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1.
Circulation ; 149(4): 305-316, 2024 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-38047387

RESUMEN

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.


Asunto(s)
Enfermedades Cardiovasculares , Ácidos Grasos Omega-3 , Animales , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Factores de Riesgo , Ácidos Docosahexaenoicos , Biomarcadores
2.
Mol Psychiatry ; 26(11): 6293-6304, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33859359

RESUMEN

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.


Asunto(s)
Estudio de Asociación del Genoma Completo , Hipertensión , Presión Sanguínea/genética , Sitios Genéticos/genética , Humanos , Hipertensión/genética , Polimorfismo de Nucleótido Simple/genética , Sueño/genética
3.
Eur J Epidemiol ; 37(6): 591-601, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35471691

RESUMEN

The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer's disease. Accumulating evidence has linked ε4 carriership to abnormal structural brain changes across the adult lifespan. To better understand the underlying causal mechanisms, we investigated the extent to which the effect of the ε4 allele on cognition is mediated by structural brain imaging markers in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). This study included 4527 participants (aged 76.3 ± 5.4 at baseline) who underwent the brain magnetic resonance imaging assessment (of brain tissue volumes, white matter lesion volume, subcortical and cortical infarcts, and cerebral microbleeds) and a battery of neuropsychological tests at baseline. Causal mediation analysis was used to quantify the mediation of the ε4 effect on cognition by these MRI markers, both individually and jointly. We observed that about 9% of the total effect of ε4 carriership on cognition was mediated by white matter lesion volume. This proportion increased to 25% when total brain tissue volume was jointly considered with white matter lesion volume. In analyses separating ε4 homozygotes from ε4 heterozygotes, the effect on global cognition of specifically ε4 homozygosity appeared to be partially mediated by cerebral microbleeds, particularly lobar microbleeds. There was no evidence of mediation of the ε4 effect by cortical or subcortical infarcts. This study shows that the ε4 effect on cognition is partly mediated by white matter lesion volume and total brain tissue volume. These findings suggest the joint role of cerebral small vessel disease and neurodegeneration in the ε4-cognition relationship.


Asunto(s)
Enfermedad de Alzheimer , Apolipoproteína E4 , Encéfalo , Cognición , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E , Biomarcadores , Encéfalo/diagnóstico por imagen , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/genética , Hemorragia Cerebral/patología , Humanos , Infarto/patología , Imagen por Resonancia Magnética , Neuroimagen , Pruebas Neuropsicológicas
4.
Aging Clin Exp Res ; 34(5): 1027-1035, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35075586

RESUMEN

BACKGROUND: Participation in leisure activities and extensive social network have been associated with lower risk of cognitive impairment (CI) and dementia. AIMS: We examined whether leisure activities (cognitive solitary, cognitive group, social, physical, or creative activities) and social involvement are associated with less incidence of CI or dementia. METHODS: Analyses were performed from data of 2933 cognitively intact individuals at baseline included in the AGES-REYKJAVIK study. Odds ratios (OR) were calculated for incident CI and dementia in relation to cognitive individual, cognitive group, social, physical, and creative leisure activities as well as social networks. Models were adjusted for a number of known risk factors for cognitive decline. RESULTS: In 5 years, 12% of the cohort were diagnosed with CI or dementia. All leisure activities were associated with reduced likelihood of cognitive decline in the raw model, but in adjusted models, cognitive solitary [OR 0.49 (Confidence Interval (CI) 0.38-0.64)], cognitive group [OR 0.50 (CI 0.30-0.82)], and creative activities [OR 0.53 (CI 0.35-0.83)] were significantly associated with less cognitive decline. Analyses examining creative leisure activities independently, controlling for all other activities, suggested individuals participating in creative activities exhibited less CI [OR 0.64 (CI 0.41-0.98)]. Among social networks variables, frequency of meeting with friends and relatives was associated with reduced likelihood of CI [OR 0.49 (CI 0.31-0.75)]. DISCUSSION: Cognitive and creative leisure activities and frequent gatherings with friends and relatives are associated with reduced incidence of CI in this older cohort. CONCLUSION: Creative leisure activities might have special benefit for cognitive ability.


Asunto(s)
Disfunción Cognitiva , Demencia , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/epidemiología , Demencia/diagnóstico , Humanos , Actividades Recreativas/psicología , Factores de Riesgo , Participación Social
5.
Circulation ; 139(21): 2422-2436, 2019 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-30971107

RESUMEN

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.


Asunto(s)
Ácido Araquidónico/sangre , Enfermedades Cardiovasculares/sangre , Dieta Saludable , Grasas de la Dieta/sangre , Ácido Linoleico/sangre , Prevención Primaria/métodos , Conducta de Reducción del Riesgo , Anciano , Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Grasas de la Dieta/administración & dosificación , Femenino , Humanos , Ácido Linoleico/administración & dosificación , Masculino , Persona de Mediana Edad , Valor Nutritivo , Estudios Observacionales como Asunto , Factores Protectores , Ingesta Diaria Recomendada , Medición de Riesgo , Factores de Riesgo
6.
Nicotine Tob Res ; 22(6): 935-941, 2020 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-31091312

RESUMEN

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.


Asunto(s)
Fumar Cigarrillos/efectos adversos , Músculo Esquelético/patología , Músculo Cuádriceps/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/efectos de los fármacos , Estudios Prospectivos , Músculo Cuádriceps/diagnóstico por imagen , Músculo Cuádriceps/efectos de los fármacos , Fumadores , Tomografía Computarizada por Rayos X
7.
Am J Respir Crit Care Med ; 200(2): 175-183, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-30673508

RESUMEN

Rationale: Interstitial lung abnormalities (ILA) are radiologic abnormalities on chest computed tomography scans that have been associated with an early or mild form of pulmonary fibrosis. Although ILA have been associated with radiologic progression, it is not known if specific imaging patterns are associated with progression or risk of mortality. Objectives: To determine the role of imaging patterns on the risk of death and ILA progression. Methods: ILA (and imaging pattern) were assessed in 5,320 participants from the AGES-Reykjavik Study, and ILA progression was assessed in 3,167 participants. Multivariable logistic regression was used to assess factors associated with ILA progression, and Cox proportional hazards models were used to assess time to mortality. Measurements and Main Results: Over 5 years, 327 (10%) had ILA on at least one computed tomography, and 1,435 (45%) did not have ILA on either computed tomography. Of those with ILA, 238 (73%) had imaging progression, whereas 89 (27%) had stable to improved imaging; increasing age and copies of MUC5B genotype were associated with imaging progression. The definite fibrosis pattern was associated with the highest risk of progression (odds ratio, 8.4; 95% confidence interval, 2.7-25; P = 0.0003). Specific imaging patterns were also associated with an increased risk of death. After adjustment, both a probable usual interstitial pneumonia and usual interstitial pneumonia pattern were associated with an increased risk of death when compared with those indeterminate for usual interstitial pneumonia (hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P = 0.001; hazard ratio, 3.9; 95% confidence interval, 2.3-6.8;P < 0.0001), respectively. Conclusions: In those with ILA, imaging patterns can be used to help predict who is at the greatest risk of progression and early death.


Asunto(s)
Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Factores de Edad , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Islandia , Fibrosis Pulmonar Idiopática/mortalidad , Fibrosis Pulmonar Idiopática/fisiopatología , Modelos Logísticos , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/mortalidad , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Mucina 5B/genética , Análisis Multivariante , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de Supervivencia , Tomografía Computarizada por Rayos X
8.
Am J Respir Crit Care Med ; 200(11): 1402-1413, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31339356

RESUMEN

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.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Fibrosis Pulmonar Idiopática/genética , Enfermedades Pulmonares Intersticiales/genética , Anciano , Estudios de Casos y Controles , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Mucina 5B/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Proteínas Similares a la Proteína de Unión a TATA-Box , beta Carioferinas/genética
9.
Am J Respir Crit Care Med ; 199(5): 631-642, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30199657

RESUMEN

RATIONALE: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. METHODS: Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs. RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; ßSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; ßSNP×DHA interaction = 36.2 ml). CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.


Asunto(s)
Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/fisiología , Ácidos Grasos Omega-3/sangre , Fenómenos Fisiológicos Respiratorios/genética , Anciano , Biomarcadores/sangre , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Ácidos Docosahexaenoicos/sangre , Ácido Eicosapentaenoico/sangre , Ácidos Grasos Insaturados/sangre , Femenino , Volumen Espiratorio Forzado/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores Sexuales , Fumar/efectos adversos , Capacidad Vital/genética , Ácido alfa-Linolénico/sangre
10.
BMC Pediatr ; 20(1): 25, 2020 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-31964368

RESUMEN

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.


Asunto(s)
Trastorno Depresivo Mayor , Obesidad Infantil , Adolescente , Anciano , Índice de Masa Corporal , Niño , Depresión/epidemiología , Depresión/etiología , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/etiología , Humanos , Longevidad , Estudios Longitudinales , Sobrepeso/complicaciones , Sobrepeso/epidemiología , Obesidad Infantil/complicaciones , Obesidad Infantil/epidemiología
11.
Eur Heart J ; 40(6): 529-538, 2019 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-30445559

RESUMEN

Aims: Non-ischaemic cardiomyopathies (NICM) can cause heart failure and death. Cardiac magnetic resonance (CMR) detects myocardial scar/fibrosis associated with myocardial infarction (MI) and NICM with late gadolinium enhancement (LGE). The aim of this study was to determine the prevalence and prognosis of ischaemic and non-ischaemic myocardial fibrosis in a community-based sample of older adults. Methods and results: The ICELAND-MI cohort, a substudy of the Age, Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) study, provided a well-characterized population of 900 subjects after excluding subjects with pre-existing heart failure. Late gadolinium enhancement CMR divided subjects into four groups: MI (n = 211), major (n = 54) non-ischaemic fibrosis (well-established, classic patterns, associated with myocarditis, infiltrative cardiomyopathies, or pathological hypertrophy), minor (n = 238) non-ischaemic fibrosis (remaining localized patterns not meeting major criteria), and a no LGE (n = 397) reference group. The primary outcome was time to death or first heart failure hospitalization. During a median follow-up of 5.8 years, 192 composite events occurred (115 deaths and 77 hospitalizations for incident heart failure). After inverse probability weighting, major non-ischaemic fibrosis [hazard ratio (HR) 3.2, P < 0.001] remained independently associated with the primary endpoint, while MI (HR 1.4, P = 0.10) and minor non-ischaemic LGE (HR 1.2, P = 0.39) did not. Major non-ischaemic fibrosis was associated with a poorer outcome than MI (HR = 2.3, P = 0.001) in the adjusted analysis. Conclusion: Major non-ischaemic patterns of myocardial fibrosis portended worse prognosis than no fibrosis/scar in an older community-based cohort. Traditional risk factors largely accounted for the effect of MI and minor non-ischaemic LGE.


Asunto(s)
Cardiomiopatías/epidemiología , Isquemia Miocárdica/epidemiología , Miocardio/patología , Anciano , Anciano de 80 o más Años , Cardiomiopatías/diagnóstico , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/patología , Femenino , Fibrosis , Corazón/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/patología , Prevalencia , Pronóstico
12.
Clin Chem ; 65(3): 406-418, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30647123

RESUMEN

BACKGROUND: Clinical practice guidelines recommend estimation of glomerular filtration rate (eGFR) using validated equations based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys). However, when compared with the measured GFR (mGFR), only eGFRcr-cys meets recommended performance standards. Our goal was to develop a more accurate eGFR method using a panel of metabolites without creatinine, cystatin C, or demographic variables. METHODS: An ultra-performance liquid chromatography-tandem mass spectrometry assay for acetylthreonine, phenylacetylglutamine, pseudouridine, and tryptophan was developed, and a 20-day, multiinstrument analytical validation was conducted. The assay was tested in 2424 participants with mGFR data from 4 independent research studies. A new GFR equation (eGFRmet) was developed in a random subset (n = 1615) and evaluated in the remaining participants (n = 809). Performance was assessed as the frequency of large errors [estimates that differed from mGFR by at least 30% (1 - P30); goal <10%]. RESULTS: The assay had a mean imprecision (≤10% intraassay, ≤6.9% interassay), linearity over the quantitative range (r 2 > 0.98), and analyte recovery (98.5%-113%). There was no carryover, no interferences observed, and analyte stability was established. In addition, 1 - P30 in the validation set for eGFRmet (10.0%) was more accurate than eGFRcr (13.1%) and eGFRcys (12.0%) but not eGFRcr-cys (8.7%). Combining metabolites, creatinine, cystatin C, and demographics led to the most accurate equation (7.0%). Neither equation had substantial variation among population subgroups. CONCLUSIONS: The new eGFRmet equation could serve as a confirmatory test for GFR estimation.


Asunto(s)
Cromatografía Liquida/métodos , Tasa de Filtración Glomerular , Espectrometría de Masas en Tándem/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Glutamina/análogos & derivados , Glutamina/sangre , Humanos , Masculino , Persona de Mediana Edad , Seudouridina/sangre , Reproducibilidad de los Resultados , Treonina/análogos & derivados , Treonina/sangre , Triptófano/sangre
13.
Lipids Health Dis ; 18(1): 7, 2019 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-30621701

RESUMEN

BACKGROUND: Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. METHODS: In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. RESULTS: Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. CONCLUSION: Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy.


Asunto(s)
Atrofia Geográfica/sangre , Degeneración Macular/sangre , Neovascularización Retiniana/sangre , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Atrofia Geográfica/diagnóstico , Atrofia Geográfica/patología , Humanos , Lisofosfatidilcolinas/sangre , Degeneración Macular/diagnóstico , Degeneración Macular/patología , Masculino , Neovascularización Retiniana/diagnóstico , Neovascularización Retiniana/patología , Factores de Riesgo , Índice de Severidad de la Enfermedad
14.
Rheumatol Int ; 39(4): 669-677, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30671597

RESUMEN

To investigate the association between osteoarthritis (OA) and microvascular pathology, we examined the relationship between retinal microvascular caliber and osteoarthritis of the hand and knee in an elderly population. The AGES-Reykjavik is a population-based, multidisciplinary longitudinal cohort study of aging. Retinal vessel caliber, hand osteoarthritis and total knee joint replacements due to OA were examined in 4757 individuals (mean age 76 ± 5 years; 57% female). Incident knee joint replacements during 5-year follow-up (n = 2961, mean age 75 ± 5 years; 58% female) were also assessed. Logistic regression analysis, adjusting for age, sex, and body mass index, showed an association between narrow arteriolar caliber and hand OA, as well as knee replacement. After adjustment for other covariates, including statin therapy, this association was significant for both hand OA in men and women [OR 1.10(1.03-1.17), p < 0.01] (per unit standard deviation decrease in CRAE) and TKR prevalence [OR 1.15 (1.01-1.32), p = 0.04], especially for men [OR 1.22 (1.00-1.51) p = 0.04] and also for incident TKRs in men [OR 1.50 (1.07-2.10), p = 0.04]. Narrow venular caliber was associated with hand OA in women [OR 1.10 (1.01-1.21), p = 0.03]. Retinal arterial narrowing in hand and knee OA is present in males as well as females. Venular narrowing in hand OA in women was an unexpected finding and is in contrast with the venular widening usually observed in cardiovascular diseases.


Asunto(s)
Artroplastia de Reemplazo de Rodilla/estadística & datos numéricos , Articulaciones de la Mano , Osteoartritis de la Rodilla/epidemiología , Arteria Retiniana/patología , Vena Retiniana/patología , Anciano , Anciano de 80 o más Años , Arteriolas/patología , Femenino , Humanos , Islandia/epidemiología , Modelos Logísticos , Estudios Longitudinales , Masculino , Tamaño de los Órganos , Osteoartritis/epidemiología , Osteoartritis de la Rodilla/cirugía , Factores Sexuales , Vénulas/patología
15.
PLoS Genet ; 12(10): e1006327, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27764101

RESUMEN

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 (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, 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 ß-amyloid cascade.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas de Drosophila/genética , Proteínas de la Membrana/genética , Receptores Notch/genética , Tropomiosina/genética , Edad de Inicio , Anciano , Alelos , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Apolipoproteínas E/genética , Drosophila melanogaster/genética , Exoma/genética , Femenino , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Islandia , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Mutación , Fenotipo , Población Blanca
17.
J Sports Sci ; 37(15): 1746-1754, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30929574

RESUMEN

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.


Asunto(s)
Acelerometría/instrumentación , Metabolismo Energético , Ejercicio Físico/fisiología , Conducta Sedentaria , Sedestación , Adolescente , Adulto , Índice de Masa Corporal , Femenino , Monitores de Ejercicio , Humanos , Masculino , Síndrome Metabólico , Persona de Mediana Edad , Factores de Riesgo , Circunferencia de la Cintura , Adulto Joven
18.
Stroke ; 49(8): 1812-1819, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30002152

RESUMEN

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.


Asunto(s)
Encéfalo/diagnóstico por imagen , Exoma/genética , Variación Genética/genética , Imagen por Resonancia Magnética/métodos , Proteínas Mitocondriales/genética , Sustancia Blanca/diagnóstico por imagen , Estudios de Cohortes , Humanos
19.
Kidney Int ; 94(3): 608-615, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29960746

RESUMEN

Decreased glomerular filtration rate (GFR) and albuminuria may be accompanied by brain pathology. Here we investigated whether changes in these kidney measures are linked to development of new MRI-detected infarcts and microbleeds, and progression of white matter hyperintensity volume. The study included 2671 participants from the population-based AGES-Reykjavik Study (mean age 75, 58.7% women). GFR was estimated from serum creatinine, and albuminuria was assessed by urinary albumin-to-creatinine ratio. Brain MRI was acquired at baseline (2002-2006) and 5 years later (2007-2011). New MRI-detected infarcts and microbleeds were counted on the follow-up scans. White matter hyperintensity progression was estimated as percent change in white matter hyperintensity volumes between the two exams. Participants with a large eGFR decline (over 3 ml/min/1.73m2 per year) had more incident subcortical infarcts (odds ratio 1.53; 95% confidence interval 1.05, 2.22), and more marked progression of white matter hyperintensity volume (difference: 8%; 95% confidence interval: 4%, 12%), compared to participants without a large decline. Participants with incident albuminuria (over 30 mg/g) had 21% more white matter hyperintensity volume progression (95% confidence interval: 14%, 29%) and 1.86 higher odds of developing new deep microbleeds (95% confidence interval 1.16, 2.98), compared to participants without incident albuminuria. The findings were independent of cardiovascular risk factors. Changes in kidney measures were not associated with occurrence of cortical infarcts. Thus, larger changes in eGFR and albuminuria are associated with increased risk for developing manifestations of cerebral small vessel disease. Individuals with larger changes in these kidney measures should be considered as a high risk population for accelerated brain pathology.


Asunto(s)
Albuminuria/fisiopatología , Enfermedades de los Pequeños Vasos Cerebrales/epidemiología , Riñón/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Sustancia Blanca/patología , Anciano , Albuminuria/orina , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Creatinina/orina , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular/fisiología , Humanos , Incidencia , Vida Independiente , Imagen por Resonancia Magnética , Masculino , Estudios Prospectivos , Insuficiencia Renal Crónica/orina , Factores de Riesgo , Albúmina Sérica , Sustancia Blanca/diagnóstico por imagen
20.
Thorax ; 73(9): 884-886, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29317545

RESUMEN

We investigated the association between interstitial lung abnormalities (ILA) and self-reported measures of health and functional status in 5764 participants from the Age, Gene/Environment Susceptibility-Reykjavik study. The associations of ILA to activities of daily living (ADLs), general health status and physical activity were explored using logistic regression models. Participants with ILA were less likely to be independent in ADLs (OR 0.70; 95% CI 0.55 to 0.90) to have good or better self-reported health (OR 0.66; 95% CI 0.52 to 0.82) and to participate in physical activity (OR 0.72; CI 0.56 to 0.91). The results demonstrate ILA's association with worsening self-reported health and functional status.


Asunto(s)
Estado de Salud , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/fisiopatología , Autoinforme , Actividades Cotidianas , Anciano , Ejercicio Físico , Femenino , Humanos , Modelos Logísticos , Masculino , Reproducibilidad de los Resultados
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