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2.
Am J Hum Genet ; 105(1): 15-28, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178129

RESUMO

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

3.
Mol Nutr Food Res ; 62(3)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28941034

RESUMO

SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure. CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.

4.
Neurology ; 89(14): 1441-1447, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28878051

RESUMO

OBJECTIVE: To investigate olfaction in relation to incident Parkinson disease (PD) in US white and black older adults. METHODS: The study included 1,510 white (mean age 75.6 years) and 952 black (75.4 years) participants of the Health, Aging, and Body Composition study. We evaluated the olfaction of study participants with the Brief Smell Identification Test (BSIT) in 1999-2000. We retrospectively adjudicated PD cases identified through August 31, 2012, using multiple data sources. We used multivariable Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During an average of 9.8 years of follow-up, we identified a total of 42 incident PD cases, including 30 white and 12 black participants. Overall, poor sense of smell, as indicated by a lower BSIT score, was associated with higher risk of PD. Compared with the highest tertile of BSIT (t3), the HR was 1.3 (95% CI 0.5-3.6) for the second tertile (t2) and 4.8 (95% CI 2.0-11.2) for the lowest tertile (t1) (ptrend < 0.00001). Further analyses revealed significant associations for incident PD in both the first 5 years of follow-up (HRt1/[t2+t3] 4.2, 95% CI 1.7-10.8) and thereafter (HRt1/[t2+t3] 4.1, 95% CI 1.7-9.8). This association appeared to be stronger in white (HRt1/[t2+t3] 4.9, 95% CI 2.3-10.5) than in black participants (HRt1/[t2+t3] 2.5, 95% CI 0.8-8.1), and in men (HRt1/[t2+t3] 5.4, 95% CI 2.3-12.9) than in women (HRt1/[t2+t3] 2.9, 95% CI 1.1-7.8). CONCLUSIONS: Poor olfaction predicts PD in short and intermediate terms; the possibility of stronger associations among men and white participants warrants further investigation.


Assuntos
Grupo com Ancestrais do Continente Africano , Grupo com Ancestrais do Continente Europeu , Doença de Parkinson , Olfato/fisiologia , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Doença de Parkinson/epidemiologia , Doença de Parkinson/etnologia , Doença de Parkinson/fisiopatologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Estados Unidos/epidemiologia
5.
Age Ageing ; 46(2): 250-257, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28399220

RESUMO

Background/Objective: studies on the association of dementia with specific body composition (BC) components are scarce. Our aim was to investigate associations of BC measures with different levels of cognitive function in late-life. Methods: we studied 5,169 participants (mean age 76 years, 42.9% men) in the AGES-Reykjavik Study of whom 485 (9.4%) were diagnosed with mild cognitive impairment (MCI) and 307 (5.9%) with dementia. Visceral fat, abdominal and thigh subcutaneous fat, and thigh muscle were assessed by computed tomography. MCI and dementia were based on clinical assessment and a consensus meeting; those without MCI or dementia were categorised as normal. Multinomial regression models assessed the associations stratified by sex and in additional analyses by midlife body mass index (BMI). Results: among women, there was a decreased likelihood of dementia per SD increase in abdominal subcutaneous fat (OR 0.72; 95% CI: 0.59-0.88), thigh subcutaneous fat (0.81; 0.67-0.98) and thigh muscle (0.63; 0.52-0.76), but not visceral fat, adjusting for demographics, vascular risk factors, stroke and depression. Inverse associations of fat with dementia were attenuated by weight change from midlife and were strongest in women with midlife BMI <25. In men, one SD increase in thigh muscle was associated with a decreased likelihood of dementia (0.75; 0.61-0.92). BC was not associated with MCI in men or women. Conclusion: a higher amount of abdominal and thigh subcutaneous fat were associated with a lower likelihood of dementia in women only, while more thigh muscle was associated with a lower likelihood of dementia in men and women.


Assuntos
Gordura Abdominal/fisiopatologia , Adiposidade , Transtornos Cognitivos/psicologia , Cognição , Envelhecimento Cognitivo/psicologia , Músculo Esquelético/fisiopatologia , Gordura Abdominal/diagnóstico por imagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Estudos Transversais , Feminino , Humanos , Islândia/epidemiologia , Masculino , Testes de Estado Mental e Demência , Músculo Esquelético/diagnóstico por imagem , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Gordura Subcutânea , Tomografia Computadorizada por Raios X
7.
PLoS Genet ; 12(10): e1006327, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27764101

RESUMO

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.


Assuntos
Doença de Alzheimer/genética , Proteínas de Drosophila/genética , Proteínas de Membrana/genética , Receptores Notch/genética , Tropomiosina/genética , Idade de Início , Idoso , Alelos , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Apolipoproteínas E/genética , Drosophila melanogaster/genética , Grupo com Ancestrais do Continente Europeu , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla , Genômica , Humanos , Islândia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mutação , Fenótipo
8.
Aging Cell ; 15(5): 792-800, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27325353

RESUMO

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (ß = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-ß (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.


Assuntos
Estudo de Associação Genômica Ampla , Força da Mão/fisiologia , Força Muscular/genética , Adulto , Idoso , Imunoprecipitação da Cromatina , Estudos de Coortes , Epigênese Genética , Humanos , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes
9.
Circ Arrhythm Electrophysiol ; 9(5): e003525, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27052031

RESUMO

BACKGROUND: Age is the foremost risk factor for atrial fibrillation (AF), and AF has a rising prevalence in older adults. How AF may contribute to decline in physical performance in older adults has had limited investigation. We examined the associations of incident AF and 4-year interval declines in physical performance at ages 70, 74, 78, and 82 years in the Health, Aging, and Body Composition (Health ABC) Study. METHODS AND RESULTS: Health ABC is a prospective cohort of community-dwelling older adults (n=3075). The study conducted serial assessments of physical performance with the Health ABC physical performance battery (scored 0-4), grip strength, 2-minute walk distance, and 400-m walking time. Incident AF was identified from the Center for Medicare and Medicaid Services and related to 4-year interval decline in physical performance. After exclusions, the analysis included 2753 Health ABC participants (52% women, 41% black race). Participants with AF had a significantly greater 4-year physical performance battery decline than those without AF at age 70, 74, 78, and 82, with mean estimated decline ranging from -0.08 to -0.10 U (95% confidence interval, -0.18 to -0.01; P<0.05 for all estimates) after multivariable adjustment. Grip strength, walk distance, and walk time similarly showed significantly greater declines at each 4-year age interval in participants with AF. CONCLUSIONS: In community-based cohort older adults, incident AF was associated with increased risk of decline in physical performance. Further research is essential to identify mechanisms and preventive strategies for how AF may contribute toward declining physical performance in older adults.


Assuntos
Envelhecimento , Fibrilação Atrial/fisiopatologia , Composição Corporal , Avaliação da Deficiência , Nível de Saúde , Atividade Motora/fisiologia , Medição de Risco/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/reabilitação , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Prevalência , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia
10.
J Psychiatry Neurosci ; 41(3): 162-8, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26505140

RESUMO

BACKGROUND: Arterial stiffness may contribute to depression via cerebral microvascular damage, but evidence for this is scarce. We therefore investigated whether arterial stiffness is associated with depressive symptoms and whether cerebral small vessel disease contributes to this association. METHODS: This cross-sectional study included a subset of participants from the AGES-Reykjavik study second examination round, which was conducted from 2007 to 2011. Arterial stiffness (carotid-femoral pulse wave velocity [CFPWV]), depressive symptoms (15-item geriatric depression scale [GDS-15]) and cerebral small vessel disease (MRI) were determined. Manifestations of cerebral small vessel disease included higher white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces and lower total brain parenchyma volume. RESULTS: We included 2058 participants (mean age 79.6 yr; 59.0% women) in our analyses. Higher CFPWV was associated with a higher GDS-15 score, after adjustment for potential confounders (ß 0.096, 95% confidence interval [CI] 0.005-0.187). Additional adjustment for white matter hyperintensity volume or subcortical infarcts attenuated the association between CFPWV and the GDS-15 score, which became nonsignificant (p > 0.05). Formal mediation tests showed that the attenuating effects of white matter hyperintensity volume and subcortical infarcts were statistically significant. Virchow-Robin spaces, cerebral microbleeds and cerebral atrophy did not explain the association between CFPWV and depressive symptoms. LIMITATIONS: Our study was limited by its cross-sectional design, which precludes any conclusions about causal mediation. Depressive symptoms were assessed by a self-report questionnaire. CONCLUSION: Greater arterial stiffness is associated with more depressive symptoms; this association is partly accounted for by white matter hyperintensity volume and subcortical infarcts. This study supports the hypothesis that arterial stiffness leads to depression in part via cerebral small vessel disease.


Assuntos
Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Doenças de Pequenos Vasos Cerebrais/psicologia , Depressão/fisiopatologia , Rigidez Vascular , Idoso , Atrofia , Encéfalo/diagnóstico por imagem , Artérias Carótidas/fisiopatologia , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/fisiopatologia , Hemorragia Cerebral/psicologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Estudos Transversais , Depressão/diagnóstico por imagem , Feminino , Artéria Femoral/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Análise de Onda de Pulso , Autorrelato , Substância Branca/diagnóstico por imagem
11.
Am J Clin Nutr ; 102(5): 1266-78, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26354543

RESUMO

BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance. CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).


Assuntos
Hiperglicemia/etiologia , Hiperinsulinismo/etiologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Produtos da Carne/efeitos adversos , Carne/efeitos adversos , Glicemia/análise , Estudos de Coortes , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hiperglicemia/sangue , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperinsulinismo/sangue , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Insulina/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
12.
J Nutr ; 145(10): 2317-24, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26311808

RESUMO

BACKGROUND: Higher intake of polyunsaturated fatty acids (PUFAs) and higher circulating PUFAs are associated with lower cardiovascular disease (CVD) risk. The positive influence of PUFAs might be via lowering arterial stiffness, resulting in a better CVD risk profile; however, studies investigating circulating PUFAs in relation to arterial stiffness in a general population are limited. OBJECTIVE: We investigated the associations of plasma phospholipid n-3 (ω-3) and n-6 PUFAs and fish oil intake with arterial stiffness. METHODS: We used data from a subgroup of the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) Study (n = 501, 75.0 ± 4.96 y, 46% men), a population-based study of community-dwelling older adults. Plasma phospholipid PUFAs were measured by GC at baseline, and fish oil intake was assessed at 3 time points: early life (ages 14-19 y), midlife (ages 40-50 y), and late life (ages 66-96 y, AGES-Reykjavik baseline) with the use of a validated food-frequency questionnaire. Arterial stiffness was determined as carotid-femoral pulse wave velocity (cf-PWV) with the use of an electrocardiogram after a mean follow-up of 5.2 ± 0.3 y. Regression coefficients (95% CIs), adjusted for demographics, follow-up time, risk factors, cholesterol, triglycerides, and serum vitamin D, were calculated by linear regression per SD increment in PUFAs. RESULTS: Plasma total n-3 PUFAs, eicosapentaenoic acid, and docosahexaenoic acid were associated with lower cf-PWV [ß (95% CI): -0.036 (-0.064, -0.008); -0.031 (-0.059, -0.003); -0.036 (-0.064, -0.009), respectively]. In contrast, plasma total n-6 PUFAs and linoleic acid were associated with higher cf-PWV [0.035 (0.009, 0.061) and 0.034 (0.008, 0.059)]. Regular fish oil consumption at early-, mid-, and late-life was not associated with cf-PWV. CONCLUSIONS: Our results show a positive association between plasma n-6 PUFAs and arterial stiffness, and suggest that higher concentrations of plasma long-chain n-3 PUFAs are associated with less arterial stiffness and therein may be one of the mechanisms underlying the association between plasma n-3 PUFAs and lower CVD risk.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Suplementos Nutricionais , Fenômenos Fisiológicos da Nutrição do Idoso , Ácidos Graxos Ômega-3/uso terapêutico , Óleos de Peixe/uso terapêutico , Fosfolipídeos/sangue , Rigidez Vascular , Adolescente , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Estudos de Coortes , Suplementos Nutricionais/efeitos adversos , Ácidos Graxos Ômega-3/efeitos adversos , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/efeitos adversos , Ácidos Graxos Ômega-6/sangue , Ácidos Graxos Ômega-6/uso terapêutico , Feminino , Óleos de Peixe/efeitos adversos , Seguimentos , Humanos , Islândia/epidemiologia , Masculino , Estudos Prospectivos , Análise de Onda de Pulso , Fatores de Risco
13.
Neurology ; 85(11): 976-83, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26291281

RESUMO

OBJECTIVE: We investigated the associations of morning and evening salivary cortisol levels with regional brain volumes and cognitive functioning in community-dwelling older persons without dementia. METHOD: From the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we included 4,244 persons without dementia (age 76 ± 5 years, 58% women) who had 1.5T brain MRI, assessment of cognitive functioning, and saliva collected at home 45 minutes after awakening and at night. Linear regression analysis was used to estimate the cross-sectional relationship among cortisol levels, brain volumes, and cognitive functioning, adjusting for covariates. RESULTS: Higher evening cortisol was associated with smaller total brain volume (highest vs lowest tertile -16.0 mL; 95% confidence interval -19.7 to -12.2 mL, adjusted for age, sex, education, intracranial volume, smoking, steroid use, white matter lesions, and brain infarcts on MRI). The smaller volumes were observed in all brain regions, but were significantly smaller in gray matter than in white matter regions. Poorer cognitive functioning across all domains was also associated with higher evening cortisol. Higher levels of morning cortisol were associated with slightly greater normal white matter volume and better processing speed and executive functioning, but not with gray matter volume or with memory performance. CONCLUSIONS: In older persons, evening and morning cortisol levels may be differentially associated with tissue volume in gray and white matter structures and cognitive function. Understanding these differential associations may aid in developing strategies to reduce the effects of hypothalamic-pituitary-adrenal axis dysfunction on late-life cognitive impairment.


Assuntos
Encéfalo/patologia , Cognição/fisiologia , Hidrocortisona/análise , Saliva/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Transtornos Cognitivos/fisiopatologia , Estudos Transversais , Demência/patologia , Feminino , Humanos , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Sistema Hipófise-Suprarrenal/patologia , Saliva/química
15.
J Gerontol A Biol Sci Med Sci ; 70(8): 1030-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25748031

RESUMO

BACKGROUND: Aging is associated with increased risk of reduced mobility. However, data on muscle components in relation to subjective and objective indicators of disability is limited. METHODS: Data were from 2,725 participants (43% men) aged 74.8±4.7 years from the AGES-Reykjavik Study. At baseline, maximal isometric thigh strength (dynamometer chair), and midthigh muscle area and muscle fat infiltration were assessed with computed tomography. Usual 6 m gait speed and mobility disability were assessed at baseline and after 5.2±0.3 years. Incident mobility disability was defined as having much difficulty or unable to walk 500 m or climb-up 10 steps. A decrease of ≥0.1 m/s in gait speed was considered clinically relevant. RESULTS: Greater strength and area were protective for mobility disability risk and gait speed decline. After adjustment for other muscle components, greater strength was independently associated with lower mobility disability risk in women odds ratios (OR) 0.78 (95% CI 0.62, 0.99), and lower decline in gait speed risk among both men OR 0.64 (0.54, 0.76), and women OR 0.72 (0.62, 0.82). Larger muscle area was independently associated with lower mobility disability risk in women OR 0.67 (0.52, 0.87) and lower decline in gait speed risk in men OR 0.74 (0.61, 0.91). CONCLUSIONS: Greater muscle strength and area were independently associated with 15-30% decreased risk of mobility disability in women and gait speed decline in men. Among women, greater muscle strength was also associated with lower risk of gait speed decline. Interventions aimed at maintaining muscle strength and area in old age might delay functional decline.


Assuntos
Tecido Adiposo/metabolismo , Envelhecimento/fisiologia , Marcha/fisiologia , Limitação da Mobilidade , Força Muscular , Músculo Esquelético/metabolismo , Idoso , Feminino , Interação Gene-Ambiente , Humanos , Masculino
16.
Am J Clin Nutr ; 101(5): 947-55, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25787995

RESUMO

BACKGROUND: Polyunsaturated fatty acids (PUFAs) may play a role in fracture, but studies have been largely confined to estimates of dietary intake. OBJECTIVE: We aimed to examine associations between fatty acids measured in late life and fish-oil consumption in early life, midlife, and late life with osteoporotic fracture risk. DESIGN: Osteoporotic fractures were determined from medical records over 5-9 y of follow-up in men and women aged 66-96 y. Data were analyzed from 1438 participants including 898 participants who were randomly selected from the Age, Gene/Environment Susceptibility Study, which is an observational study, and 540 participants with incident fracture. Plasma phospholipid fatty acids were assessed by using gas chromatography. Fish-oil consumption was assessed by using validated questionnaires as never (referent), less than daily, or daily. HRs and 95% CIs adjusted for age, education, height, weight, diabetes, physical activity, and medications were estimated by using Cox regression. RESULTS: In men, the highest tertile of PUFAs, n-3 (ω-3), and eicosapentaenoic acid were associated with decreased fracture risk [HRs (95% CIs): 0.60 (95% CI: 0.41, 0.89), 0.66 (0.45, 0.95), and 0.59 (0.41, 0.86), respectively]. In women, PUFAs tended to be inversely associated with fracture risk (P-trend = 0.06), but tertiles 2 and 3 were not independently associated with risk. Tertile 2 of n-6 and arachidonic acid was associated with fracture risk in women [HRs (95% CIs): 1.43 (1.10, 1.85) and 1.42 (1.09, 1.85), respectively]. Daily fish-oil consumption in late life was associated with lower fracture risk in men (HR: 0.64; 95% CI: 0.45, 0.91). Daily fish-oil consumption in midlife was associated with lower fracture risk in women (HR: 0.75; 95% CI: 0.58, 0.98). CONCLUSIONS: Greater PUFA concentrations may be associated with lower osteoporotic fracture risk in older adults, particularly in men. Critical time periods for n-3 fatty acid consumption may differ by sex.


Assuntos
Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Óleos de Peixe/administração & dosagem , Fraturas por Osteoporose/sangue , Fosfolipídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Ácido Araquidônico/sangue , Ácido Eicosapentaenoico/sangue , Feminino , Seguimentos , Humanos , Masculino , Fraturas por Osteoporose/prevenção & controle , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários
17.
Nat Commun ; 6: 5897, 2015 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-25631608

RESUMO

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (ß=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (ß=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (ß=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (ß=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Exoma/genética , Jejum/sangue , Predisposição Genética para Doença , Variação Genética , Taxa de Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Grupo com Ancestrais do Continente Africano/genética , Diabetes Mellitus Tipo 2/sangue , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Loci Gênicos , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Glucose-6-Fosfatase/genética , Humanos , Insulina/sangue , Polimorfismo de Nucleotídeo Único/genética
18.
J Gerontol A Biol Sci Med Sci ; 70(1): 110-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25199915

RESUMO

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies. METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity. RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)). CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.


Assuntos
Apolipoproteínas E/genética , Fatores de Transcrição Forkhead/genética , Longevidade/genética , Idoso , Idoso de 80 Anos ou mais , Moléculas de Adesão Celular/genética , Estudos de Coortes , Feminino , Proteína Forkhead Box O3 , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Ácido Caínico/genética
19.
Mol Psychiatry ; 20(5): 647-656, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25288136

RESUMO

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.


Assuntos
Coffea/metabolismo , Comportamento Alimentar , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Citocromo P-450 CYP1A2/genética , Humanos , Fenótipo
20.
Diabetes Care ; 37(12): 3213-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25315206

RESUMO

OBJECTIVE: Studies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality. RESEARCH DESIGN AND METHODS: The AGES-Reykjavik cohort comprised participants aged 66-96 years with diabetes defined by fasting glucose, medications, or self-report. BMI was determined from measured height and weight and classified as normal (18.5-24.9 kg/m(2), n = 117), overweight (25.0-29.9 kg/m(2), n = 293, referent group) or obese (≥30.0 kg/m(2), n = 227). Thigh muscle area and intermuscular, visceral, and subcutaneous adipose tissues were assessed with computed tomography. Function was assessed from gait speed and knee extensor strength. Hazard ratios (HRs) and 95% CIs were estimated by Cox proportional hazards regression adjusted for demographics and diabetes-related risk factors. RESULTS: The median follow-up was 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12-2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87-2.11]) and gait speed (HR 1.44 [95% CI 0.91-2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality. CONCLUSIONS: Normal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size.


Assuntos
Composição Corporal , Peso Corporal/fisiologia , Diabetes Mellitus Tipo 2/mortalidade , Atividade Motora , Tecido Adiposo/patologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Músculo Esquelético/patologia , Obesidade/complicações , Obesidade/metabolismo , Obesidade/mortalidade , Sobrepeso/complicações , Sobrepeso/metabolismo , Sobrepeso/mortalidade , Fatores de Risco
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