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1.
Nat Commun ; 12(1): 2329, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888689

RESUMO

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.


Assuntos
Causas de Morte , Ácidos Graxos Ômega-3/sangue , Mortalidade Prematura , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Proteção , Fatores de Risco
2.
Am J Clin Nutr ; 114(1): 16-28, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33826696

RESUMO

BACKGROUND: Threshold serum 25-hydroxyvitamin D [25(OH)D] concentrations for extraskeletal outcomes are uncertain and could differ from recommendations (20-30 ng/mL) for skeletal health. OBJECTIVES: We aimed to identify and validate sex-specific threshold 25(OH)D concentrations for older adults' physical function. METHODS: Using 5 large prospective, population-based studies-Age, Gene/Environment Susceptibility-Reykjavik (n = 4858, Iceland); Health, Aging, and Body Composition (n = 2494, United States); Invecchiare in Chianti (n = 873, Italy); Osteoporotic Fractures in Men (n = 2301, United States); and Study of Osteoporotic Fractures (n = 5862, United States)-we assessed 16,388 community-dwelling adults (10,376 women, 6012 men) aged ≥65 y. We analyzed 25(OH)D concentrations with the primary outcome (incident slow gait: women <0.8 m/s; men <0.825 m/s) and secondary outcomes (gait speed, incident self-reported mobility, and stair climb impairment) at median 3.0-y follow-up. We identified sex-specific 25(OH)D thresholds that best discriminated incident slow gait using machine learning in training data (2/3 cohort-stratified random sample) and validated using the remaining (validation) data and secondary outcomes. RESULTS: Mean age in the cohorts ranged from 74.4 to 76.5 y in women and from 73.3 to 76.6 y in men. Overall, 1112/6123 women (18.2%) and 494/3937 men (12.5%) experienced incident slow gait, 1098/7011 women (15.7%) and 474/3962 men (12.0%) experienced incident mobility impairment, and 1044/6941 women (15.0%) and 432/3993 men (10.8%) experienced incident stair climb impairment. Slow gait was best discriminated by 25(OH)D <24.0 ng/mL compared with 25(OH)D ≥24.0 ng/mL in women (RR: 1.29; 95% CI: 1.10, 1.50) and 25(OH)D <21.0 ng/mL compared with 25(OH)D ≥21.0 ng/mL in men (RR: 1.43; 95% CI: 1.01, 2.02). Most associations between 25(OH)D and secondary outcomes were modest; estimates were similar between validation and training datasets. CONCLUSIONS: Empirically identified and validated sex-specific threshold 25(OH)D concentrations for physical function for older adults, 24.0 ng/mL for women and 21.0 ng/mL for men, may inform candidate reference concentrations or the design of vitamin D intervention trials.


Assuntos
Vida Independente , Desempenho Físico Funcional , Vitamina D/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Composição Corporal , Feminino , Humanos , Itália , Masculino , Fatores Sexuais , Estados Unidos , Vitamina D/sangue , Deficiência de Vitamina D
3.
Mol Psychiatry ; 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859359

RESUMO

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

4.
Exp Gerontol ; 149: 111306, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713735

RESUMO

OBJECTIVE: This study aimed to investigate how skeletal muscle attenuation and adipose tissue (AT) attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle vary according to the targeted muscles, sex, and age. DESIGN: Population-based cross-sectional study. SETTING: Community-dwelling old population in Reykjavik, Iceland. SUBJECTS: A total of 5331 older adults (42.8% women), aged 66-96 years from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study, who participated in the baseline visit (between 2002 and 2006) and had valid thigh and abdominal computed tomography (CT) scans were studied. METHODS: Muscle attenuation and AT attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle were determined using CT. Linear mixed model analysis of variance was performed for each sex, with skeletal muscle or AT attenuation as the dependent variable. RESULTS: Muscle attenuation decreased, and AT attenuation increased with age in both sexes, and these differences were specific for each muscle, although not in all age groups. Age-related differences in muscle and AT attenuation varied with specific muscle. In general, for both sexes, skeletal muscle attenuation of the hamstrings declined more than average with age. Men and women displayed a different pattern in the age differences in AT attenuation for each muscle. CONCLUSIONS: Our data support the hypotheses that skeletal muscle attenuation decreases, and AT attenuation increases with aging. In addition, our data add new evidence, supporting that age-related differences in skeletal muscle and AT attenuation vary between muscles.


Assuntos
Envelhecimento , Músculo Esquelético , Tecido Adiposo/diagnóstico por imagem , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Tomografia Computadorizada por Raios X
5.
Exp Gerontol ; 149: 111314, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33741458

RESUMO

OBJECTIVE: This study aimed to examine whether an accelerated decline in quadriceps cross-sectional area (CSA), attenuation (a surrogate of quality), and strength, as well as lower limb muscular function, are associated with hip fractures in older adults with impaired kidney function. DESIGN: Prospective population-based study. SETTING: Community-dwelling old population in Reykjavik, Iceland. SUBJECTS: A total of 875 older adults (mean baseline age 76 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study with impaired kidney function. METHODS: Quadriceps CSA and density were determined using computed tomography (CT), knee extension strength was measured with an isometric dynamometer chair, and muscular function was assessed using the Timed Up and Go (TUG) test. All muscle-related measurements were assessed twice over a mean follow-up of 5.2 years. Data on hip fracture incidence was obtained from medical records during a maximum of 8.4 years of follow-up time. RESULTS: Fully adjusted cox-proportional hazard regression models showed that a faster decline in quadriceps CSA and TUG test performance were significantly associated with increased hip fracture risk (HR = 1.55, 95% CI = 1.02-2.36, and HR = 1.80, 95% CI = 1.19-2.72, respectively). A faster decrease in quadriceps density and isometric knee extension strength were not associated with fracture risk. CONCLUSIONS: Accelerated decline in CT-derived quadriceps CSA and muscular function, as measured by the TUG test's performance, are predictive of hip fracture risk in older adults with impaired kidney function. TUG test is a simple measure and easily included in routine medical examinations, compared to CT scans, which seems to be useful for identifying a subgroup of individuals with high risk of fracture.


Assuntos
Fraturas do Quadril , Equilíbrio Postural , Idoso , Fraturas do Quadril/epidemiologia , Humanos , Rim , Estudos Prospectivos , Estudos de Tempo e Movimento
6.
J Clin Endocrinol Metab ; 106(2): 372-387, 2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33231259

RESUMO

CONTEXT: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. OBJECTIVE: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. DESIGN: Genetics of Obesity-associated Liver Disease Consortium. SETTING: Population-based. MAIN OUTCOME: Computed tomography measured liver attenuation. RESULTS: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. CONCLUSIONS: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.


Assuntos
Doença de Depósito de Glicogênio/etiologia , Glicogênio Hepático/metabolismo , Síndrome Metabólica/etiologia , Infarto do Miocárdio/prevenção & controle , Polimorfismo de Nucleotídeo Único , Proteína Fosfatase 1/genética , Adulto , Idoso , Biomarcadores/análise , Feminino , Seguimentos , Doença de Depósito de Glicogênio/metabolismo , Doença de Depósito de Glicogênio/patologia , Humanos , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Prognóstico , Estudos Prospectivos
7.
J Clin Endocrinol Metab ; 106(3): e1156-e1169, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33326040

RESUMO

CONTEXT: Follicle-stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high after menopause. Loss of bone mineral density (BMD) and gain of bone marrow adiposity (BMA) and body fat mass also occur during this time. In mice, blocking the action of FSH increases bone mass and decreases fat mass. OBJECTIVE: To investigate the associations between endogenous FSH levels and BMD, BMA, and body composition in older adults, independent of estradiol and testosterone levels. DESIGN, SETTING, AND PARTICIPANTS: Older adults from the AGES-Reykjavik Study, an observational cohort study. MAIN OUTCOME MEASURES: Areal BMD, total body fat, and lean mass were measured with dual-energy x-ray absorptiometry. Lumbar vertebral BMA was measured by 1H-magnetic resonance spectroscopy. Volumetric BMD and visceral and subcutaneous adipose tissue (VAT, SAT) areas were measured with quantitative computed tomography. The least squares means procedure was used to determine sex hormone-adjusted associations between quartiles of serum FSH and BMD, BMA, and body composition. RESULTS: In women (N = 238, mean age 81 years), those in the highest FSH quartile, compared with the lowest quartile, had lower adjusted mean spine integral BMD (-8.6%), lower spine compressive strength index (-34.8%), higher BMA (+8.4%), lower weight (-8.4%), lower VAT (-17.6%), lower lean mass (-6.1%), and lower fat mass (-11.9%) (all P < 0.05). In men, FSH level was not associated with any outcome. CONCLUSIONS: Older postmenopausal women with higher FSH levels have higher BMA, but lower BMD and lower fat and lean mass, independent of estradiol and testosterone levels. Longitudinal studies are needed to better understand the underlying mechanisms.


Assuntos
Composição Corporal/fisiologia , Densidade Óssea/fisiologia , Medula Óssea/metabolismo , Hormônio Foliculoestimulante/sangue , Adiposidade/fisiologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Envelhecimento/metabolismo , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Islândia , Metabolismo dos Lipídeos/fisiologia , Estudos Longitudinais , Masculino
8.
Nat Commun ; 11(1): 6285, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293549

RESUMO

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.


Assuntos
Doença de Alzheimer/genética , Doenças de Pequenos Vasos Cerebrais/genética , Hipertensão/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Imagem de Tensor de Difusão , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/epidemiologia , Masculino , Anamnese , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Substância Branca/diagnóstico por imagem , Adulto Jovem
9.
BMC Pediatr ; 20(1): 25, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964368

RESUMO

BACKGROUND: Obesity has been longitudinally associated with depression but only few studies take a life course approach. This longitudinal study investigates whether being overweight or obese at age 8 and 13 years is associated with depressive symptoms more than 60 years later and whether this association is independent of late-life body mass index (BMI). We also investigated the association of being overweight/obese at age 8 or 13 years with ever having major depressive disorder (lifetime MDD). METHOD: This analysis is based on a sub-sample of 889 AGES-Reykjavik participants with measured BMI data from early life. Late-life depressive symptoms were measured with the Geriatric Depression Scale (GDS) and lifetime MDD was assessed at late-life using the Mini International Neuropsychiatric Interview. Logistic regression analysis was used to estimate the relationships between BMI (continuous and categorical) at age 8 or 13 years, and late-life depressive symptoms (measured as GDS ≥ 5) or lifetime MDD, adjusted for sex, education, physical activity, smoking status and alcohol use. In a separate model, additional adjustments were made for late-life BMI. RESULTS: One hundred and one subjects (11%) had depressive symptoms at late-life (GDS ≥ 5), and 39 subjects (4.4%) had lifetime MDD. Being overweight or obese at age 8 or 13 years was not associated with higher depressive symptoms during late-life, irrespective of late-life BMI. Being overweight or obese at age 8 years, but not age 13 years was associated with an increased risk of lifetime MDD (Odds Ratio (OR) (95% confidence interval [CI]) for age 8 = 4.03[1.16-13.96]P = 0.03 and age 13 = 2.65[0.69-10.26] P = 0.16, respectively). CONCLUSION: Being overweight in childhood was associated with increased odds of lifetime MDD, although the magnitude of the risk is uncertain given the small numbers of participants with lifetime MDD. No clear association was observed between childhood and adolescent overweight/obesity and late-life depressive symptoms irrespective of late life BMI.


Assuntos
Transtorno Depressivo Maior , Obesidade Pediátrica , Adolescente , Idoso , Índice de Massa Corporal , Criança , Depressão/epidemiologia , Depressão/etiologia , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/etiologia , Humanos , Longevidade , Estudos Longitudinais , Sobrepeso/complicações , Sobrepeso/epidemiologia , Obesidade Pediátrica/complicações , Obesidade Pediátrica/epidemiologia
10.
J Bone Miner Res ; 35(2): 326-332, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31618468

RESUMO

Bone marrow adiposity (BMA) is associated with aging and osteoporosis, but whether BMA can predict bone loss and fractures remains unknown. Using data from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study, we investigated the associations between 1 H-MRS-based measures of vertebral bone marrow adipose tissue (BMAT), annualized change in bone density/strength by quantitative computed tomography (QCT) and DXA, and secondarily, with incident clinical fractures and radiographic vertebral fractures among older adults. The associations between BMAT and annualized change in bone density/strength were evaluated using linear regression models, adjusted for age, body mass index (BMI), diabetes, estradiol, and testosterone. Cox proportional hazards models were used to evaluate the associations between baseline BMAT and incident clinical fractures, and logistic regression models for incident vertebral fractures. At baseline, mean ± SD age was 80.9 ± 4.2 and 82.6 ± 4.2 years in women (n = 148) and men (n = 150), respectively. Mean baseline BMAT was 55.4% ± 8.1% in women and 54.1% ± 8.2% in men. Incident clinical fractures occurred in 7.4% of women over 2.8 years and in 6.0% of men over 2.2 years. Incident vertebral fractures occurred in 12% of women over 3.3 years and in 17% of men over 2.7 years. Each 1 SD increase in baseline BMAT was associated with a 3.9 mg2 /cm4 /year greater loss of spine compressive strength index (p value = .003), a 0.9 mg/cm3 /year greater loss of spine trabecular BMD (p value = .02), and a 1.2 mg/cm3 /year greater loss of femoral neck trabecular BMD (p value = .02) in women. Among men, there were no associations between BMAT and changes in bone density/strength. There were no associations between BMAT and incident fractures in women or men. In conclusion, we found greater BMAT is associated with greater loss of trabecular bone at the spine and femoral neck, and greater loss of spine compressive strength, in older women. © 2019 American Society for Bone and Mineral Research.


Assuntos
Doenças Ósseas Metabólicas , Adipócitos , Adiposidade , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Medula Óssea/diagnóstico por imagem , Feminino , Humanos , Masculino , Fraturas da Coluna Vertebral
11.
Nicotine Tob Res ; 22(6): 935-941, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-31091312

RESUMO

INTRODUCTION: In addition to well-established links with cardiovascular and respiratory diseases, cigarette smoking may affect skeletal muscle; however, associations with quadriceps atrophy, density, and function are unknown. This study explored the associations of current and former smoking with quadriceps muscle area and attenuation as well as muscle force (assessed as knee extension peak torque) and rate of torque development-a measure of muscle power in older adults. METHODS: Data from 4469 older adults, aged 66-95 years at baseline in the Age, Gene/Environment Susceptibility-Reykjavik Study with measurements of thigh computed tomography, isometric knee extension testing, self-reported smoking history, and potential covariates were analyzed. RESULTS: Sex differences were observed in these data; therefore, our final analyses are stratified by sex. In men, both former smokers and current smokers had lower muscle area (with ß= -0.10, 95% confidence interval [CI] = -0.17 to -0.03 and ß = -0.19, 95% CI = -0.33 to -0.05, respectively) and lower muscle attenuation (ie, higher fat infiltration, ß = -0.08, 95% CI = -0.16 to -0.01 and ß = -0.17, 95% CI = -0.34 to -0.01, respectively) when compared with never smokers. Smoking status was not associated with male peak torque or rate of torque development. In women, current smoking was associated with lower muscle attenuation (ß = -0.24, 95% CI = -0.34 to -0.13) compared to never smoking. Among female smokers (current and former), muscle attenuation and peak torque were lower with increasing pack-years. CONCLUSIONS: Results suggest that cigarette smoking is related to multiple muscle properties at older age and that these relationships may be different among men and women. IMPLICATIONS: This article presents novel data, as it examined for the first time the relationship between smoking and computed tomography-derived quadriceps muscle size (cross-sectional area) and attenuation. This study suggests that current cigarette smoking is related to higher muscle fat infiltration, which may have significant health implications for the older population, because of its known association with poor physical function, falls, and hip fractures.


Assuntos
Fumar Cigarros/efeitos adversos , Músculo Esquelético/patologia , Músculo Quadríceps/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/efeitos dos fármacos , Estudos Prospectivos , Músculo Quadríceps/diagnóstico por imagem , Músculo Quadríceps/efeitos dos fármacos , Fumantes , Tomografia Computadorizada por Raios X
12.
Acta Ophthalmol ; 2019 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-31885211

RESUMO

PURPOSE: To study associations between body size at birth and age-related macular degeneration (AMD) in old age. METHODS: The study sample consists of 1497 community-dwelling individuals (56.1% women) aged 67-89 years with birth data and retinal data collected twice in old age 5 years apart. Birth data (weight, length, birth order) were extracted from original birth records. Digital retinal photographs were graded to determine AMD status. Data on covariates were collected at the baseline physical examination in old age. Multivariable regression analyses were used to study the association between birth data and AMD adjusting for known confounding factors, including birth year cohort effects. RESULTS: The prevalence and 5-year incidence of any AMD were 33.1% and 17.0%, respectively. Men and women born in 1930-1936 were significantly leaner and slightly longer at birth compared to those in earlier birth cohorts. There were no consistent associations between weight, length or ponderal index (PI) at birth and AMD in old age even when stratified by birth cohort. Age-related macular degeneration (AMD) prevalence (39.8%) and 5-year incidence (28.6%) were highest in individuals who were in the highest quartile of PI at birth and who were obese in old age. CONCLUSION: Body size at birth was not consistently associated with AMD in old age, suggesting that intrauterine growth might have little direct importance in the development of AMD in old age. It is possible that some yet unknown factors related to larger size at birth and obesity in old age may explain differences in the prevalence and incidence of AMD in the ageing population.

13.
Sci Rep ; 9(1): 15192, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645637

RESUMO

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.


Assuntos
Envelhecimento/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Perda Auditiva/genética , Animais , Vias Auditivas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Fenótipo , Reprodutibilidade dos Testes
14.
PLoS One ; 14(8): e0221474, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31442261

RESUMO

BACKGROUND: The debate whether "asymptomatic hyperuricemia" should be treated is still ongoing. The objective of this cross-sectional study was to analyze whether hyperuricema in the elderly is associated with joint pain. METHODS AND FINDINGS: Participants in the population-based AGES-Reykjavik Study (males 2195, females 2975, mean age 76(6)) answered standardized questions about joint pain. In addition they recorded intermittent hand joint pain by marking a diagram of the hand. In males, no association was found between hyperuricemia and pain. Females however, showed a positive association between hyperuricemia and joint pain at many sites. After adjustment for age, BMI and hand osteoarthritis however, only intermittent hand joint pain (OR 1.30(1.07-1.58), p = 0.008) and intermittent pain in ≥10 hand joints (OR 1.75(1.32-2.31), p<0.001) remained significant. The best model for describing the relationship between serum uric acid levels (SUA) and intermittent hand joint pain in ≥10 joints was non-linear with a cut-off at 372 µmol/L. The attributable surplus number of symptomatic females with SUA ≥372 µmol/L was approximately 2.0% of the study population for those reporting pain in ≥10 hand joints. Next after having severe hand osteoarthritis, SUA ≥372 was an independent predictive factor of intermittent pain in ≥10 hand joints. Intermittent hand joint pain was also an independent risk factor for worse general health description. CONCLUSION: Results from this population based study indicate that hyperuricemia in elderly females may be a rather frequent cause of intermittent hand joint pain, often in many joints. The most likely explanation relates to low-grade urate crystal induced inflammation. Our data do not allow for assessment of the severity of symptoms or whether they merit specific treatment, but intermittent hand joint pain was an independent predictor of worse general health. These findings may be an important contribution to the debate on whether hyperuricemia should be treated.


Assuntos
Artralgia/etiologia , Articulação da Mão/patologia , Hiperuricemia/complicações , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Artralgia/sangue , Estudos Transversais , Feminino , Humanos , Hiperuricemia/sangue , Islândia , Osteoartrite/etiologia , Ácido Úrico/sangue
15.
Am J Respir Crit Care Med ; 200(11): 1402-1413, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31339356

RESUMO

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.


Assuntos
Predisposição Genética para Doença/genética , Fibrose Pulmonar Idiopática/genética , Doenças Pulmonares Intersticiais/genética , Idoso , Estudos de Casos e Controles , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mucina-5B/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Proteínas Semelhantes à Proteína de Ligação a TATA-Box , beta Carioferinas/genética
16.
J Am Coll Cardiol ; 73(24): 3118-3131, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221261

RESUMO

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.


Assuntos
Cálcio/sangue , Doenças Cardiovasculares , Eletrocardiografia/métodos , Técnicas Eletrofisiológicas Cardíacas/métodos , Magnésio/sangue , Potássio/sangue , Doenças Assintomáticas/epidemiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Correlação de Dados , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
17.
JAMA Neurol ; 76(8): 956-961, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31107514

RESUMO

Importance: It is uncertain whether unrecognized myocardial infarction (MI) is a risk factor for cerebral infarction. Objective: To determine whether unrecognized MI detected by cardiac magnetic resonance imaging (MRI) is associated with cerebral infarction. Design, Setting, and Participants: This is a cross-sectional study of ICELAND MI, a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study conducted in Iceland. Enrollment occurred from January 2004 to January 2007 from a community-dwelling cohort of older Icelandic individuals. Participants aged 67 to 93 years who underwent both brain MRI and late gadolinium enhancement cardiac MRI were included. Data analysis was performed from September 2018 to March 2019. Exposures: Unrecognized MI identified by cardiac MRI. Main Outcomes and Measures: Unrecognized MI was defined as cardiac MRI evidence of MI without a history of clinically evident MI. Recognized MI was defined as cardiac MRI evidence of MI with a history of clinically evident MI. Cerebral infarctions on brain MRI were included regardless of associated symptoms. Multiple logistic regression was used to evaluate the association between MI status (no MI, unrecognized MI, or recognized MI) and cerebral infarction after adjustment for demographic factors and vascular risk factors. In addition, we evaluated the association between unrecognized MI and embolic infarcts of undetermined source. Results: Five enrolled participants had nondiagnostic brain MRI studies and were excluded. Among 925 participants, 480 (51.9%) were women; the mean (SD) age was 75.9 (5.3) years. There were 221 participants (23.9%) with cardiac MRI evidence of MI, of whom 68 had recognized MI and 153 unrecognized MI. There were 308 participants (33.3%) with brain MRI evidence of cerebral infarction; 93 (10.0%) had embolic infarcts of undetermined source. After adjustment for demographic factors and vascular risk factors, the likelihood (odds ratio) of having cerebral infarction was 2.0 (95% CI, 1.2-3.4; P = .01) for recognized MI and 1.5 (95% CI, 1.02-2.2; P = .04) for unrecognized MI. After adjustment for demographics and vascular risk factors, unrecognized MI was also associated with embolic infarcts of undetermined source (odds ratio, 2.0 [95% CI, 1.1-3.5]; P = .02). Conclusions and Relevance: In a population-based sample, we found an association between unrecognized MI and cerebral infarction. These findings suggest that unrecognized MI may be a novel risk factor for cardiac embolism and cerebral infarction.

18.
J Sports Sci ; 37(15): 1746-1754, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30929574

RESUMO

Dynamic sitting, such as fidgeting and desk work, might be associated with health, but remains difficult to identify out of accelerometry data. We examined, in a laboratory study, whether dynamic sitting can be identified out of triaxial activity counts. Among 18 participants (56% men, 27.3 ± 6.5 years), up to 236 counts per minute were recorded in the anteroposterior and mediolateral axes during dynamic sitting using a hip-worn accelerometer. Subsequently, we examined in 621 participants (38% men, 80.0 ± 4.7 years) from the AGES-Reykjavik Study whether dynamic sitting was associated with cardio-metabolic health. Compared to participants who recorded the fewest dynamic sitting minutes (Q1), those with more dynamic sitting minutes had a lower BMI (Q2 = -1.39 (95%CI = -2.33;-0.46); Q3 = -1.87 (-2.82;-0.92); Q4 = -3.38 (-4.32;-2.45)), a smaller waist circumference (Q2 = -2.95 (-5.44;-0.46); Q3 = -3.47 (-6.01;-0.93); Q4 = -8.21 (-10.72;-5.71)), and a lower odds for the metabolic syndrome (Q2 = 0.74 [0.45;1.20] Q3 = 0.58 [0.36;0.95]; Q4 = 0.36 [0.22;0.59]). Our findings suggest that dynamic sitting might be identified using accelerometry and that this behaviour was associated with health. This might be important given the large amounts of time people spend sitting. Future studies with a focus on validation, causation and physiological pathways are needed to further examine the possible relevance of dynamic sitting.


Assuntos
Acelerometria/instrumentação , Metabolismo Energético , Exercício Físico/fisiologia , Comportamento Sedentário , Postura Sentada , Adolescente , Adulto , Índice de Massa Corporal , Feminino , Monitores de Aptidão Física , Humanos , Masculino , Síndrome Metabólica , Pessoa de Meia-Idade , Fatores de Risco , Circunferência da Cintura , Adulto Jovem
19.
Circulation ; 139(21): 2422-2436, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30971107

RESUMO

BACKGROUND: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. METHODS: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). RESULTS: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. CONCLUSIONS: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.


Assuntos
Ácido Araquidônico/sangue , Doenças Cardiovasculares/sangue , Dieta Saudável , Gorduras na Dieta/sangue , Ácido Linoleico/sangue , Prevenção Primária/métodos , Comportamento de Redução do Risco , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Gorduras na Dieta/administração & dosagem , Feminino , Humanos , Ácido Linoleico/administração & dosagem , Masculino , Pessoa de Meia-Idade , Valor Nutritivo , Estudos Observacionais como Assunto , Fatores de Proteção , Recomendações Nutricionais , Medição de Risco , Fatores de Risco
20.
Am J Clin Nutr ; 109(2): 276-287, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30721968

RESUMO

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.


Assuntos
Tecido Adiposo/metabolismo , Composição Corporal/genética , Compartimentos de Líquidos Corporais/metabolismo , Músculo Esquelético/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas ADAMTS/genética , Absorciometria de Fóton , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Impedância Elétrica , Grupo com Ancestrais do Continente Europeu/genética , Proteínas da Matriz Extracelular/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/genética , Receptor Tipo 4 de Melanocortina/genética , Versicanas/genética , Adulto Jovem
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