Aims/hypothesis
In this study, we aimed to examine the association between age at natural menopause and risk of type 2 diabetes, and to assess whether this association is independent of potential ...mediators.
Methods
We included 3639 postmenopausal women from the prospective, population-based Rotterdam Study. Age at natural menopause was self-reported retrospectively and was treated as a continuous variable and in categories (premature, <40 years; early, 40–44 years; normal, 45–55 years; and late menopause, >55 years reference). Type 2 diabetes events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits. HRs and 95% CIs were calculated using Cox proportional hazards models, adjusted for confounding factors; in another model, they were additionally adjusted for potential mediators, including obesity, C-reactive protein, glucose and insulin, as well as for levels of total oestradiol and androgens.
Results
During a median follow-up of 9.2 years, we identified 348 individuals with incident type 2 diabetes. After adjustment for confounders, HRs for type 2 diabetes were 3.7 (95% CI 1.8, 7.5), 2.4 (95% CI 1.3, 4.3) and 1.60 (95% CI 1.0, 2.8) for women with premature, early and normal menopause, respectively, relative to those with late menopause (
p
trend
<0.001). The HR for type 2 diabetes per 1 year older at menopause was 0.96 (95% CI 0.94, 0.98). Further adjustment for BMI, glycaemic traits, metabolic risk factors, C-reactive protein, endogenous sex hormone levels or shared genetic factors did not affect this association.
Conclusions/interpretation
Early onset of natural menopause is an independent marker for type 2 diabetes in postmenopausal women.
The Longitudinal Aging Study Amsterdam (LASA) is a prospective cohort study of older adults in the Netherlands, initially based on a nationally representative sample of people aged 55–84 years. The ...study has been ongoing since 1992, and focuses on the determinants, trajectories and consequences of physical, cognitive, emotional and social functioning. Strengths of the LASA study include its multidisciplinary character, the availability of over 25 years of follow-up, and the cohort-sequential design that allows investigations of longitudinal changes, cohort differences and time trends in functioning. The findings from LASA have been reported in over 600 publications so far (see
www.lasa-vu.nl
). This article provides an update of the design of the LASA study and its methods, on the basis of recent developments. We describe additional data collections, such as additional nine-monthly measurements in-between the regular three-yearly waves that have been conducted among the oldest old during 2016–2019, and the inclusion of a cohort of older Turkish and Moroccan migrants.
Abstract
Background
Previous studies have suggested that the association between APOE ɛ 4 and dementia is moderated by physical activity (PA), but the results remain inconclusive and longitudinal ...data on cognitive decline are missing. In this study, we examine whether there is a gene–environment interaction between APOE and PA on cognitive decline in older adults using 9-year follow-up data of three cohort studies.
Methods
We followed 7,176 participants from three longitudinal cohort studies: Longitudinal Aging Study Amsterdam (LASA), InCHIANTI, and Rotterdam Study for 9 years. PA was assessed with self-reported questionnaires and was categorized in low, moderate, and high PA. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and cognitive decline was defined as a decrease of three points or more on the MMSE during 3 years follow-up. We fitted logistic regression models using generalized estimating equations adjusting for age, sex, education, depressive symptoms, and number of chronic disease. Interaction between APOE and PA was tested on multiplicative and additive scale.
Results
Cohorts were similar in most aspects but InCHIANTI participants were on average older and had lower education. APOE ɛ 4 carriers had higher odds of cognitive decline (odds ratio OR = 1.46, 95% confidence interval CI: 1.29–1.64) while PA was not significantly associated with cognitive decline overall (moderate PA: OR = 0.87, 0.67–1.13; high PA: OR = 0.71, 0.36–1.40). There was no evidence for an interaction effect between PA and APOE ɛ 4 in cognitive decline in older adults (APOE × moderate PA: p = .83; APOE × high PA: p = .90).
Conclusions
Previous claims of a gene–environment interaction between APOE ɛ 4 and PA in cognitive decline are not supported by our results.
Chagas disease (CD) is a major public health concern in Latin America and a potentially serious emerging threat in non-endemic countries. Although the association between CD and cardiac abnormalities ...is widely reported, study design diversity, sample size and quality challenge the information, calling for its update and synthesis, which would be very useful and relevant for physicians in non-endemic countries where health care implications of CD are real and neglected. We performed to systematically review and meta-analyze population-based studies that compared prevalence of overall and specific ECG abnormalities between CD and non-CD participants in the general population.
Six databases (EMBASE, Ovid Medline, Web of Science, Cochrane Central, Google Scholar and Lilacs) were searched systematically. Observational studies were included. Odds ratios (OR) were computed using random-effects model.
Forty-nine studies were selected, including 34,023(12,276 CD and 21,747 non-CD). Prevalence of overall ECG abnormalities was higher in participants with CD (40.1%; 95%CIs=39.2-41.0) compared to non-CD (24.1%; 95%CIs=23.5-24.7) (OR=2.78; 95%CIs=2.37-3.26). Among specific ECG abnormalities, prevalence of complete right bundle branch block (RBBB) (OR=4.60; 95%CIs=2.97-7.11), left anterior fascicular block (LAFB) (OR=1.60; 95%CIs=1.21-2.13), combination of complete RBBB/LAFB (OR=3.34; 95%CIs=1.76-6.35), first-degree atrioventricular block (A-V B) (OR=1.71; 95%CIs=1.25-2.33), atrial fibrillation (AF) or flutter (OR=2.11; 95%CIs=1.40-3.19) and ventricular extrasystoles (VE) (OR=1.62; 95%CIs=1.14-2.30) was higher in CD compared to non-CD participants.
This systematic review and meta-analysis provides an update and synthesis in this field. This research of observational studies indicates a significant excess in prevalence of ECG abnormalities (40.1%) related to T. cruzi infection in the general population from Chagas endemic regions, being the most common ventricular (RBBB and LAFB), and A-V B (first-degree) node conduction abnormalities as well as arrhythmias (AF or flutter and VE). Also, prevalence of ECG alterations in children was similar to that in adults and suggests earlier onset of cardiac disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study evaluates the radiological changes in tissue height after maxillary sinus floor elevation (MSFE) using three types of calcium phosphate ceramics over a period of up to 5 years after dental ...implant placement. In 163 patients, MSFE was performed. Three groups of patients were distinguished and treated based on the type of calcium phosphate ceramic used and radiologically evaluated: 40 patients with β-tricalcium phosphate (β-TCP), 76 patients with biphasic calcium phosphate (BCP) 20% hydroxyapatite (HA)-80% β-TCP, and 47 patients with BCP 60% HA-40% β-TCP. Radiological measurements were performed on panoramic radiographs at several time points up to 5 years after dental implant placement. After MSFE, a slow decrease in tissue height measured over time was seen in all three study groups. Resorption of the grafted bone substitutes was more prominent in β-TCP than in BCP ceramics with an HA component (60/40 and 20/80). Loss of tissue height after 5 years was lowest in BCP 60/40 and highest in β-TCP. This radiological study shows a predictable and comparable behavior of the slow decrease in tissue height over time for all three types of calcium phosphate ceramics used in MSFE. The fraction of HA in calcium phosphate ceramics and dental implant loading seems to be beneficial for tissue height maintenance after MSFE.
Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer's disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and ...longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for
-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.
Abstract
Objectives
To replicate the phenotypic associations of grip strength with frailty, physical performance and functional limitations in older adults for longer follow-up periods and to examine ...whether these associations are due to shared genetic factors.
Methods
In total 2,262 participants 55 years and older with follow-up data up to 23 years (Nobservations = 8,262) from the Longitudinal Aging Study Amsterdam were included. Weighted polygenic risk scores for grip strength (PRS-GS) were built using the genome-wide meta-analysis results from UK Biobank as reference. Grip strength was measured two times on each hand using a dynamometer. Frailty index (FI) and frailty phenotype were operationalised following standard procedures. Performance tests included a timed walk test, a repeated chair stands test and put on–take off cardigan test. Functional limitations were assessed using a questionnaire with six items.
Results
Higher grip strength was phenotypically associated with lower FI (b = −0.013, 95% CI (−0.016, −0.009)), better physical performance (b = 0.040, 95% CI (0.026, 0.054)) and less functional limitations (OR = 0.965, 95% CI (0.954, 0.977)) over time for follow-up periods up to 23 years. However, PRS-GS was not associated with any of the traits.
Conclusion
The phenotypic associations between grip strength, frailty, physical performance and functional limitations were replicated for follow-up periods up to 23 years. However, the associations between the traits could not be explained by shared genetics potentially indicating a more relevant involvement of non-genetic factors.
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 ...years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10
), arthritis (GDF5 p = 4 × 10
), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
Abstract
Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct ...polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.
The detection of genetic loci associated with Alzheimer's disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect ...sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants. We used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3 ± 7.9 years), 1,664 age-matched controls (66.0 ± 6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4 ± 1.3 years). We estimated the effect size of 29 variants that were previously associated with AD in genome-wide association studies. Comparing extreme AD cases with centenarian controls increased the variant effect size relative to published effect sizes by on average 1.90-fold (SE = 0.29, p = 9.0 × 10
). The effect size increase was largest for the rare high-impact TREM2 (R74H) variant (6.5-fold), and significant for variants in/near ECHDC3 (4.6-fold), SLC24A4-RIN3 (4.5-fold), NME8 (3.8-fold), PLCG2 (3.3-fold), APOE-ε2 (2.2-fold), and APOE-ε4 (twofold). Comparing extreme phenotypes enabled us to replicate the AD association for 10 variants (p < 0.05) in relatively small samples. The increase in effect sizes depended mainly on using centenarians as extreme controls: the average variant effect size was not increased in a comparison of extreme AD cases and age-matched controls (0.94-fold, p = 6.8 × 10
), suggesting that on average the tested genetic variants did not explain the extremity of the AD cases. Concluding, using centenarians as extreme controls in AD case-control studies boosts the variant effect size by on average twofold, allowing the replication of disease-association in relatively small samples.
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