducted so far have been based on the traditional case-control design with subjects consisting of young controls and long-lived cases. The genotype frequency pattern in and between the two age-groups has been rarely investigated due to limitations in either research design or data analytical method. In this study, we genotyped 748 individuals (including both twin pairs and unrelated individuals) aged from 73 to 95 with aim at examining the genotype frequency trajectory of ApoE gene at high ages. Binomial and multinomial logistic regression models have been applied to model the gene frequency as a function of age and to investigate the modes of gene function (dominant, recessive, additive). The generalized estimation equations (GEEs) are introduced to account for the intra-pair genotype correlation in the twin pairs included in the data. Both the observed and the fitted frequencies show a constantly declining pattern of ApoE epsilon4 allele as age advances indicating a significant and steadily deleterious effect of the dominant allele that increases the hazard of death at high ages.

Aged↗
PubMed2004

The catalase -262C/T promoter polymorphism and aging phenotypes.

A low level of the central antioxidant enzyme catalase has been suggested to be a risk factor for diseases influenced by oxidative stress. In this study, we investigated the possible association of the catalase -262C/T polymorphism with survival, physical and cognitive functioning, and a number of oxidative stress-mediated disorders. The study population was 2223 Danish individuals, aged 45-93 years, drawn from three population-based surveys. The results suggest that the catalase -262C/T polymorphism is not associated with either survival, or the majority of the age-related phenotypes investigated. However, our data indicate a statistical significant association of TT homozygosity with improved physical functioning as well as a trend of the T allele conferring an improved general cognitive functioning, although these results did not remain significant after correcting for multiple testing. The results raise the hypothesis that the catalase -262T allele serves as protection against neurodegenerative and physical decline, although replication in other studies is warranted for confirmation of these findings.

Aged↗
PubMed2003

ACE genotype and physical training effects: a randomized study among elderly Danes.

BACKGROUND AND AIMS: The level of physical functioning (PF) late in life has, in recent years, been shown to be influenced by genetic factors. One of the most extensively studied genetic variants associated with PF and trainability is insertion/deletion (I/D) polymorphism in the gene encoding Angiotensin Converting Enzyme (ACE). However, ACE studies have mainly been conducted among younger persons in excellent physical shape. In this study, we examine whether the level of PF, trainability, or rate-of-change are associated with the ACE genotype among the elderly. METHODS: We used data from 4 randomized training studies of elderly Danes (N = 203). The measures of PF were self-report, maximal oxygen uptake, muscle strength, walking speed, and body composition. RESULTS: Overall, a favorable change in the measures of PF was observed in training groups compared with control groups. However, within groups, neither pre- or post-training/control period levels of PF nor differences in pre- and post-levels were associated with the ACE genotype. CONCLUSIONS: On the basis of our randomized studies, we could not detect any association between the ACE genotype and the level of PF or change, regardless of whether response to physical training or spontaneous changes was studied.

Aged↗
PubMed2003

Angiotensin I-converting enzyme (ACE) gene polymorphism in relation to physical performance, cognition and survival--a follow-up study of elderly Danish twins.

PURPOSE: Studies of younger individuals have suggested an association between ACE genotype and physical and cognitive performance. Using a longitudinal study of elderly twins we studied the association between ACE genotype and physical and cognitive functioning and survival in old age. METHODS: Participants were 684 twins aged 73+ years from the 1997 and 1999 surveys of the Longitudinal Study of Aging Danish Twins. Cognitive skills were assessed by the MMSE, while physical abilities were determined through self-report in 1997 and through both self-report and measurement of performance in two physical tasks in 1999. Survival status was obtained through linkage with a national death register. RESULTS: Neither physical nor cognitive performance was associated with ACE genotype at baseline in 1997, or at follow-up in 1999. For participants in both surveys longitudinal changes in these skills did not depend on ACE genotype. The relative risk of dying was increased in II compared with the DI and DD genotype with relative risks of 1.6 (95 percent confidence intervals 1.1-2.5) and 1.3 (0.8-2.1), respectively. CONCLUSION: We found no substantial effects of ACE genotype on physical and cognitive performance, or rate of change among elderly. Persons with the D allele may have a lower mortality at older ages.

Aged↗