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.
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.
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.
This study aimed to investigate the association of lipoprotein and triglyceride levels with all-cause mortality in a population free from diabetes and cardiovascular disease (CVD) at baseline. The European Guidelines on cardiovascular disease prevention state that in general total cholesterol (TC) should be
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.
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.
Cites: Am J Hum Genet. 1999 Oct;65(4):1178-9310486337
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.
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.
BACKGROUND: The number of CAG repeats (CAG(n)) within the CAG repeat polymorphism of the androgen receptor gene correlates inversely with the transactivation of the receptor. OBJECTIVE: To examine the impact of CAG(n) on muscle, fat distribution, and circulating androgen levels. Design, settings and participants Population-based, cross-sectional study of 783 Danish men aged 20-29 years. METHODS: Genotyping was performed in 767 men. Areas of thigh and lower trunk muscle (muscle(thigh) and muscle(lower trunk)), subcutaneous adipose tissues (SAT(thigh) and SAT(lower trunk)), and deep adipose tissues (i.m. and visceral) were measured in 393 men by magnetic resonance imaging (MRI). Lean body mass (LBM) and fat mass (FM) were measured in all men by whole body dual-energy X-ray absorptiometry (DEXA). The absolute areas acquired by MRI were the main outcomes. The absolute DEXA measurements and relative assessments of both modalities were considered as the secondary outcomes. Results CAG(n) (range: 10-32) correlated inversely with absolute muscle(thigh) (r=-0.108), absolute muscle(lower trunk) (r=-0.132), relative muscle(thigh) (r=-0.128), relative muscle(lower trunk) (r=-0.126), relative LBM(lower extremity) (r=-0.108), and relative LBM(total) (r=-0.082), and positively with relative SAT(thigh) (r=0.137), relative SAT(lower trunk) (r=0.188), relative FM(lower extremity) (r=0.107), and relative FM(total) (r=0.082). These relationships remained significant, controlling for physical activity, smoking, chronic disease, and age. CAG(n) did not correlate with any circulating androgen. CONCLUSIONS: The CAG repeat polymorphism affects body composition in young men: absolute muscle(thigh) and absolute muscle(lower trunk) increase as CAG(n) decreases. Expressed relatively, muscle areas and LBM increase, while SAT and FM decrease as CAG(n) decreases. The polymorphism does not affect deep adipose tissues or circulating androgen levels in young men.
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.