Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and ...DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.
Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a ...mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors lysophosphatidylcholine 18∶1 (hazard ratio HR per standard deviation SD increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015). Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
In the following brief report, we examined gender differences in incidence rates of any dementia, Alzheimer's disease (AD) alone, and non-Alzheimer's dementia alone in 16,926 women and men in the ...Swedish Twin Registry aged 65+. Dementia diagnoses were based on clinical workup and national health registry linkage. Incidence rates of any dementia and AD were greater in women than men, with any dementia rates diverging after age 85 and AD rates diverging around 80. This pattern is consistent with women's survival to older ages compared to men. These findings are similar to incidence rates reported in other Swedish samples.
Biological age measurements (BAs) assess aging-related physiological change and predict health risks among individuals of the same chronological age (CA). Multiple BAs have been proposed and are well ...studied individually but not jointly. We included 845 individuals and 3973 repeated measurements from a Swedish population-based cohort and examined longitudinal trajectories, correlations, and mortality associations of nine BAs across 20 years follow-up. We found the longitudinal growth of functional BAs accelerated around age 70; average levels of BA curves differed by sex across the age span (50-90 years). All BAs were correlated to varying degrees; correlations were mostly explained by CA. Individually, all BAs except for telomere length were associated with mortality risk independently of CA. The largest effects were seen for methylation age estimators (GrimAge) and the frailty index (FI). In joint models, two methylation age estimators (Horvath and GrimAge) and FI remained predictive, suggesting they are complementary in predicting mortality.
There is evidence for long-lasting effects of birth characteristics on cognitive ability in childhood and adulthood. Further, low cognitive ability throughout the lifetime has been linked to ...age-related cognitive decline and dementia risk. However, little is known about the effects of birth characteristics on cognitive dysfunction late in life. Here we explore potential associations between birth characteristics (weight, head circumference, length, and gestational age), adjusted and not adjusted for gestational age, and cognitive impairment and dementia late in life.
Data from twins in the Swedish Twin Registry born 1926-1960 were merged with information from the Swedish birth, patient, and cause of death registries, resulting in a sample of 35,191 individuals. A subsample of 4,000 twins aged 65 years and older also participated in a telephone cognitive screening in 1998-2002. Associations of birth characteristics with registry-based dementia diagnoses and on telephone-assessed cognitive impairment were investigated in the full sample and subsample, respectively. The full sample contained 907 (2.6%) individuals with a dementia diagnosis (an incidence rate of 5.9% per 100,000 person-years), 803 (2.4%) individuals born small for gestational age, and 929 (2.8%) individuals born with a small head for gestational age. The subsample contained 569 (14.2%) individuals with cognitive impairment. Low birth weight for gestational age and being born with a small head for gestational age were significant risk factors for cognitive dysfunction late in life, with an up to 2-fold risk increase (p < 0.001) compared to infants with normal growth and head size, even after controlling for familial factors, childhood socioeconomic status, and education in adulthood. In line with this, each additional 100 g birth weight and each additional millimeter head circumference significantly reduced the risk for dementia (hazard ratio 0.98, 95% confidence interval 0.97 to 0.99, p = 0.004) and cognitive impairment (odds ratio 0.99, 95% confidence interval 0.99 to 1.00, p = 0.004), respectively. Within-pair analyses of identical twins, though hampered by small sample size, suggested that the observed associations between birth characteristics and dementia are likely not due to underlying shared genetic or environmental etiology. A limitation of the present study is that registry-based dementia diagnoses likely miss some of the true dementia cases in the population. Further, a more precise measure of cognitive reserve early in life as well as a date of onset for the cognitive impairment measure in the subsample would have been favorable.
In this study, we found that infants of smaller birth size (i.e., low birth weight or small head circumference adjusted and unadjusted for gestational age) have a significantly higher risk of age-related cognitive dysfunction compared to those with normal growth, highlighting the importance of closely monitoring the cognitive development of such infants and evaluating the potential of early life interventions targeted at enhancing cognitive reserve.
Abstract
Objective
We examined changes in participation in cognitive, social, and physical leisure activities across middle and older adulthood and tested moderation of trajectories of change in ...participation by gender.
Method
In all, 1,398 participants in the Swedish Adoption/Twin Study of Aging (SATSA) completed a 7-item leisure activity questionnaire up to 4 times over 17 years. Mean baseline age was 64.9 years (range = 36–91); 59% were women. Factor analysis identified physical, social, and cognitive/sedentary leisure activity participation factors. Age-based latent growth curve models adjusted for marital status, gender, education, depressive symptoms, and physical health were used.
Results
Overall, results indicated stability in social activities, increase in cognitive/sedentary activities, and decrease in physical activities, as well as accelerated decline in all three types of activities after about the age of 70 years. Social activity remained mostly stable for women and declined for men. Women reported higher levels of cognitive/sedentary leisure activity across the study. Both men and women declined in physical leisure activity. Variance in leisure activities increased with age; men demonstrated more variance in social activities and women in physical activities.
Conclusions
Understanding change in leisure activities with age and by gender can have important implications for interventions and for use of leisure activity data in epidemiological research.
Telomere attrition is associated with increased morbidity and mortality of various age-related diseases. Reports of association between telomere length (TL) and all-cause mortality remain ...inconsistent. In the present study, a meta-analysis was performed using published cohort studies and un-published data from the Swedish Twin Registry (STR). Twenty-five studies were included: four STR cohorts (12,083 individuals with 2517 deaths) and 21 published studies. In the STR studies, one standard deviation (SD) decrement of leukocyte TL corresponded to 13% increased all-cause mortality risk (95% confidence interval CI: 7%-19%); individuals in the shortest TL quarter had 44% higher hazard (95% CI: 27%-63%) than those in the longest quarter. Meta-analysis of all eligible studies (121,749 individuals with 21,763 deaths) revealed one SD TL decrement-associated hazard ratio of 1.09 (95% CI: 1.06-1.13); those in the shortest TL quarter had 26% higher hazard (95% CI: 15%-38%) compared to the longest quarter, although between-study heterogeneity was observed. Analyses stratified by age indicated that the hazard ratio was smaller in individuals over 80 years old. In summary, short telomeres are associated with increased all-cause mortality risk in the general population. However, TL measurement techniques and age at measurement contribute to the heterogeneity of effect estimation.
To examine whether vagotomy decreases the risk of Parkinson disease (PD).
Using data from nationwide Swedish registers, we conducted a matched-cohort study of 9,430 vagotomized patients (3,445 ...truncal and 5,978 selective) identified between 1970 and 2010 and 377,200 reference individuals from the general population individually matched to vagotomized patients by sex and year of birth with a 40:1 ratio. Participants were followed up from the date of vagotomy until PD diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first. Vagotomy and PD were identified from the Swedish Patient Register. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox models stratified by matching variables, adjusting for country of birth, chronic obstructive pulmonary disease, diabetes mellitus, vascular diseases, rheumatologic disease, osteoarthritis, and comorbidity index.
A total of 4,930 cases of incident PD were identified during 7.3 million person-years of follow-up. PD incidence (per 100,000 person-years) was 61.8 among vagotomized patients (80.4 for truncal and 55.1 for selective) and 67.5 among reference individuals. Overall, vagotomy was not associated with PD risk (HR 0.96, 95% CI 0.78-1.17). However, there was a suggestion of lower risk among patients with truncal vagotomy (HR 0.78, 95% CI 0.55-1.09), which may be driven by truncal vagotomy at least 5 years before PD diagnosis (HR 0.59, 95% CI 0.37-0.93). Selective vagotomy was not related to PD risk in any analyses.
Although overall vagotomy was not associated the risk of PD, we found suggestive evidence for a potential protective effect of truncal, but not selective, vagotomy against PD development.
To evaluate how self-reported leisure-time physical activity (PA) changes during the adult life span, and to study how PA is related to cardiovascular risk factors using longitudinal studies.
Several ...Swedish population-based longitudinal studies were used in the present study (PIVUS, ULSAM, SHE, and SHM, ranging from hundreds to 30,000 participants) to represent information across the adult life span in both sexes. Also, two cross-sectional studies were used as comparison (EpiHealth, LifeGene). PA was assessed by questionnaires on a four or five-level scale.
Taking results from several samples into account, an increase in PA from middle-age up to 70 years was found in males, but not in females. Following age 70, a decline in PA was seen. Young adults reported both a higher proportion of sedentary behavior and a higher proportion high PA than the elderly. Females generally reported a lower PA at all ages. PA was mainly associated with serum triglycerides and HDL-cholesterol, but also weaker relationships with fasting glucose, blood pressure and BMI were found. These relationships were generally less strong in elderly subjects.
Using data from multiple longitudinal samples the development of PA over the adult life span could be described in detail and the relationships between PA and cardiovascular risk factors were portrayed. In general, a higher or increased physical activity over time was associated with a more beneficial cardiovascular risk factor profile, especially lipid levels.
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