| 1. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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| 2. |
- Carrasquilla, Germán D, et al.
(författare)
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Does menopausal hormone therapy reduce myocardial infarction risk if initiated early after menopause? : A population-based case-control study
- 2014
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Ingår i: Menopause. - 1072-3714 .- 1530-0374. ; 22:6, s. 598-606
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study aims to assess whether the timing of menopausal hormone therapy initiation in relation to onset of menopause and hormone therapy duration is associated with myocardial infarction risk.METHODS: This study was based on the Stockholm Heart Epidemiology Program, a population-based case-control study including 347 postmenopausal women who had experienced a nonfatal myocardial infarction and 499 female control individuals matched for age and residential area. Odds ratios (with 95% CIs) for myocardial infarction were calculated using logistic regression.RESULTS: Early initiation of hormone therapy (within 10 y of onset of menopause or before age 60 y), compared with never use, was associated with an odds ratio of 0.87 (95% CI, 0.58-1.30) after adjustments for lifestyle factors, body mass index, and socioeconomic status. For late initiation of hormone therapy, the corresponding odds ratio was 0.97 (95% CI, 0.53-1.76). For hormone therapy duration of 5 years or more, compared with never use, the adjusted odds ratio was 0.64 (95% CI, 0.35-1.18). For hormone therapy duration of less than 5 years, the odds ratio was 0.97 (95% CI, 0.63-1.48).CONCLUSIONS: Neither the timing of hormone therapy initiation nor the duration of therapy is significantly associated with myocardial infarction risk.
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| 3. |
- Carrasquilla, Germán D, et al.
(författare)
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Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity
- 2022
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Physical inactivity and increased sedentary time are associated with excess weight gain in observational studies. However, some longitudinal studies indicate reverse causality where weight gain leads to physical inactivity and increased sedentary time. As observational studies suffer from reverse causality, it is challenging to assess the true causal directions. Here, we assess the bidirec- tional causality between physical inactivity, sedentary time, and adiposity by bidirectional Mendelian randomization analysis. We used results from genome-wide association studies for accelerometer- based physical activity and sedentary time in 91,105 individuals and for body mass index (BMI) in 806,834 individuals. We implemented Mendelian randomization using CAUSE method that accounts for pleiotropy and sample overlap using full genome-wide data. We also applied inverse variance- weighted, MR-Egger, weighted median, and weighted mode methods using genome-wide signif- icant variants only. We found evidence of bidirectional causality between sedentary time and BMI: longer sedentary time was causal for higher BMI [beta (95% CI) from CAUSE method: 0.11 (0.02, 0.2), p = 0.02], and higher BMI was causal for longer sedentary time (0.13 (0.08, 0.17), p = 6.3 x 10-4). Our analyses suggest that higher moderate and vigorous physical activity are causal for lower BMI (moderate: –0.18 (-0.3,–0.05), p = 0.006; vigorous: –0.16 (-0.24,–0.08), p = 3.8 × 10-4), but indicate that the association between higher BMI and lower levels of physical activity is due to hori- zontal pleiotropy. The bidirectional, causal relationship between sedentary time and BMI suggests that decreasing sedentary time is beneficial for weight management, but also that targeting adiposity may lead to additional health benefits by reducing sedentary time.
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| 4. |
- Carrasquilla, Germán D
(författare)
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Postmenopausal hormone therapy and cardiovascular risk
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction and aims: Postmenopausal hormone therapy (HT) is the most effective treatment for menopausal symptoms, but its safety has been debated during the past 15 years. Previous observational studies showed benefits from HT, whereas subsequent large randomized clinical trials showed an increased risk for cardiovascular disease (CVD) and other chronic diseases; the pivotal difference between these studies was the average age at HT initiation. Subsequent re-analyses of these observational studies and the randomized clinical trials, which considered age at HT initiation and years since menopause onset, showed less dissimilar results. This phenomenon gave support to the timing hypothesis, stating that HT, if initiated early in relation to menopause onset, may exert vascular protection, whereas there may be negative consequences if initiated late. This stresses the need for further studies. There is also limited knowledge about whether oestrogen type, route of administration, and duration of HT are important for the association between HT and cardiovascular risk, while considering the timing of HT initiation. In the present thesis, the aim was to assess how HT associates with the risk of CVD in menopausal women, with a specific focus on the role of timing of HT initiation, and with consideration of oestrogen types and combinations, routes of administration, and duration of use. Material and methods: The present thesis was based on observational data from a case- control study and pooled individual participant data from five population based cohorts. HT was categorized as early or late initiation in relation to the onset of menopause. Different groups of HT regimens and durations were considered. Coronary heart disease, stroke (composite end point), and haemorrhagic stroke end points were assessed from population registers. To assess the association between HT and CVD we performed logistic regression for the case-control study and Laplace regression for the pooled cohort data. The reference category was never use. Single and multivariable confounding control was performed for an array of factors. Results: After multivariable-adjustment, early HT initiation was not associated with an increased risk of coronary heart disease, nor for stroke. These results held regardless of oestrogen regimen or combination (oestrogen-progestin), route of administration, and the duration. However, a specific analysis of haemorrhagic stroke revealed an increased risk if single conjugated equine oestrogens were used. Late HT initiation was associated with increased risk for coronary heart disease when the therapy was composed of equine oestrogens combined with a progestin. Risk of stroke and haemorrhagic stroke, on the other hand, were increased when single equine oestrogens were initiated late. Late initiation of combined HT was associated with an increased haemorrhagic stroke risk. Interpretation: HT did generally not increase the risk of CVD when initiated close to the onset of menopause. The results contribute to the scientific basis that may guide clinicians who handle patients seeking treatment for climacteric symptom control. The results should however not change current practice that recommends against the use of HT for prevention of CVD.
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| 5. |
- Carrasquilla, Germán D, et al.
(författare)
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Postmenopausal hormone therapy and risk of stroke : A pooled analysis of data from population-based cohort studies.
- 2017
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.METHODS AND FINDINGS: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.CONCLUSIONS: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.
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| 6. |
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| 7. |
- Kennedy, Beatrice, et al.
(författare)
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Sociodemographic characteristics and COVID-19 testing rates : spatiotemporal patterns and impact of test accessibility in Sweden
- 2024
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Ingår i: European Journal of Public Health. - 1101-1262 .- 1464-360X. ; 34:1, s. 14-21
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDiagnostic testing is essential for disease surveillance and test–trace–isolate efforts. We aimed to investigate if residential area sociodemographic characteristics and test accessibility were associated with Coronavirus Disease 2019 (COVID-19) testing rates.MethodsWe included 426 224 patient-initiated COVID-19 polymerase chain reaction tests from Uppsala County in Sweden from 24 June 2020 to 9 February 2022. Using Poisson regression analyses, we investigated if postal code area Care Need Index (CNI; median 1.0, IQR 0.8–1.4), a composite measure of sociodemographic factors used in Sweden to allocate primary healthcare resources, was associated with COVID-19 daily testing rates after adjustments for community transmission. We assessed if the distance to testing station influenced testing, and performed a difference-in-difference-analysis of a new testing station targeting a disadvantaged neighbourhood.ResultsWe observed that CNI, i.e. primary healthcare need, was negatively associated with COVID-19 testing rates in inhabitants 5–69 years. More pronounced differences were noted across younger age groups and in Uppsala City, with test rate ratios in children (5–14 years) ranging from 0.56 (95% CI 0.47–0.67) to 0.87 (95% CI 0.80–0.93) across three pandemic waves. Longer distance to the nearest testing station was linked to lower testing rates, e.g. every additional 10 km was associated with a 10–18% decrease in inhabitants 15–29 years in Uppsala County. The opening of the targeted testing station was associated with increased testing, including twice as high testing rates in individuals aged 70–105, supporting an intervention effect.ConclusionsEnsuring accessible testing across all residential areas constitutes a promising tool to decrease inequalities in testing.
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