[Show abstract][Hide abstract] ABSTRACT: Objective:
Subjective health is a complex indicator predicting longevity independent of objective health. Few studies examine genetic and environmental mechanisms underlying different facets of subjective health across the life course.
Three subjective health measures were examined in 12,900 twins (Mage = 63.38, range = 25-102) from nine studies in the Interplay of Genes and Environment across Multiple Studies Consortium: self-rated health (SRH), health compared with others (COMP), and health interfering with activities (ACT).
Analyses indicated age and sex differences in mean scores depending on the measure. SRH and ACT showed significant linear and non-linear moderation by age for individual differences in both genetic and environmental variance. Significant sex differences in components of variance were found for SRH and ACT, but not COMP.
Subjective health appears to be dependent on frame of reference and reflect different aspects of health. Results suggest different genetic and environmental mechanisms underlie each facet.
No preview · Article · Jan 2016 · Journal of Aging and Health
[Show abstract][Hide abstract] ABSTRACT: While longitudinal changes in biomarker levels and their impact on health have been characterized for individual markers, little is known about how overall marker profiles may change during aging and affect mortality risk. We implemented the recently developed measure of physiological dysregulation based on the statistical distance of biomarker profiles in the framework of the stochastic process model of aging, using data on blood pressure, heart rate, cholesterol, glucose, hematocrit, body mass index and mortality in the Framingham original cohort. This allowed us to evaluate how physiological dysregulation is related to different aging-related characteristics such as decline in stress resistance and adaptive capacity (which typically are not observed in the data and thus can be analyzed only indirectly), and, ultimately, to estimate how such dynamic relationships increase mortality risk with age. We found that physiological dysregulation increases with age; that increased dysregulation is associated with increased mortality, and increasingly so with age; and that, in most but not all cases, there is a decreasing ability to return quickly to baseline physiological state with age. We also revealed substantial sex differences in these processes, with women becoming dysregulated more quickly but with men showing a much greater sensitivity to dysregulation in terms of mortality risk.
Full-text · Article · Jan 2016 · Frontiers in Public Health
[Show abstract][Hide abstract] ABSTRACT: Background Age is the strongest risk factor for developing cancer. The aim of the present analysis is to give an overview of the trends in cancer incidence, mortality, prevalence, and relative survival in Denmark from 1980 to 2012 focusing on age, comparing persons aged 70 years or more with those aged less than 70 years. Material and methods Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries. The Danish data originate from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. Results Incidence and mortality rates of all sites, but non-melanoma skin cancer, were higher and relative survival was lower among persons aged 70 years or more than those aged less than 70 years. The age distribution (age group-specific percentages of total number of incident cases) remained constant over time while the percentage of persons dying from cancer decreased with time up to the age of 79 years but increased for those aged 80 years or more, in whom about a third of all cancer deaths occurred in 2012. In 2003-2007, the five-year relative survival was 48% for men aged 70-79 years, 38% for men aged 80-89 years, and 29% for men aged 90 years or more and the corresponding figures for women were 46%, 39%, and 36%, respectively. There was a substantial increase in the number of prevalent cancer cases aged 70 years or older, especially among those aged 90 years or more. Conclusion An increase in elderly cancer patients is expected over the coming 20 years due to an increasing elderly population. Healthcare providers need to focus on developing specific strategies for treatment of elderly cancer patients in the future.
No preview · Article · Jan 2016 · Acta oncologica (Stockholm, Sweden)
[Show abstract][Hide abstract] ABSTRACT: Background:
Postoperative cognitive dysfunction is common, but it remains unclear whether there are long-term adverse cognitive effects of surgery combined with anesthesia. The authors examined the association between exposure to surgery and level of cognitive functioning in a sample of 8,503 middle-aged and elderly twins.
Results from five cognitive tests were compared in twins exposed to surgery, classified as major, minor, hip and knee replacement, or other, with those of a reference group without surgery using linear regression adjusted for sex and age. Genetic and shared environmental confounding was addressed in intrapair analyses of 87 monozygotic and 124 dizygotic same-sexed twin pairs in whom one had a history of major surgery and the other did not.
Statistically significantly lower composite cognitive score was found in twins with at least one major surgery compared with the reference group (mean difference, -0.27; 95% CI, -0.48 to -0.06), corresponding to one tenth of an SD, that is, a negligible effect size. In the intrapair analysis, the surgery-exposed co-twin had the lower cognitive score in 49% (95% CI, 42 to 56%) of the pairs. None of the other groups differed from the reference group except the knee and hip replacement group that tended to have higher cognitive scores (mean difference, 0.35; 95% CI, -0.18 to 0.87).
A history of major surgery was associated with a negligibly lower level of cognitive functioning. The supplementary analyses suggest that preoperative cognitive functioning and underlying diseases were more important for cognitive functioning in mid- and late life than surgery and anesthesia.
[Show abstract][Hide abstract] ABSTRACT: Background:
Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. There is strong evidence of genetic susceptibility. Objective of the study was to identify genetic variants contributing to PTB.
Genotyping was performed for 24 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NR5A2, FSHR, FOXP3, SERPINH1). Genotyping was completed on 728 maternal triads (mother & maternal grandparents of a preterm infant). Data were analyzed with Family Based Association Test.
For all maternal triads rs2737667 of NR5A2 showed significant association at P= 0.02. When stratifying by gestational age three SNPs in NR5A2 had p values <0.05 in the <32 weeks gestational age group (rs12131233, p=0.007; rs2737667, p=0.04; rs2816949, p=0.02). When preterm premature rupture of membranes (PPROM) cases were excluded rs2737667 of NR5A2 showed the strongest association with a p value <0.0002. This association remained significant after correction for multiple testing.
This study suggests a potential association between intronic SNPs in the NR5A2 gene and PTB. NR5A2 gene encodes for the Liver receptor homolog 1(LRH1) protein, which plays a critical role in regulation of cholesterol metabolism, steroidogenesis and progesterone synthesis. These findings suggest NR5A2 may be important in the pathophysiology of PTB and exploring of non-coding regulators of NR5A2 is warranted.Pediatric Research (2016); doi:10.1038/pr.2016.7.
No preview · Article · Jan 2016 · Pediatric Research
[Show abstract][Hide abstract] ABSTRACT: Epidemiological cancer data shed light on key questions within basic science, clinical medicine and public health. For decades, Denmark has had linkable health registers that contain individual level data on the entire population with virtually complete follow-up. This has enabled high quality studies of cancer epidemiology and minimized the challenges often faced in many countries, such as uncertain identification of the study base, age misreporting, and low validity of the cancer diagnoses. However, methodological challenges still remain to be addressed, especially in cancer epidemiology studies among the elderly and the oldest-old. For example, a characteristic pattern for many cancer types is that the incidence increases up to a maximum at about ages 75–90 years and is then followed by a decline or a leveling off at the oldest ages. It has been suggested that the oldest individuals may be asymptomatic, or even insusceptible to cancer. An alternative interpretation is that this pattern is an artifact due to lower diagnostic intensity among the elderly and oldest-old caused by higher levels of co-morbidities in this age group. Currently, the available cancer epidemiology data are not able to provide clear evidence for any of these hypotheses.
[Show abstract][Hide abstract] ABSTRACT: A latent infection with cytomegalovirus (CMV), a ubiquitous beta herpesvirus, is associated with an accumulation of late-differentiated
memory T-cells, often accompanied by a reciprocal reduced frequency of early-differentiated cells (commonly also referred
to as “naïve”). However, this impact of CMV on T-cell phenotypes is variable between individuals. Our previous findings in
a subgroup of participants in the Leiden familial Longevity Study indicated an important role of genetics. For further testing,
we have analyzed middle-aged monozygotic (MZ, n = 42) and dizygotic (DZ, n = 39) twin pairs from the Danish Twin Registry for their T-cell differentiation status, assessed by surface expression of
CD27, CD28, CD57, and KLRG-1. We observed a significant intraclass correlation between cotwins of MZ, but not DZ pairs for
the differentiation status of CD4+ and CD8+ subsets. Classical heritability analysis confirmed a substantial contribution of genetics to the differentiation status of
T-cells in CMV infection. The humoral (IgG) response to different CMV antigens also seems to be genetically influenced, suggesting
that a similar degree of immune control of the virus in MZ twins might be responsible for their similar T-cell differentiation
status. Thus, the way T-cells differentiate in the face of a latent CMV infection, and the parallel humoral responses, both
controlling the virus, are genetically influenced.
No preview · Article · Jan 2016 · The Journals of Gerontology Series A Biological Sciences and Medical Sciences
[Show abstract][Hide abstract] ABSTRACT: Importance
Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction.Objective
To estimate familial risk and heritability of cancer types in a large twin cohort.Design, Setting, and Participants
Prospective study of 80 309 monozygotic and 123 382 same-sex dizygotic twin individuals (N = 203 691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50 990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up.Exposures
Shared environmental and heritable risk factors among pairs of twins.Main Outcomes and Measures
The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twin’s development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death.Results
A total of 27 156 incident cancers were diagnosed in 23 980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%).Conclusions and Relevance
In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.
Full-text · Article · Jan 2016 · JAMA The Journal of the American Medical Association
[Show abstract][Hide abstract] ABSTRACT: Sex differences in religion are well known, with females generally being more religious than males, and shared environmental factors have been suggested to have a large influence on religiousness. Twins from opposite-sex (OS) and same-sex (SS) pairs may differ because of a dissimilar psycho-social rearing environment and/or because of different exposures to hormones in utero. We hypothesized that OS females may display more masculine patterns of religiousness and, vice versa, that OS males may display more feminine patterns. We used a web-based survey conducted in Denmark, which is a secular society. The survey included 2,997 twins aged 20-40 years, identified through the population-based Danish Twin Registry. We applied la Cour and Hvidt's adaptation of Fishman's three conceptual dimensions of meaning: Cognition, Practice, and Importance, and we used Pargament's measure of religious coping (RCOPE) for the assessment of positive and negative religious coping patterns. Differences between OS and SS twins were investigated using logistic regression for each sex. The analyses were adjusted for dependence within twin pairs. No significant differences in religiousness and religious coping were found for OS and SS twins except that more OS than SS females were members of the Danish National Evangelical Lutheran Church and fewer OS than SS females were Catholic, Muslim, or belonged to other religious denominations. Moreover, OS males at age 12 had higher rates of church attendance than did SS males. This study did not provide evidence for masculinization of female twins with male co-twins with regard to religiousness. Nor did it show any significant differences between OS and SS males except from higher rates of church attendance in childhood among males with female co-twins.
No preview · Article · Dec 2015 · Twin Research and Human Genetics
[Show abstract][Hide abstract] ABSTRACT: Higher perceived age (PA) is reported to be associated with age-related diseases. Because osteoporosis is considered an age-related disease, we hypothesized that age perceived from photographs is associated with bone mineral density (BMD)/trabecular bone score (TBS) when controlled for chronological age. This is a cross-sectional study of 460 women aged 25–93 years. BMD/TBS was measured. Twenty physicians assessed age from facial and whole-body photographs. Residual PA (RPACA) was calculated from the regression of PA on chronological age. Participants were divided into “looking old” (LO) or “looking young” (LY). Linear mixed models and general linear models fitted with BMD/TBS as outcome and either RPACA or LO/LY as an independent variable, considering chronological age. Estimates of RPACA were all negative; i.e., an increase in RPAC is associated with lower BMD, consistent with the hypothesis (e.g., β −0.29 %; 95 % confidence interval (CI) 0.55, 0.03). Statistical significance of the association of age-adjusted facial RPACA with BMD was found. Adjusted for body mass index (BMI), menopause, and hormone replacement therapy, higher RPACA from all photographic presentations were significantly associated with lower BMD based on statistical significance. BMD/TBS was in all analyses higher in the group LY compared with LO, when adjusted for age and BMI (e.g., β 4.37 %; 95 CI 0.62, 8.26), but statistical significance was obtained only from the BMD analyses. A higher PA was significantly associated with a lower BMD/TBD, and the size of association in older women indicates that it might have value as part of the clinical assessment of osteoporotic risk.
No preview · Article · Dec 2015 · Journal of the American Aging Association
[Show abstract][Hide abstract] ABSTRACT: Twin pairs discordant for disease may help elucidate the epigenetic mechanisms and causal environmental factors in disease development and progression. To obtain the numbers of pairs, especially monozygotic (MZ) twin pairs, necessary for in-depth studies while also allowing for replication, twin studies worldwide need to pool their resources. The Discordant Twin (DISCOTWIN) consortium was established for this goal. Here, we describe the DISCOTWIN Consortium and present an analysis of type 2 diabetes (T2D) data in nearly 35,000 twin pairs. Seven twin cohorts from Europe (Denmark, Finland, Norway, the Netherlands, Spain, Sweden, and the United Kingdom) and one from Australia investigated the rate of discordance for T2D in same-sex twin pairs aged 45 years and older. Data were available for 34,166 same-sex twin pairs, of which 13,970 were MZ, with T2D diagnosis based on self-reported diagnosis and medication use, fasting glucose and insulin measures, or medical records. The prevalence of T2D ranged from 2.6% to 12.3% across the cohorts depending on age, body mass index (BMI), and national diabetes prevalence. T2D discordance rate was lower for MZ (5.1%, range 2.9-11.2%) than for same-sex dizygotic (DZ) (8.0%, range 4.9-13.5%) pairs. Across DISCOTWIN, 720 discordant MZ pairs were identified. Except for the oldest of the Danish cohorts (mean age 79), heritability estimates based on contingency tables were moderate to high (0.47-0.77). From a meta-analysis of all data, the heritability was estimated at 72% (95% confidence interval 61-78%). This study demonstrated high T2D prevalence and high heritability for T2D liability across twin cohorts. Therefore, the number of discordant MZ pairs for T2D is limited. By combining national resources, the DISCOTWIN Consortium maximizes the number of discordant MZ pairs needed for in-depth genotyping, multi-omics, and phenotyping studies, which may provide unique insights into the pathways linking genes to the development of many diseases.
No preview · Article · Dec 2015 · Twin Research and Human Genetics
[Show abstract][Hide abstract] ABSTRACT: One method by which to identify fundamental biological processes that may contribute to age-related disease and disability, instead of disease-specific processes, is to construct endophenotypes comprising linear combinations of physiological measures. Applying factor analyses methods to phenotypic data (2006-2009) on 28 traits representing 5 domains (cognitive, cardiovascular, metabolic, physical, and pulmonary) from 4,472 US and Danish individuals in 574 pedigrees from the Long Life Family Study (United States and Denmark), we constructed endophenotypes and assessed their relationship with mortality. The most dominant endophenotype primarily reflected the physical activity and pulmonary domains, was heritable, was significantly associated with mortality, and attenuated the association of age with mortality by 24.1%. Using data (1997-1998) on 1,794 Health, Aging and Body Composition Study participants from Memphis, Tennessee, and Pittsburgh, Pennsylvania, we obtained strikingly similar endophenotypes and relationships to mortality. We also reproduced the endophenotype constructs, especially the dominant physical activity and pulmonary endophenotype, within demographic subpopulations of these 2 cohorts. Thus, this endophenotype construct may represent an underlying phenotype related to aging. Additional genetic studies of this endophenotype may help identify genetic variants or networks that contribute to the aging process.
Preview · Article · Nov 2015 · American Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Background: Family history is an established risk factor for breast cancer. Although some important genetic factors have been identified, the extent to which familial risk can be attributed to genetic factors versus common environment remains unclear. Methods: We estimated the familial concordance and heritability of breast cancer among 21,054 monozygotic and 30,939 dizygotic female twin pairs from the Nordic Twin Study of Cancer, the largest twin study of cancer in the world. We accounted for left-censoring, right-censoring, as well as the competing risk of death. Results: From 1943 through 2010, 3,933 twins were diagnosed with breast cancer. The cumulative lifetime incidence of breast cancer taking competing risk of death into account was 8.1% for both zygosities, although the cumulative risk for twins whose co-twins had breast cancer was 28% among monozygotic and 20% among dizygotic twins. The heritability of liability to breast cancer was 31% [95% confidence interval (CI), 10%-51%] and the common environmental component was 16% (95% CI, 10%-32%). For premenopausal breast cancer these estimates were 27% and 12%, respectively, and for postmenopausal breast cancer 22% and 16%, respectively. The relative contributions of genetic and environmental factors were constant between ages 50 and 96. Our results are compatible with the Peto-Mack hypothesis. Conclusion: Our findings indicate that familial factors explain almost half of the variation in liability to develop breast cancer, and results were similar for pre- and postmenopausal breast cancer Impact: We estimate heritability of breast cancer, taking until now ignored sources of bias into account.
No preview · Article · Nov 2015 · Cancer Epidemiology Biomarkers & Prevention
[Show abstract][Hide abstract] ABSTRACT: Despite emerging interest in gene-environment interaction (GxE) effects, there is a dearth of studies evaluating its potential relevance apart from specific hypothesized environments and biometrical variance trends. Using a monozygotic within-pair approach, we evaluated evidence of G×E for body mass index (BMI), depressive symptoms, and cognition (verbal, spatial, attention, working memory, perceptual speed) in twin studies from four countries. We also evaluated whether APOE is a 'variability gene' across these measures and whether it partly represents the 'G' in G×E effects. In all three domains, G×E effects were pervasive across country and gender, with small-to-moderate effects. Age-cohort trends were generally stable for BMI and depressive symptoms; however, they were variable-with both increasing and decreasing age-cohort trends-for different cognitive measures. Results also suggested that APOE may represent a 'variability gene' for depressive symptoms and spatial reasoning, but not for BMI or other cognitive measures. Hence, additional genes are salient beyond APOE.
No preview · Article · Nov 2015 · Behavior Genetics
[Show abstract][Hide abstract] ABSTRACT: An epigenetic profile defining the DNA methylation age (DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. In this study, we estimated the DNAm age of 378 Danish twins, age 30-82 years, and furthermore included a 10-year longitudinal study of the 86 oldest-old twins (mean age of 86.1 at follow-up), which subsequently were followed for mortality for 8 years. We found that the DNAm age is highly correlated with chronological age across all age groups (r = 0.97), but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co-twin and a 'dose-response pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging.
[Show abstract][Hide abstract] ABSTRACT: From the IGEMS Consortium, data were available from 26,579 individuals aged 23 to 102 years on 3 subjective health items: self-rated health (SRH), health compared to others (COMP), and impact of health on activities (ACT). Marital status was a marker of environmental resources that may moderate genetic and environmental influences on subjective health. Results differed for the 3 subjective health items, indicating that they do not tap the same construct. Although there was little impact of marital status on variance components for women, marital status was a significant modifier of variance in all 3 subjective health measures for men. For both SRH and ACT, single men demonstrated greater shared and nonshared environmental variance than married men. For the COMP variable, genetic variance was greater for single men vs. married men. Results suggest gender differences in the role of marriage as a source of resources that are associated with subjective health.
No preview · Article · Oct 2015 · Behavior Genetics