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1.
  • Artigas Soler, María, et al. (författare)
  • Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
  • 2011
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
  • Tidskriftsartikel (refereegranskat)abstract
    • Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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2.
  • Bjornsdottir, Gudlaug, et al. (författare)
  • Longitudinal changes in size and composition of carotid artery plaques using ultrasound: Adaptation and validation of methods (inter-and intraobserver variability)
  • 2014
  • Ingår i: Journal for Vascular Ultrasound. - : SAGE Publications. - 1544-3175 .- 1544-3167. ; 38:4, s. 198-208
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction.—B-mode ultrasonography of the carotid arteries enables quantitative measurements of atherosclerotic plaque area and composition assessed as grayscale median (GSM). The purpose of this study was to set up a standardized ultrasound protocol to measure longitudinal changes in plaque area and composition and to determine the intra-and interobserver variability of the measurements in a longitudinal population based study, the Age Gene/ Environment Susceptibility Reykjavik study. Method.—A total of 219 participants from the Age Gene/Environment Susceptibility Reykjavik study (76 ± 6 years old, 36% males) underwent 2-dimensional, B-mode ultrasound examination of the carotid arteries approximately 5 years apart for a longitudinal assessment of plaque area and composition. Standardized protocol was used to acquire comparable images from both visits. Ultrasound was performed bilaterally on the common carotid artery, internal carotid artery, and bifurcation. An image analysis program was modified and adapted for a longitudinal assessment of plaque area and plaque composition by GSM. Twenty-five subjects were selected from the group of 219 for intra-and interobserver variability assessment. Results.—Intraobserver variability for plaque area ranged from 12.10 to 18.63% and 0.89 to 0.96 for coefficient of variation and correlation (r), respectively, for plaque GSM ranged from 7.77 to 8.04% and 0.86 to 0.90. Interobserver variability for plaque area was 23.29% and 0.81 and 8.55% and 0.87 for plaque GSM. Conclusion.—The results from this study show that ultrasound can be used consistently for assessment of changes in plaque area and GSM over time. This can be achieved by proper training of ultrasound sonographers and by applying and following strict image acquisition and image analysis protocols.
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3.
  • Boeger, Carsten A., et al. (författare)
  • CUBN Is a Gene Locus for Albuminuria
  • 2011
  • Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 22:3, s. 555-570
  • Tidskriftsartikel (refereegranskat)abstract
    • Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 x 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
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5.
  • Carlsen, Hanne Krage, et al. (författare)
  • Increased respiratory morbidity associated with exposure to a mature volcanic plume from a large Icelandic fissure eruption.
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The 2014-15 Holuhraun eruption in Iceland was the largest fissure eruption in over 200 years, emitting prodigious amounts of gas and particulate matter into the troposphere. Reykjavík, the capital area of Iceland (250km from eruption site) was exposed to air pollution events from advection of (i) a relatively young and chemically primitive volcanic plume with a high sulphur dioxide gas (SO2) to sulphate PM (SO42-) ratio, and (ii) an older and chemically mature volcanic plume with a low SO2/SO42- ratio. Whereas the advection and air pollution caused by the primitive plume were successfully forecast and forewarned in public advisories, the mature plume was not. Here, we show that exposure to the mature plume is associated with an increase in register-measured health care utilisation for respiratory disease by 23% (95% CI 19.7-27.4%) and for asthma medication dispensing by 19.3% (95% CI 9.6-29.1%). Absence of public advisories is associated with increases in visits to primary care medical doctors and to the hospital emergency department. We recommend that operational response to volcanic air pollution considers both primitive and mature types of plumes.
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6.
  • Carlsen, Hanne Krage, et al. (författare)
  • Respiratory health among professionals exposed to extreme SO2 levels from a volcanic eruption.
  • 2019
  • Ingår i: Scandinavian journal of work, environment & health. - : Scandinavian Journal of Work, Environment and Health. - 1795-990X .- 0355-3140. ; 45:3, s. 312-5
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective The Holuhraun eruption of fall and winter 2014-15 produced large amounts of sulfur dioxide (SO 2). The aim of this study was to determine if exposure to extreme SO 2levels affected the health of individuals working at the eruption site. Methods During January‒March 2015, earth scientists, technicians, and law enforcement personnel who were about to work at the eruption site were invited to a respiratory health examination. Symptom reports and lung function measures, forced expiratory volume in one second (FEV 1) and forced vital capacity (FVC) were collected before and after an eruption site visit. Those with previous exposure (N=27) reported symptoms retrospectively. Results Altogether, 41 individuals were invited to participate, 32 underwent a clinical examination at a hospital respiratory health clinic (baseline); 27 reported symptoms during earlier visits to the eruption site (retrospective symptom reports), 17 were re-examined 1-6 days after visiting the eruption site (follow-up). All participants' lung function was within normal range both before and after exposure. At baseline, average FEV 1was 107.4% of predicted versus 106.6 at follow-up (P =0.82); average FVC was 107.0% of predicted at baseline versus 107.4% at follow-up (P=0.35). Eye and nasal irritation were more frequently reported during eruption site exposure by 24% versus 6% (P =0.37) for both. Conclusion Although "healthy-worker" effects cannot be excluded, our data indicate that SO 2exposure was associated with relatively mild and transient respiratory symptoms with no clinical signs of airway inflammation or airway obstruction.
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7.
  • Carlsen, Hanne Krage, et al. (författare)
  • Severe volcanic SO2 exposure and respiratory morbidity in the Icelandic population – a register study
  • 2021
  • Ingår i: Environmental Health: A Global Access Science Source. - : Springer Science and Business Media LLC. - 1476-069X. ; 20
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The Holuhraun volcanic eruption September 2014 to February 2015 emitted large amounts of sulfur dioxide (SO ). The aim of this study was to determine the association between volcanic SO gases on general population respiratory health some 250 km from the eruption site, in the Icelandic capital area. Methods: Respiratory health outcomes were: asthma medication dispensing (AMD) from the Icelandic Medicines Register, medical doctor consultations in primary care (PCMD) and hospital emergency department visits (HED) in Reykjavík (population: 215000) for respiratory disease from 1 January 2010 to 31 December 2014. The associations between daily counts of health events and daily mean SO concentration and high SO levels (24-h mean SO > 125 μg/m3) were analysed using generalized additive models. Results: After the eruption began, AMD was higher than before (129.4 vs. 158.4 individuals per day, p < 0.05). For PCMD and HED, there were no significant differences between the number of daily events before and after the eruption (142.2 vs 144.8 and 18.3 vs 17.5, respectively). In regression analysis adjusted for other pollutants, SO was associated with estimated increases in AMD by 0.99% (95% CI 0.39–1.58%) per 10 μg/m at lag 0–2, in PCMD for respiratory causes 1.26% (95% CI 0.72–1.80%) per 10 μg/m SO at lag 0–2, and in HED by 1.02% (95% CI 0.02–2.03%) per 10 μg/m SO at lag 0–2. For days over the health limit, the estimated increases were 10.9% (95% CI 2.1–19.6%), 17.2% (95% CI 10.0–24.4%) for AMD and PCMD. Dispensing of short-acting medication increased significantly by 1.09% (95% CI 0.49–1.70%), and PCMD for respiratory infections and asthma and COPD diagnoses and increased significantly by 1.12% (95% CI 0.54–1.71%) and 2.08% (1.13–3.04%). Conclusion: High levels of volcanic SO are associated with increases in dispensing of AMD, and health care utilization in primary and tertiary care. Individuals with prevalent respiratory disease may be particularly susceptible. 2 2 2 2 2 2 2 2 2 3 3 3
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8.
  • Chasman, Daniel I., et al. (författare)
  • Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
  • 2012
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
  • Tidskriftsartikel (refereegranskat)abstract
    • In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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9.
  • Daníelsdóttir, Hilda Björk, et al. (författare)
  • Adverse Childhood Experiences and Adult Mental Health Outcomes
  • 2024
  • Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 81:6, s. 586-594
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE: Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given that ACEs and psychiatric disorders cluster within families, it remains to be comprehensively assessed to what extent familial confounding contributes to associations between ACEs and clinically confirmed adult psychiatric disorders.OBJECTIVE: To investigate whether associations between ACEs and adult mental health outcomes remain after adjusting for familial (genetic and environmental) confounding.DESIGN, SETTING, AND PARTICIPANTS: This Swedish twin cohort study used a discordant twin pair design based on monozygotic (MZ) and dizygotic (DZ) twins. A total of 25 252 adult twins (aged 18-47 years) from the Swedish Twin Registry born between 1959 and 1998 were followed up from age 19 years until 2016, with a maximum follow-up time of 39 years. Data were analyzed from April 2022 to November 2023.EXPOSURES: A total of 7 ACEs, including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape, and hate crime, were assessed with items from the Life Stressor Checklist-Revised in a web-based survey.MAIN OUTCOMES AND MEASURES: Adult (ages >18 years) clinical diagnosis of psychiatric disorders (ie, depressive, anxiety, alcohol or drug misuse, or stress-related disorders) were obtained from the Swedish National Patient Register.RESULTS: Of 25 252 twins included in the study (15 038 female [59.6%]; mean [SD] age at ACE assessment, 29.9 [8.7] years), 9751 individuals (38.6%) reported exposure to at least 1 ACE. A greater number of ACEs was associated with increased odds of any psychiatric disorder in the full cohort (odds ratio [OR] per additional ACE, 1.52; 95% CI, 1.48-1.57). The association remained but ORs per additional ACE were attenuated in DZ (1.29; 95% CI, 1.14-1.47) and MZ (1.20; 95% CI, 1.02-1.40) twin pairs. Individuals who were exposed to sexual abuse compared with those who were not exposed had increased odds of any clinically confirmed psychiatric disorder in all comparisons: full cohort (OR, 3.09; 95% CI, 2.68-3.56), DZ twin pairs (OR, 2.10; 95% CI, 1.33-3.32), and MZ twin pairs (1.80; 95% CI, 1.04-3.11).CONCLUSIONS AND RELEVANCE: This study found that associations between ACEs and adult mental health outcomes remained after controlling for shared genetic and environmental factors, which was particularly evident after multiple ACEs or sexual abuse. These findings suggest that targeted interventions may be associated with reduced risks of future psychopathology.
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10.
  • Daníelsdóttir, Hilda Björk, et al. (författare)
  • Adverse childhood experiences and resilience among adult women : A population-based study
  • 2022
  • Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Adverse childhood experiences (ACEs) have consistently been associated with elevated risk of multiple adverse health outcomes, yet their contribution to coping ability and psychiatric resilience in adulthood is unclear.Methods: Cross-sectional data were derived from the ongoing Stress-And-Gene-Analysis cohort, representing 30% of the Icelandic nationwide female population, 18-69 years. Participants in the current study were 26,198 women with data on 13 ACEs measured with the ACE-International Questionnaire. Self-reported coping ability was measured with the Connor-Davidson Resilience Scale and psychiatric resilience was operationalized as absence of psychiatric morbidity. Generalized linear regression assuming normal or Poisson distribution were used to assess the associations of ACEs with coping ability and psychiatric resilience controlling for multiple confounders.Results: Number of ACEs was inversely associated with adult resilience in a dose-dependent manner; every 1SD unit increase in ACE scores was associated with both lower levels of coping ability (β = -0.14; 95% CI-0.15,-0.13) and lower psychiatric resilience (β = -0.28; 95% CI-0.29,-0.27) in adulthood. Compared to women with 0 ACEs, women with ≥5 ACEs had 36% lower prevalence of high coping ability (PR = 0.64, 95% CI 0.59,0.70) and 58% lower prevalence of high psychiatric resilience (PR = 0.42; 95% CI 0.39,0.45). Specific ACEs including emotional neglect, bullying, sexual abuse and mental illness of household member were consistently associated with reduced adult resilience. We observed only slightly attenuated associations after controlling for adult socioeconomic factors and social support in adulthood.Conclusions: Cumulative ACE exposure is associated with lower adult resilience among women, independent of adult socioeconomic factors and social support, indicating that adult resilience may be largely determined in childhood.
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11.
  • Dickerman, Barbra A., et al. (författare)
  • Midlife metabolic factors and prostate cancer risk in later life
  • 2018
  • Ingår i: International Journal of Cancer. - Hoboken, USA : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 142:6, s. 1166-1173
  • Tidskriftsartikel (refereegranskat)abstract
    • Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n = 9,097, enrolled 1967-1987) were followed for incident (n = 1,084 total; n = 378 advanced; n = 148 high-grade) and fatal (n = 340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI ≥30 kg/m2 ; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mm Hg or taking antihypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dl or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides were associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p trend = 0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer.
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12.
  • Elks, Cathy E, et al. (författare)
  • Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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13.
  • Emilsson, Össur Ingi, et al. (författare)
  • Nocturnal gastro-oesophageal reflux and respiratory symptoms are increased in sleep apnoea : comparison with the general population
  • 2024
  • Ingår i: BMJ Open Respiratory Research. - : BMJ Publishing Group Ltd. - 2052-4439. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim To assess respiratory symptoms and nocturnal gastro-oesophageal reflux (nGER) among untreated obstructive sleep apnoea (OSA) patients, compared with the general population. Also, if nGER associates differently with respiratory symptoms among OSA patients.Methods 2 study cohorts were included: 822 newly diagnosed subjects with moderate–severe OSA and 738 Icelandic general population study participants. All participants answered the same questionnaires. Those reporting nGER symptoms at least once per week were defined as ‘with nGER’; those without nGER symptoms and without nGER medication were defined as ‘no nGER’; and other participants were defined as having ‘possible nGER’. Propensity score-based weights were used to minimise confounding and selection bias and facilitate causal interpretations.Results The prevalence of nGER among OSA patients was 14.1%, compared with 5.8% in the general population. This increased prevalence in OSA was not explained by differences in age, gender, body mass index, smoking, hypertension and diabetes (adjusted OR (95% CI)=3.79 (2.24 to 6.43)). OSA patients ‘with nGER’ and with ‘possible nGER’ reported more wheezing (44% and 44% vs 25%, respectively) and productive cough (47% and 42% vs 29%, respectively), compared with OSA patients with ‘no nGER’. The same pattern was seen in the general population, although with a generally lower prevalence. The effect of nGER on respiratory symptoms was similar between the two cohorts.Conclusion nGER was more often reported among untreated moderate–severe OSA patients than in the general population. Participants with nGER had more wheezing and productive cough, both among untreated OSA patients and in the general population.
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14.
  • Emilsson, Össur Ingi, et al. (författare)
  • Positive airway pressure treatment affects respiratory symptoms and gastro-oesophageal reflux : the Icelandic Sleep Apnea Cohort Study
  • 2023
  • Ingår i: ERJ Open Research. - : European Respiratory Society. - 2312-0541. ; 9:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: To study the effect of positive airway pressure (PAP) treatment on nocturnal gastro-oesophageal reflux (nGOR) and respiratory symptoms among clinical obstructive sleep apnoea (OSA) patients.Methods: 822 patients newly diagnosed with OSA referred for PAP treatment were recruited. 732 patients had a 2-year follow-up visit with continuous PAP compliance data (366 full PAP users, 366 partial/non-PAP users). They answered questionnaires, including reporting of nGOR, sleep and respiratory symptoms and general health. Patients with nGOR symptoms once a week or more were defined as "with nGOR". Those without nGOR symptoms and nGOR medication were defined as "no nGOR". Others were defined as "possible nGOR".Results: At 2-year follow-up, PAP treatment among full users resulted in decreased nGOR (adjusted OR 0.58, 95% CI 0.40-0.86) and wheezing (adjusted OR 0.56, 95% CI 0.35-0.88) compared with partial/non-PAP users. Decreased nGOR, among both full and partial/non-users of PAP treatment, was associated with a decrease in productive morning cough (adjusted OR 4.70, 95% CI 2.22-9.99) and a decrease in chronic bronchitis (adjusted OR 3.86, 95% CI 1.74-8.58), but not decreased wheezing (adjusted OR 0.90, 95% CI 0.39-2.08). A mediation analysis found that PAP treatment directly led to a decrease in wheezing, not mediated through nGOR. Conversely, PAP treatment decreased productive cough mediated through a decrease in nGOR.Conclusion: In an unselected group of OSA patients, PAP treatment for 2 years was associated with a decrease in nGOR and respiratory symptoms. The PAP treatment itself was associated with less wheezing. A decrease in nGOR through PAP treatment was associated with a decrease in productive cough.
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15.
  • Emilsson, Össur Ingi, et al. (författare)
  • Snoring and nocturnal reflux : association with lung function decline and respiratory symptoms
  • 2019
  • Ingår i: ERJ Open Research. - : European Respitory Society (ERS). - 2312-0541. ; 5:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The study aim was to examine the association of snoring and nocturnal gastro-oesophageal reflux (nGOR) with respiratory symptoms and lung function, and if snoring and/or nGOR associated with a steeper decline in lung function. Methods: Data from the third visit of the European Community Respiratory Health Survey (ECRHS) was used for cross-sectional analysis. Pre- and post-bronchodilator spirometry was performed, and information on sleep, nGOR and respiratory symptoms was collected (n=5715). Habitual snoring and nGOR were assessed by questionnaire reports. Pre-bronchodilator spirometry from ECRHS I, II and III (20 years follow-up) were used to analyse lung function changes by multivariate regression analysis. Results: Snoring and nGOR were independently associated with a higher prevalence of wheeze, chest tightness, breathlessness, cough and phlegm. The prevalence of any respiratory symptom was 79% in subjects with both snoring and nGOR versus 56% in those with neither (p<0.001). Subjects with both snoring and nGOR had more frequent exacerbations (adjusted prevalence 32% versus 19% among "no snoring, no nGOR", p=0.003). Snoring but not nGOR was associated with a steeper decline in forced expiratory volume in 1 s over 10 years after adjusting for confounding factors (change in % predicted -5.53, versus -4.58 among "no snoring", p=0.04) and forced vital capacity (change in % predicted -1.94, versus -0.99 among "no snoring", p=0.03). Conclusions: Adults reporting both habitual snoring and nGOR had more respiratory symptoms and more frequent exacerbations of these symptoms. Habitual snoring was associated with a steeper decline in lung function over time.
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17.
  • Estrada, Karol, et al. (författare)
  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
  • 2012
  • Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
  • Tidskriftsartikel (refereegranskat)abstract
    • Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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18.
  • Gislason, Thorarinn, et al. (författare)
  • Persistent Chlamydia pneumonia serology is related to a more rapid decline in lung function in women but not in men
  • 2010
  • Ingår i: BMC Pulmonary Medicine. - : Springer Science and Business Media LLC. - 1471-2466. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Chlamydia pneumoniae (C pn) infection causes an acute inflammation in the respiratory system that may become persistent, but little is known about the long-term respiratory effects of C pn infections. Aim: To estimate the long term respiratory effects of C pn with change in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) as a main outcome variable.Methods The study comprised of 1109 subjects (500 men and 609 women, mean age 28 ± 6 years) that participated in the Reykjavik Heart Study of the Young. Spirometry and blood samples for measurements of IgG antibodies for C pn were done at inclusion and at the end of the follow-up period (mean follow-up time 27 ± 4 years).Results Having IgG against C pn at both examinations was significantly associated to a larger decrease in FEV1 (6 mL/year) and FVC (7 mL/year) in women but not in men. In women the association between C pn and larger FEV1 decline was only found in women that smoked at baseline where having C pn IgG was associated with 10 mL/year decline compared to smokers without C pn IgG. These results were still significant after adjustment for age, smoking and change in body weight.Conclusion Our results indicate that persistent C pn serology is related to increased decline in lung function in women but not in men. This effect was, however, primarily found in smoking women. This study is a further indication that the pathophysiological process leading to lung impairment may differ between men and women.
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19.
  • Gorski, Mathias, et al. (författare)
  • 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
  • 2017
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
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20.
  • Hardardottir, Hronn, et al. (författare)
  • Optimal communication associated with lower risk of acute traumatic stress after lung cancer diagnosis
  • 2022
  • Ingår i: Supportive Care in Cancer. - : Springer. - 0941-4355 .- 1433-7339. ; 30:1, s. 259-269
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: The aim of this study was to assess the role of the patient's background and perceived healthcare-related factors in symptoms of acute stress after lung cancer diagnosis.Methods: The study population consisted of 89 individuals referred for diagnostic work-up at Landspitali National University Hospital in Iceland and subsequently diagnosed with lung cancer. Before diagnosis, the patients completed questionnaires on sociodemographic characteristics, pre-diagnostic distress (Hospital Anxiety and Depression Scale), social support, and resilience. At a median of 16 days after diagnosis, the patients reported symptoms of acute stress on the Impact of Event Scale-Revised (IES-R) and experience of communication and support from healthcare professionals and family during the diagnostic period.Results: Patients were on average 68 years and 52% reported high levels of post-diagnostic acute stress (IES-R > 23) while 24% reported symptoms suggestive of clinical significance (IES-R > 32). Prior history of cancer (beta = 6.7, 95% CI: 0.1 to 13.3) and pre-diagnostic distress were associated with higher levels of post-diagnostic acute stress (beta = 8.8, 95% CI: 2.7 to 14.9), while high educational level (beta = - 7.9, 95% CI: - 14.8 to - 1.1) was associated with lower levels. Controlling for the abovementioned factors, the patients' perception of optimal doctor-patient (beta = - 9.1, 95% CI: - 14.9 to - 3.3) and family communication (beta = - 8.6, 95% CI: - 14.3 to - 2.9) was inversely associated with levels of post-diagnostic acute stress after lung cancer diagnosis.Conclusions: A high proportion of patients with newly diagnosed lung cancer experience high levels of acute traumatic stress of potential clinical significance. Efforts to improve doctor-patient and family communication may mitigate the risk of these adverse symptoms.
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21.
  • Hardardottir, Hronn, et al. (författare)
  • Psychobiological stress response to a lung cancer diagnosis : a prospective study of patients in Iceland and Sweden
  • 2023
  • Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 62:10, s. 1338-1347
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: A diagnostic work-up leading to a lung cancer diagnosis is a severely stressful experience that may impact tumor progression. Yet, prospective data are scarce on psychological and biological components of stress at the time of lung cancer diagnosis. The aim of this study was to assess pre-to-post diagnosis change in psychological distress and urinary excretion of catecholamines in patients with suspected lung cancer.Methods: Participants were 167 patients within the LUCASS study, recruited at referral for suspected lung cancer to University Hospitals in Iceland and Sweden. Patients completed questionnaires on perceived distress (Hospital Anxiety and Depression Scale, HADS) before and after diagnosis of lung cancer or a non-malignant origin. A subpopulation of 85 patients also provided overnight urine for catecholamine analysis before and at a median of 24 days after diagnosis but before treatment.Results: A lung cancer diagnosis was confirmed in 123 (73.7%) patients, with a mean age of 70.1 years. Patients diagnosed with lung cancer experienced a post-diagnosis increase in psychological distress (p = 0.010), while patients with non-malignant lung pathology showed a reduction in distress (p = 0.070). Both urinary epinephrine (p = 0.001) and norepinephrine (p = 0.032) levels were higher before the diagnosis among patients eventually diagnosed with lung cancer compared to those with non-malignant lung pathology. We observed indications of associations between pre-to-post diagnosis changes in perceived distress and changes in urinary catecholamine levels.Conclusion: Receiving a lung cancer diagnosis is associated with an increase in psychological distress, while elevated catecholamine levels are evident already before lung cancer diagnosis.
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22.
  • Heard-Costa, Nancy L, et al. (författare)
  • NRXN3 is a novel locus for waist circumference : a genome-wide association study from the CHARGE Consortium
  • 2009
  • Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000539-
  • Tidskriftsartikel (refereegranskat)abstract
    • Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
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23.
  • Heid, Iris M, et al. (författare)
  • Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
  • Tidskriftsartikel (refereegranskat)abstract
    • Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
  •  
24.
  • Jakobsdottir, Johanna, et al. (författare)
  • Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
  • 2016
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:10
  • Tidskriftsartikel (refereegranskat)abstract
    • We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade.
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25.
  • Johannesdottir, Fjola, et al. (författare)
  • Distribution of cortical bone in the femoral neck and hip fracture: A prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study
  • 2011
  • Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 48:6, s. 1268-1276
  • Tidskriftsartikel (refereegranskat)abstract
    • In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm(2), DXA-like), (p = 0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n = 143) from controls (n = 298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture. (C) 2011 Elsevier Inc. All rights reserved.
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26.
  • Johannesdottir, Fjola, et al. (författare)
  • Mid-Thigh Cortical Bone Structural Parameters, Muscle Mass and Strength, and Association with Lower Limb Fractures in Older Men and Women (AGES-Reykjavik Study)
  • 2012
  • Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 1432-0827 .- 0171-967X. ; 90:5, s. 354-364
  • Tidskriftsartikel (refereegranskat)abstract
    • In a cross-sectional study we investigated the relationship between muscle and bone parameters in the mid-thigh in older people using data from a single axial computed tomographic section through the mid-thigh. Additionally, we studied the association of these variables with incident low-trauma lower limb fractures. A total of 3,762 older individuals (1,838 men and 1,924 women), aged 66-96 years, participants in the AGES-Reykjavik study, were studied. The total cross-sectional muscular area and knee extensor strength declined with age similarly in both sexes. Muscle parameters correlated most strongly with cortical area and total shaft area (adjusted for age, height, and weight) but explained < 10 % of variability in those bone parameters. The increment in medullary area (MA) and buckling ratio (BR) with age was almost fourfold greater in women than men. The association between MA and muscle parameters was nonsignificant. During a median follow-up of 5.3 years, 113 women and 66 men sustained incident lower limb fractures. Small muscular area, low knee extensor strength, large MA, low cortical thickness, and high BR were significantly associated with fractures in both sexes. Our results show that bone and muscle loss proceed at different rates and with different gender patterns.
  •  
27.
  • Köttgen, Anna, et al. (författare)
  • New loci associated with kidney function and chronic kidney disease
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:5, s. 376-384
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
  •  
28.
  • Lango Allen, Hana, et al. (författare)
  • Hundreds of variants clustered in genomic loci and biological pathways affect human height.
  • 2010
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
  •  
29.
  • Loth, Daan W, et al. (författare)
  • Genome-wide association analysis identifies six new loci associated with forced vital capacity
  • 2014
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
  • Tidskriftsartikel (refereegranskat)abstract
    • Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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30.
  • Lynch, Rebekka, et al. (författare)
  • Lifetime exposure to violence and other life stressors and hair cortisol concentration in women
  • 2022
  • Ingår i: Stress. - : Informa UK Limited. - 1025-3890 .- 1607-8888. ; 25:1, s. 48-56
  • Tidskriftsartikel (refereegranskat)abstract
    • Women are exposed to a variety of life stressors, particularly violence, during their lifetime which increases the risk of developing various psychiatric and somatic diseases, with the dysregulated secretion of cortisol as one potential biological mechanism. We examined the association between violence and other life stressors and hair cortisol concentration (HCC) in a population of urban women. We included 470 adult women (age = 21-86 years) attending the Cancer Detection Clinic in Iceland. The Life Stressor Checklist-Revised (LSC-R; 30-items) was used to assess exposure. HCC was measured with liquid chromatography coupled with tandem mass spectrometry. We used linear regression models to assess the association between life stressors and log-transformed HCC. The median HCC (pg/mg) in the study population was 4.9 (range 0.6-616.6). HCC was not associated with background covariates, including age (p = 0.868), education level (p = 0.824), marital status (p = 0.545), income (p = 0.363), occupation (p = 0.192), but associated with current smoking (p = 0.013). We noted a 3.3% (95% CI: 0.17-6.6%) associated increase in HCC per endorsed life stressor after adjusting for age and smoking, while non-violent life stressors were not associated with HCC. Per endorsed violence item, we observed a 10.2% (95% CI: 1.4-19.7%) associated increase in HCC after age and smoking adjustment. Women with lifetime exposure to both physical and sexual violence presented with higher HCC than unexposed women (p = 0.010), after age and smoking adjustment. Lifetime exposure to violence was associated with higher levels of HCC in a community sample of women. These findings need confirmation with prospective studies.
  •  
31.
  • Moayyeri, Alireza, et al. (författare)
  • Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
  • 2014
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
  • Tidskriftsartikel (refereegranskat)abstract
    • Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
  •  
32.
  • Olafsdottir, Inga Sif, et al. (författare)
  • CRP is associated with lung function decline in men but not women : a prospective study
  • 2013
  • Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111 .- 1532-3064. ; 107:1, s. 91-97
  • Tidskriftsartikel (refereegranskat)abstract
    • Systemic inflammation is associated with impaired lung function. Studies, most cross-sectional, report a stronger association between systemic inflammation and lung function impairment in men than women. The aim was to evaluate gender differences in the longitudinal association between systemic inflammation and lung function.We used data from randomly chosen residents of Reykjavík, born 1940–54, who were investigated in three stages: Baseline (1973–75; 1983–85) and follow-up (2001–03). The participants (n = 1049, 574 women) had a mean age of 28 ± 6 years at baseline and mean follow-up time of 27 ± 4 years. At each stage lung function (FEV1 and FVC) and C-reactive protein (CRP) were evaluated.Change in FEV1 (p = 0.04) and FVC (p = 0.01) was associated with baseline CRP in men but not in women. In the multiple variable analysis, CRP at baseline was associated with a decline in FEV1 (−3.1 mL/year, 95% CI: −5.1, −0.99) and FVC (−2.5 mL/year, 95% CI: −4.4, −0.65) in men but not in women. Similarly during follow-up, change in CRP, standardised to 1SD, was associated with a decline in FEV1 (−0.19 mL/year, 95% CI: −0.30, −0.07) and FVC (−0.11 mL/year, 95% CI: −0.22, −0.01)) in men but not in women.This prospective study confirms a stronger association between systemic inflammation and lung function decline in men than in women. This may indicate a gender difference in the mechanisms of lung function decline.
  •  
33.
  • Parsa, Afshin, et al. (författare)
  • Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
  • 2013
  • Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:12, s. 2105-2117
  • Tidskriftsartikel (refereegranskat)abstract
    • Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
  •  
34.
  • Pattaro, Cristian, et al. (författare)
  • Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
  • 2016
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
  •  
35.
  • Pattaro, Cristian, et al. (författare)
  • Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function
  • 2012
  • Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002584-
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
  •  
36.
  • Pennells, Lisa, et al. (författare)
  • Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
  • 2019
  • Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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37.
  • Shen, Qing, et al. (författare)
  • Cardiovascular disease and subsequent risk of psychiatric disorders : a nationwide sibling-controlled study
  • 2022
  • Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated.Methods: We identified 869 056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910 178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N=8 690 560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls.Results: The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to thirty years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6 and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62-2.87) and thereafter (1.45; 95% CI, 1.42-1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR 1.55; 95% CI 1.44-1.67).Conclusions: Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed CVD patients.Funding: This work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, grant no. 847776 to UV, PFS and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no: 726413 to UV), Swedish Research Council (grant no. D0886501 to PFS) and US NIMH R01 MH123724 (to PFS).
  •  
38.
  • Shen, Qing, et al. (författare)
  • Psychiatric disorders and subsequent risk of cardiovascular disease : a longitudinal matched cohort study across three countries
  • 2023
  • Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 61
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Several psychiatric disorders have been associated with increased risk of cardiovascular disease (CVD), however, the role of familial factors and the main disease trajectories remain unknown.METHODS: In this longitudinal cohort study, we identified a cohort of 900,240 patients newly diagnosed with psychiatric disorders during January 1, 1987 and December 31, 2016, their 1,002,888 unaffected full siblings, and 1:10 age- and sex-matched reference population from nationwide medical records in Sweden, who had no prior diagnosis of CVD at enrolment. We used flexible parametric models to determine the time-varying association between first-onset psychiatric disorders and incident CVD and CVD death, comparing rates of CVD among patients with psychiatric disorders to the rates of unaffected siblings and matched reference population. We also used disease trajectory analysis to identify main disease trajectories linking psychiatric disorders to CVD. Identified associations and disease trajectories of the Swedish cohort were validated in a similar cohort from nationwide medical records in Denmark (N = 875,634 patients, same criteria during January 1, 1969 and December 31, 2016) and in Estonian cohorts from the Estonian Biobank (N = 30,656 patients, same criteria during January 1, 2006 and December 31, 2020), respectively.FINDINGS: During up to 30 years of follow-up of the Swedish cohort, the crude incidence rate of CVD was 9.7, 7.4 and 7.0 per 1000 person-years among patients with psychiatric disorders, their unaffected siblings, and the matched reference population. Compared with their siblings, patients with psychiatric disorders experienced higher rates of CVD during the first year after diagnosis (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.79-1.98) and thereafter (1.37; 95% CI, 1.34-1.39). Similar rate increases were noted when comparing with the matched reference population. These results were replicated in the Danish cohort. We identified several disease trajectories linking psychiatric disorders to CVD in the Swedish cohort, with or without mediating medical conditions, including a direct link between psychiatric disorders and hypertensive disorder, ischemic heart disease, venous thromboembolism, angina pectoris, and stroke. These trajectories were validated in the Estonian Biobank cohort.INTERPRETATION: Independent of familial factors, patients with psychiatric disorders are at an elevated risk of subsequent CVD, particularly during first year after diagnosis. Increased surveillance and treatment of CVDs and CVD risk factors should be considered as an integral part of clinical management, in order to reduce risk of CVD among patients with psychiatric disorders.
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39.
  • Siggeirsdottir, Kristin, et al. (författare)
  • Effect of vertebral fractures on function, quality of life and hospitalisation the AGES-Reykjavik study
  • 2012
  • Ingår i: Age and Ageing. - : Oxford University Press (OUP). - 1468-2834 .- 0002-0729. ; 41:3, s. 351-357
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: assess the effect of clinical vertebral and other osteoporotic fractures on function and the subsequent risk of hospitalisation. Design: individuals from the prospective population-based cohort study Age, Gene/Environment Susceptibility (AGES)-Reykjavik study were examined between 2002 and 2006 and followed up for 5.4 years. Subjects: a total of 5,764 individuals, 57.7% women, born 1907-35, mean age 77. Method: four groups with a verified fracture status were used; vertebral fractures, other osteoporotic fractures excluding vertebral, non-osteoporotic fractures and not-fractured were compared and analysed for the effect on mobility, strength, QoL, ADL, co-morbidity and hospitalisation. Results: worst performance on functional tests was in the vertebral fracture group for women (P < 0.0001) and the other osteoporotic fractures group for men (P < 0.05). Both vertebral and other osteoporotic fractures, showed an increased risk of hospitalisation, HR = 1.4 (95% CI: 1.3-1.7) and 1.2 (95% CI: 1.1-1.2) respectively (P < 0.0001). Individuals with vertebral fractures had 50% (P < 0.0001) longer hospitalisation than not-fractured and 33% (P < 0.002) longer than the other osteoporotic fractures group. Conclusion: individuals with a history of clinical vertebral fracture seem to carry the greatest health burden compared with other fracture groups, emphasising the attention which should be given to those individuals.
  •  
40.
  • Siggeirsdottir, Kristin, et al. (författare)
  • Inaccuracy in self-report of fractures may underestimate association with health outcomes when compared with medical record based fracture registry
  • 2007
  • Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 22:9, s. 631-639
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction and objective Misreporting fractures in questionnaires is known. However, the effect of misreporting on the association of fractures with subsequent health outcomes has not been examined. Methods Data from a fracture registry (FR) developed from an extensive review of radiographic and medical records were related to self-report of fracture for 2,255 participants from the AGES Reykjavik Study. This data was used to determine false negative and false positive rates of self-reported fractures, correlates of misreporting, and the potential effect of the misreporting on estimates of health outcomes following fractures. Results In women, the false positive rate decreased with age as the false negative rate increased with no clear trend with age in men. Kappa values for agreement between FR and self-report were generally higher in women than men with the best agreement for forearm fracture (men 0.64 and women 0.82) and the least for rib (men 0.28 and women 0.25). Impaired cognition was a major factor associated with discordant answers between FR and self-report, OR 1.7 (95% CI: 1.3-2.1) (P < 0.0001). We estimated the effect of misreporting on health after fracture by comparison of the association of the self-report of fracture and fracture from the FR, adjusting for those factors associated with discordance. The weighted attenuation factor measured by mobility and muscle strength was 11% (95% CI: 0-24%) when adjusted for age and sex but reduced to 6% (95% CI: -10-22%) when adjusted for cognitive impairment. Conclusion Studies of hip fractures should include an independent ascertainment of fracture but for other fractures this study supports the use of self-report.
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41.
  • Sigurdardottir, Lara G., et al. (författare)
  • Pineal Gland Volume Assessed by MRI and Its Correlation with 6-Sulfatoxymelatonin Levels among Older Men
  • 2016
  • Ingår i: Journal of Biological Rhythms. - Thousand Oaks, USA : Sage Publications. - 0748-7304 .- 1552-4531. ; 31:5, s. 461-469
  • Tidskriftsartikel (refereegranskat)abstract
    • The pineal gland produces the hormone melatonin, and its volume may influence melatonin levels. We describe an innovative method for estimating pineal volume in humans and present the association of pineal parenchyma volume with levels of the primary melatonin metabolite, 6-sulfatoxymelatonin. We selected a random sample of 122 older Icelandic men nested within the AGES-Reykjavik cohort and measured their total pineal volume, their parenchyma volume, and the extent of calcification and cysts. For volume estimations we used manual segmentation of magnetic resonance images in the axial plane with simultaneous side-by-side view of the sagittal and coronal plane. We used multivariable adjusted linear regression models to estimate the association of pineal parenchyma volume and baseline characteristics, including 6-sulfatoxymelatonin levels. We used logistic regression to test for differences in first morning urinary 6-sulfatoxymelatonin levels among men with or without cystic or calcified glands. The pineal glands varied in volume, shape, and composition. Cysts were present in 59% of the glands and calcifications in 21%. The mean total pineal volume measured 207 mm(3) (range 65-536 mm(3)) and parenchyma volume 178 mm(3) (range 65-503 mm(3)). In multivariable-adjusted models, pineal parenchyma volume was positively correlated with 6-sulfatoxymelatonin levels (β = 0.52, p < 0.001). Levels of 6-sulfatoxymelatonin did not differ significantly by presence of cysts or calcification. By using an innovative method for pineal assessment, we found pineal parenchyma volume to be positively correlated with 6-sulfatoxymelatonin levels, in line with other recent studies.
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42.
  • Sigurdardottir, Lara G., et al. (författare)
  • Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men
  • 2015
  • Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 67:2, s. 191-194
  • Tidskriftsartikel (refereegranskat)abstract
    • Melatonin has anticarcinogenic properties in experimental models. We undertook a case-cohort study of 928 Icelandic men without prostate cancer (PCa) nested within the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort to investigate the prospective association between first morning-void urinary 6-sulfatoxymelatonin (aMT6s) levels and the subsequent risk for PCa, under the hypothesis that men with lower aMT6s levels have an increased risk for advanced PCa. We used weighted Cox proportional hazards models to assess the association between first morning-void aMT6s levels and PCa risk, adjusting for potential confounders. A total of 111 men were diagnosed with incident PCa, including 24 with advanced disease. Men who reported sleep problems at baseline had lower morning aMT6s levels compared with those who reported no sleep problems. Men with morning aMT6s levels below the median had a fourfold statistically significant increased risk for advanced disease compared with men with levels above the median (hazard ratio: 4.04; 95% confidence interval, 1.26-12.98). These results require replication in larger prospective studies with longer follow-up.Patient summary: In this report, we evaluated the prospective association between urinary aMT6s levels and risk of PCa in an Icelandic population. We found that lower levels of aMT6s were associated with an increased risk for advanced PCa.
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43.
  • Smari, Unnur Jakobsdottir, et al. (författare)
  • Psychiatric comorbidities in women with cardiometabolic conditions with and without ADHD : a population-based study
  • 2023
  • Ingår i: BMC Medicine. - : BioMed Central (BMC). - 1741-7015. ; 21:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Leveraging a large nationwide study of Icelandic women, we aimed to narrow the evidence gap around female attention-deficit/hyperactivity disorder (ADHD) and cardiometabolic comorbidities by determining the prevalence of obesity, hypertension, type 2 diabetes, and cardiovascular diseases among women with ADHD and examine the association between cardiometabolic conditions and co-occurring ADHD with anxiety and mood disorders, alcoholism/substance use disorder (SUD), self-harm, and suicide attempts.METHODS: We conducted a cross-sectional analysis of the nationwide, all-female, population-based SAGA Cohort Study (n = 26,668). To ascertain diagnoses and symptoms, we used self-reported history of ADHD diagnoses, selected cardiometabolic conditions and psychiatric disorders, and measured current depressive, anxiety, and PTSD symptoms through appropriate questionnaires (PHQ-9, GAD-7, and PCL-5). We calculated age-adjusted prevalences of cardiometabolic conditions by women's ADHD status and estimated adjusted prevalence ratios (PR) and 95% confidence intervals (CI), using modified Poisson regression models. Similarly, we assessed the association of cardiometabolic conditions and co-occurring ADHD with current psychiatric symptoms and psychiatric disorders, using adjusted PRs and 95% CIs.RESULTS: We identified 2299 (8.6%) women with a history of ADHD diagnosis. The age-adjusted prevalence of having at least one cardiometabolic condition was higher among women with ADHD (49.5%) than those without (41.7%), (PR = 1.19, 95% CI 1.14-1.25), with higher prevalence of all measured cardiometabolic conditions (myocardial infarctions (PR = 2.53, 95% CI 1.83--3.49), type 2 diabetes (PR = 2.08, 95% CI 1.66-2.61), hypertension (PR = 1.23, 95% CI 1.12-1.34), and obesity (PR = 1.18, 95% CI 1.11-1.25)). Women with cardiometabolic conditions and co-occurring ADHD had, compared with those without ADHD, substantially increased prevalence of (a) all measured mood and anxiety disorders, e.g., depression (PR = 2.38, 95% CI 2.19-2.58), bipolar disorder (PR = 4.81, 95% CI 3.65-6.35), posttraumatic stress disorder (PR = 2.78, 95% CI 2.52-3.07), social phobia (PR = 2.96, 95% CI 2.64-3.32); (b) moderate/severe depressive, anxiety, and PTSD symptoms with PR = 1.76 (95% CI 1.67-1.85), PR = 1.97 (95% CI 1.82-2.12), and PR = 2.01 (95% CI 1.88-2.15), respectively; (c) alcoholism/SUD, PR = 4.79 (95% CI 3.90-5.89); and (d) self-harm, PR = 1.47 (95% CI 1.29-1.67) and suicide attempts, PR = 2.37 (95% CI 2.05-2.73).CONCLUSIONS: ADHD is overrepresented among women with cardiometabolic conditions and contributes substantially to other psychiatric comorbidities among women with cardiometabolic conditions.
  •  
44.
  • Speliotes, Elizabeth K., et al. (författare)
  • Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
  •  
45.
  • Stolk, Lisette, et al. (författare)
  • Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways
  • 2012
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 260-268
  • Tidskriftsartikel (refereegranskat)abstract
    • To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
  •  
46.
  • Thanassoulis, George, et al. (författare)
  • Genetic Associations with Valvular Calcification and Aortic Stenosis
  • 2013
  • Ingår i: New England Journal of Medicine. - 0028-4793. ; 368:6, s. 503-512
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. Methods We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. Results One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0x10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5x10(-8) and P = 1.8x10(-8), respectively), but the findings were not replicated consistently. Conclusions Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
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47.
  • Thorarinsdottir, Elin H., et al. (författare)
  • Definition of excessive daytime sleepiness in the general population : Feeling sleepy relates better to sleep-related symptoms and quality of life than the Epworth Sleepiness Scale score. Results from an epidemiological study
  • 2019
  • Ingår i: Journal of Sleep Research. - : WILEY. - 0962-1105 .- 1365-2869. ; 28:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Many different subjective tools are being used to measure excessive daytime sleepiness (EDS) but the most widely used is the Epworth Sleepiness Scale (ESS). However, it is unclear if using the ESS is adequate on its own when assessing EDS. The aim of this study was to estimate the characteristics and prevalence of EDS using the ESS and the Basic Nordic Sleep Questionnaire (BNSQ) in general population samples. Participants aged 40 years and older answered questions about sleepiness, health, sleep-related symptoms and quality of life. Two groups were defined as suffering from EDS: those who scored >10 on the ESS (with increased risk of dozing off) and those reporting feeling sleepy during the day >= 3 times per week on the BNSQ. In total, 1,338 subjects (53% male, 74.1% response rate) participated, 13.1% reported an increased risk of dozing off, 23.2% reported feeling sleepy and 6.4% reported both. The prevalence of restless leg syndrome, nocturnal gastroesophageal reflux, difficulties initiating and maintaining sleep and nocturnal sweating was higher among subjects reporting feeling sleepy compared to non-sleepy subjects. Also, subjects reporting feeling sleepy had poorer quality of life and reported more often feeling unrested during the day than non-sleepy subjects. However, subjects reporting increased risk of dozing off (ESS > 10) without feeling sleepy had a similar symptom profile as the non-sleepy subjects. Therefore, reporting only risk of dozing off without feeling sleepy may not reflect problematic sleepiness and more instruments in addition to ESS are needed when evaluating daytime sleepiness.
  •  
48.
  • Thorarinsdottir, Elin H., et al. (författare)
  • Different components of excessive daytime sleepiness and the change with positive airway pressure treatment in patients with obstructive sleep apnea : Results from the Icelandic Sleep Apnea Cohort (ISAC)
  • 2022
  • Ingår i: Journal of Sleep Research. - : John Wiley & Sons. - 0962-1105 .- 1365-2869. ; 31:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Excessive daytime sleepiness includes both an inability to stay awake during the day and a general feeling of sleepiness. We describe different dimensions of daytime sleepiness in adults with moderate-severe obstructive sleep apnea (OSA) before and after 2 years of positive airway pressure (PAP) treatment. Using the Epworth Sleepiness Scale (score >10 defined as "risk of dozing") and Basic Nordic Sleep Questionnaire (feeling sleepy >= 3 times/week defined as "feeling sleepy"), participants were categorised into sleepiness phenotypes labelled non-sleepy, risk of dozing only, feeling sleepy only, or both symptoms. Participants repeated baseline assessments and PAP adherence was evaluated after 2 years. PAP-adherent subjects with sleepiness symptoms at both baseline and follow-up were considered persistently sleepy. Of the 810 participants, 722 (89%) returned for follow-up. At baseline, 17.7% were non-sleepy, 7.7% were at risk of dozing only, 24.7% were feeling sleepy only, and 49.9% had both symptoms. PAP adherence did not differ by baseline sleepiness phenotype. Patients with risk of dozing demonstrated greater PAP benefits for sleepiness symptoms than non-sleepy and feeling sleepy only phenotypes. Using these phenotypes, 42.3% of PAP users had persistent sleepiness; they had less severe OSA (p < 0.001), more persistent OSA symptoms and more often had symptoms of insomnia than patients in whom sleepiness resolved. Our present results, therefore, suggest that measuring the risk of dozing and the feeling of sleepiness reflect different sleepiness components and may respond differently to PAP. Patients feeling sleepy without risk of dozing may need more thorough evaluation for factors contributing to sleepiness before initiating treatment.
  •  
49.
  • Thorarinsdottir, Elin H., et al. (författare)
  • Polysomnographic characteristics of excessive daytime sleepiness phenotypes in obstructive sleep apnea : results from the international sleep apnea global interdisciplinary consortium
  • 2024
  • Ingår i: Sleep. - : Oxford University Press. - 0161-8105 .- 1550-9109. ; 47:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Study Objectives: Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnea (OSA). Traditional polysomnographic (PSG) measures only partially explain EDS in OSA. This study analyzed traditional and novel PSG characteristics of two different measures of EDS among patients with OSA. Methods: Sleepiness was assessed using the Epworth Sleepiness Scale (>10 points defined as "risk of dozing") and a measure of general sleepiness (feeling sleepy >= 3 times/week defined as "feeling sleepy"). Four sleepiness phenotypes were identified: "non-sleepy," "risk of dozing only," "feeling sleepy only," and "both at risk of dozing and feeling sleepy." Results: Altogether, 2083 patients with OSA (69% male) with an apnea-hypopnea index (AHI) >= 5 events/hour were studied; 46% were "non-sleepy," 26% at "risk of dozing only," 7% were "feeling sleepy only," and 21% reported both. The two phenotypes at "risk of dozing" had higher AHI, more severe hypoxemia (as measured by oxygen desaturation index, minimum and average oxygen saturation [SpO(2)], time spent < 90% SpO(2), and hypoxic impacts) and they spent less time awake, had shorter sleep latency, and higher heart rate response to arousals than "non-sleepy" and "feeling sleepy only" phenotypes. While statistically significant, effect sizes were small. Sleep stages, frequency of arousals, wake after sleep onset and limb movement did not differ between sleepiness phenotypes after adjusting for confounders. Conclusions: In a large international group of patients with OSA, PSG characteristics were weakly associated with EDS. The physiological measures differed among individuals characterized as "risk of dozing" or "non-sleepy," while "feeling sleepy only" did not differ from "non-sleepy" individuals.
  •  
50.
  • Thorsteinsdottir, Ingunn, et al. (författare)
  • High-Sensitivity Cardiac Troponin I Is a Strong Predictor of Cardiovascular Events and Mortality in the AGES-Reykjavik Community-Based Cohort of Older Individuals
  • 2016
  • Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 62:4, s. 623-630
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The objective of this study was to investigate the predictive power of a high-sensitivity cardiac troponin I (hs-cTnI) assay for cardiovascular events and mortality in a large population of older community dwellers.METHODS: Blood was collected from 5764 individuals (age 66-98 years) during the period of 2002-2006 and the outcome as to all-cause death and incidence of cardiovascular disease (CVD) and coronary heart disease (CHD) followed up to 10 years. hs-cTnI (Abbott) was measured in serum to assess the association of this marker with CVD, CHD and death, and finally, to compare the results with conventional risk factors by multivariable statistical analysis.RESULTS: The median (interquartile range) concentrations of hs-cTnI were 8.4 ng/L (5.6-14.2 ng/L) and 5.3 ng/L (3.8-8.1 ng/L) in men (2416) and women (3275), respectively, and the concentrations increased linearly with age. Outcomes as to all-cause death and incidence of CVD and CHD were significantly associated with increasing concentrations of hs-cTnI beginning well below the 99th percentile concentrations. The associations with outcome remained after adjustments for conventional risk factors and were similar in men and women.CONCLUSIONS: Our findings suggest that hs-cTnI reflects the status of the myocardium even in seemingly healthy individuals and that the measurements of hs-cTnI may be useful for primary prediction of heart disease; this should form the basis for future prospective clinical trials for determining whether measuring hs-cTnI can be used in the prevention of CVD/CHD.
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