412 research outputs found
Sex-specific Mendelian randomisation to assess the causality of sex differences in the effects of risk factors and treatment: spotlight on hypertension
Hypertension is a key modifiable risk factor for cardiovascular disease. Several observational studies have found a stronger association of blood pressure and cardiovascular disease risk in women compared to men. Since observational studies can be affected by sex-specific residual confounding and reverse causation, it remains unclear whether these differences reflect actual differential effects. Other study designs are needed to uncover the causality of sex differences in the strength of risk factor and treatment effects. Mendelian randomisation (MR) uses genetic variants as instrumental variables to provide evidence about putative causal relations between risk factors and outcomes. By exploiting the random allocation of genes at gamete forming, MR is unaffected by confounding and results in more reliable causal effect estimates. In this review, we discuss why and how sex-specific MR and cis-MR could be used to study sex differences in risk factor and drug target effects. Sex-specific MR can be helpful to strengthen causal inferences in the field of sex differences, where it is often challenging to distinguish nature from nurture. The challenge of sex-specific (drug target) MR lays in leveraging robust genetic instruments from sex-specific GWAS studies which are not commonly available. Knowledge on sex-specific causal effects of hypertension, or other risk factors, could improve clinical practice and health policies by tailoring interventions based on personalised risk. Drug target MR can help to determine the anticipated on-target effects of a drug compound and to identify targets to pursue in drug developmen
Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men
In the present cross-sectional study of 403 independently living elderly
men, we tested the hypothesis that the decreases in bone mass, body
composition, and muscle strength with age are related to the fall in
circulating endogenous testosterone (T) and estrogen concentrations. We
compared various measures of the level of bioactive androgen and estrogen
to which tissues are exposed. After exclusion of subjects with severe
mobility problems and signs of dementia, 403 healthy men (age, 73-94 yr)
were randomly selected from a population-based sample. Total T (TT), free
T (FT), estrone (E1), estradiol (E2), and sex hormone-binding globulin
(SHBG) were determined by RIA. Levels of non-SHBG-bound T (non-SHBG-T), FT
(calc-FT), the TT/SHBG ratio, non-SHBG-bound E2, and free E2 were
calculated. Physical characteristics of aging included muscle strength
measured using dynamometry, total body bone mineral density (BMD), hip
BMD, and body composition, including lean mass and fat mass, measured by
dual-energy x-ray absorptiometry. In this population of healthy elderly
men, calc-FT, non-SHBG-T, E1, and E2 (total, free, and non-SHBG bound)
decreased significantly with age. T (total and non-SHBG-T) was positively
related with muscle strength and total body BMD (for non-SHBG-T,
respectively, beta = 1.93 +/- 0.52, P < 0.001 and beta = 0.011 +/- 0.002,
P < 0.001). An inverse association existed between T and fat mass (beta =
-0.53 +/- 0.15, P < 0.001). Non-SHBG-T and calc-FT were more strongly
related to muscle strength, BMD, and fat mass than TT and were also
significantly related to hip BMD. E1 and E2 were both positively,
independently associated with BMD (for E2, beta = 0.21 +/- 0.08, P <
0.01). Non-SHBG-bound E2 was slightly strongly related to BMD than total
E2. The positive relation between T and BMD was independent of E2. E1 and
E2 were not related with muscle strength or body composition. In summary,
bioavailable T, E1, total E2, and bioavailable E2 all decrease with age in
healthy old men. In this cross-sectional study in healthy elderly men,
non-SHBG-bound T seems to be the best parameter for serum levels of
bioactive T, which seems to play a direct role in the various
physiological changes that occur during aging. A positive relation with
muscle strength and BMD and a negative relation with fat mass was found.
In addition, both serum E1 and E2 seem to play a role in the age-related
bone loss in elderly men, although the cross-sectional nature of the study
precludes a definitive conclusion. Non-SHBG-bound E2 seems to be the best
parameter of serum bioactive E2 in describing its positive relation with
BMD
Socioeconomic differences in stroke among Dutch elderly women: the Rotterdam Study
BACKGROUND AND PURPOSE: We sought to assess the association between
socioeconomic status and the risk of stroke among elderly women.
Methods--The association between socioeconomic status and stroke emerged
in cross-sectional and longitudinal data on 4274 female participants of
the Rotterdam Study, a prospective, population-based, follow-up study in
the Netherlands among older subjects. RESULTS: A history of stroke was
more common among women in lower socioeconomic strata. The same trend was
observed for the relationship between the lowest socioeconomic groups and
the incidence of stroke. Risk factors for stroke were not related to
socioeconomic status in a consistent manner. Smoking, history of
cardiovascular diseases, and overweight were more common in lower
socioeconomic groups. However, socioeconomic differences in hypertension,
antihypertensive drug use, prevalence of atrial fibrillation, and
prevalence of left ventricular hypertrophy were not observed. The complex
of established risk factors could only partly explain the association
between socioeconomic status and stroke. CONCLUSIONS: There is a strong
association among elderly women between socioeconomic status and stroke.
The association could only partly be explained by known risk factors. Our
findings indicate that not only the actual risk profile but also risk
factors earlier in life may be of importance
Peroxisome proliferator-activated receptor gamma-2 P12A polymorphism and risk of acute myocardial infarction, coronary heart disease and ischemic stroke: A case-cohort study and meta-analyses
The alanine allele of P12A polymorphism in PPARG gene in a few studies has been associated with a reduced or increased risk of acute myocardial infarction (AMI). Yet, the risk relation has not been confirmed, and data on ischemic stroke (IS) is scarce. We therefore investigated the role of this polymorphism on occurrence of AMI, coronary heart disease (CHD) and IS. We performed a case-cohort study in 15,236 initially healthy Dutch women and applied a Cox proportional hazards model to study the relation of the P12A polymorphism and AMI (n = 71), CHD (n = 211), and IS (n = 49) under different inheritance models. In addition, meta-analyses of published studies were performed. Under the dominant inheritance model, carriers of the alanine allele compared with those with the more common genotype were not at increased or decreased risk of CHD (hazard ratio [HR] = 0.82; 95% confidence interval [CI], 0.58 to 1.17) and of IS (HR = 1.03; 95% CI, 0.14 to 7.74). In addition no relations were found under the recessive and additive models. Our meta-analyses corroborated these findings by showing no significant association. For AMI we found a borderline significant association under dominant (HR = 0.49; 95% CI, 0.26 to 0.94), and additive (HR = 0.51; 95% CI, 0.26 to 1.00) models which could be due to chance, because of small cases in this subgroup. The meta-analysis did not show any association between the polymorphism and risk of AMI under the different genetic models. Our study in healthy Dutch women in combination with the meta-analyses of previous reports does not provide support for a role of P12A polymorphism in PPARG gene in MI and CHD risk. Also our study shows that the polymorphism has no association with IS ris
QTc dispersion predicts cardiac mortality in the elderly: the Rotterdam Study
BACKGROUND: Increased QTc dispersion has been associated with an increased
risk for ventricular arrhythmias and cardiac death in selected patient
populations. We examined the association between computerized
QTc-dispersion measurements and mortality in a prospective analysis of the
p
Luteinizing hormone and different genetic variants, as indicators of frailty in healthy elderly men
We investigated the possible clinical correlates between the serum LH
concentration and characteristics of frailty and determined the presence
and concentration of a genetic LH variant in an independently living
population of elderly men. After exclusion of subjects with severe
mobility problems and signs of dementia, 403 healthy men (aged 73-94 yr)
were randomly selected from a population-based sample. Total testosterone
(T), sex hormone-binding globulin (SHBG), and leptin were determined by
RIA. Non-SHBG-bound T was calculated. LH and the presence of the genetic
LH variant were measured using immunofluorometric assays. The
characteristics of frailty were leg extensor strength using dynamometry,
bone mineral density of total body and proximal femur, and body
composition, including lean mass and fat mass, measured by dual energy
x-ray absorptiometry. Disability was further assessed by the Modified
Health Assessment Questionnaire and by a measure of physical performance.
LH significantly increased with age and inversely correlated with T and
non-SHBG-bound T. LH was inversely related to muscle strength and lean
mass, and both relations were independent of T. LH was positively related
to self-reported disability (Modified Health Assessment Questionnaire);
12.5% of the study population was heterozygous for the LH variant allele.
T levels and the degree of frailty were not different in the wild-type LH
group compared with the heterozygote LH variant group. A significant
positive relation between LH and fat mass as well as leptin was only
present in the heterozygote LH variant group. In conclusion, serum LH
levels increases with age in independently living elderly men and
correlates inversely with a variety of indicators of frailty. The observed
relation between LH and frailty, independent of T, suggests that LH
reflects serum androgen activity in a different way than T, possibly
reflecting more closely the combined feedback effect of estrogen and
androgen. A difference in biological response between the two LH forms is
suggested, as a difference exists in the relation between LH and fat mass,
respectively, and leptin in the heterozygote LH variant subjects vs. the
wild-type LH subjects
Prolonged QT interval: A tricky diagnosis?
Prolonged heart-rate adjusted QT intervals on the electrocardiogram (ECG) are associated with an increased risk far coronary heart disease and sudden death. However, the diagnosis of the prolonged QT interval is hampered by lack of standards. We studied variations in the prevalence of prolonged QT, based on different common definitions, in a large nonhospitalized population, and compared our results with other studies applying the same definitions. The study population consisted of 2,200 men and 3,366 women participants of the Rotterdam Study, ≤55 years old. The QT interval was computed by our Modular ECG Analysis System (MEANS). Three different formulas to adjust QT for heart rata were used: Bazett's formula (QT(c), a linear regression equation (QT(Ir)), and the QT index (QTI). Prolonged QT occurred frequently in both men and women, and its prevalence increased with age. Women had longer heart-rate adjusted QT intervals than men (mean QT(c) 433 ms vs 422 ms), and mean values for QT(Ir) were lower than for QT(c) (mean QT(Ir) 422 ms in women and 412 ms in men). Prevalence was highest for prolonged QT(Ir) (31% in men and 26% in women) and lowest for prolonged QTI (6% in men and 9% in women). Comparison with other studies applying the same correction formulas showed large discrepancies in prevalence estimates of prolonged QT(c) and QT(Ir), and to a lesser degree of prolonged QTI, possibly due to differences in measurement techniques. Future research is needed to relate QT interval to prognosis, to obtain measurement technique specific reference values of heart-rate adjusted QT measurements, and to obtain age-and sex- specific threshold values for prolonged QT. Such data are needed to use the QT interval with confidence
Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals
In the present study, we investigated whether the negative feedback action
of glucocorticoids (GCs) on the hypothalamo-pituitary-adrenal (HPA) axis
changes with age. We performed a 1-mg dexamethasone (DEX) suppression test
in 216 healthy elderly individuals. To investigate individual variability
of feedback sensitivity in more detail, 2.5 yr later a 0.25-mg DEX
suppression test was carried out in 164 of the same individuals. We
investigated whether there was an effect of age or gender on both basal
and post-DEX cortisol levels, as well as on the concentration of DEX.
Furthermore, we examined whether the reactions to the two doses of DEX
differed, and whether indications for an intraperson stability of baseline
cortisol levels could be found. Neither the pre- nor the post-1-mg DEX
plasma cortisol concentrations showed a correlation with age, and there
were no differences between men and women. The same was true for the pre-
and post-0.25-mg DEX cortisol concentrations. In reaction to 1 mg DEX,
over 90% of the subjects investigated showed a cortisol suppression to
levels below 50 nmol/L. After the administration of 0.25 mg DEX, there was
a much wider range in post-DEX cortisol concentrations. After the
administration of 1 mg DEX, there was a significant correlation between
liver function parameters and plasma DEX concentrations in males, and
there was a correlation between body mass index and plasma DEX
concentration in females. Plasma DEX concentrations after the
administration of 1 mg and 0.25 mg DEX were closely correlated within
subjects (P < 0.001). There was an intraindividual stability of serum
cortisol levels determined at an interval of 2.5 yr. Furthermore, the
individuals with the highest baseline cortisol concentrations also had the
highest post-0.25-mg DEX cortisol concentrations, indicating a close
relationship between basal cortisol levels and the feedback sensitivity of
the HPA axis to a low dose of DEX. These observations suggest a genetic
influence on the set point of the HPA axis. Aging does not seem to lead to
a change in HPA activity as measured by early morning total cortisol
levels. Also, no changes in the sensitivity of the feedback system to DEX
were observed with age. DEX metabolism is influenced by liver function (in
males) and by body mass index (in females)
The CAMCOG: a useful screening instrument for dementia in stroke patients
BACKGROUND and PURPOSE: Most mental screening tests focus on the detection
of cognitive deficits compatible with Alzheimer's disease. Stroke patients
who develop a dementia syndrome, however, constitute a more heterogeneous
group with both cortical and subcortical disturbances. We assessed the
diagnostic accuracy of the CAMCOG (the cognitive and self-contained part
of the Cambridge Examination for Mental Disorders of the Elderly) and the
Mini-Mental State Examination (MMSE) for dementia in patients with a
recent stroke. METHODS: In patients age
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