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1.
J Dev Orig Health Dis ; : 1-9, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31474237

RESUMO

BACKGROUND: Evidence suggests that low birth weight and fetal exposure to extreme maternal undernutrition is associated with cardiovascular disease in adulthood. Hyperemesis gravidarum, a clinical entity characterized by severe nausea and excess vomiting leading to a suboptimal maternal nutritional status during early pregnancy, is associated with an increased risk of adverse pregnancy outcomes. Several studies also showed that different measures related to hyperemesis gravidarum, such as maternal daily vomiting or severe weight loss, are associated with increased risks of adverse fetal pregnancy outcomes. Not much is known about long-term offspring consequences of maternal hyperemesis gravidarum and related measures during pregnancy. We examined the associations of maternal daily vomiting during early pregnancy, as a measure related to hyperemesis gravidarum, with childhood cardiovascular risk factors. METHODS: In a population-based prospective cohort study from early pregnancy onwards among 4,769 mothers and their children in Rotterdam, the Netherlands, we measured childhood body mass index, total fat mass percentage, android/gynoid fat mass ratio, preperitoneal fat mass area, blood pressure, lipids, and insulin levels. We used multiple regression analyses to assess the associations of maternal vomiting during early pregnancy with childhood cardiovascular outcomes. RESULTS: Compared with the children of mothers without daily vomiting during early pregnancy, the children of mothers with daily vomiting during early pregnancy had a higher childhood total body fat mass (difference 0.12 standard deviation score [SDS]; 95% confidence interval [CI] 0.03-0.20), android/gynoid fat mass ratio (difference 0.13 SDS; 95% CI 0.04-0.23), and preperitoneal fat mass area (difference 0.10 SDS; 95% CI 0-0.20). These associations were not explained by birth characteristics but partly explained by higher infant growth. Maternal daily vomiting during early pregnancy was not associated with childhood blood pressure, lipids, and insulin levels. CONCLUSIONS: Maternal daily vomiting during early pregnancy is associated with higher childhood total body fat mass and abdominal fat mass levels, but not with other cardiovascular risk factors. Further studies are needed to replicate these findings, to explore the underlying mechanisms and to assess the long-term consequences.

2.
JAMA Netw Open ; 2(9): e1910915, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31539074

RESUMO

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (ß = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

4.
Eur J Epidemiol ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31372866

RESUMO

To investigate the major causes and predictive factors of death in a middle-aged and elderly Chinese population. A total of 6591 residents aged ≥ 45 years from Shanghai Changfeng community were followed up for an average of 5.4 years. The causes of death were coded according to the 10th Revision of International Classification of Diseases. The mortality rate was calculated by person-years of follow up and age-standardized according to the 2010 Chinese census data. Multivariable-adjusted Cox proportional hazards model was performed to investigate the predictors of all-cause and cause-specific mortality. During the total follow-up of 35,739 person-years, 370 deaths were documented (157 from malignant neoplasms, 70 from heart diseases, 68 from cerebrovascular diseases, 75 from other causes). The age-standardized all-cause mortality rate was 798.2 per 100,000 person-years (927.9 among men and 716.7 among women). Results from multivariable analyses showed that aging, diabetes, and osteoporosis at baseline were independent predictors of all-cause mortality, with hazard ratios (HR) of 1.11 (95% CI 1.10-1.13), 1.91 (1.51-2.42), and 1.71 (1.24-2.35), respectively. The population attributable risk percent of diabetes and osteoporosis was 19.7% and 11.7%, respectively. Cigarette smoking was associated with a higher risk of all-cause mortality in men (HR and 95%CI 1.44, 1.01-2.06). In women, diabetes and osteoporosis were related to a higher risk of cardiovascular mortality (3.27, 1.82-5.88 and 1.89, 1.04-3.46, respectively). While in men, osteoporosis was related to a higher risk of malignant neoplasms mortality (2.39, 1.07-5.33). Malignant neoplasms, heart diseases, and cerebrovascular diseases are the leading causes of death. Aging, smoking, underweight, diabetes, and osteoporosis are independent predictors of premature death among middle-aged and elderly Chinese community population. Moreover, there may have been some differences in the causes and predictors of premature death between men and women.

5.
Eur Heart J ; 40(34): 2883-2896, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31102408

RESUMO

AIMS: To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD). METHODS AND RESULTS: We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10-14 to 1.0 × 10-6 (discovery) and P = 5.6 × 10-10 to 1.1 × 10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05). CONCLUSION: Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis.

6.
Eur J Epidemiol ; 34(8): 793-799, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30993509

RESUMO

Chronological age alone is not a sufficient measure of the true physiological state of the body. The aims of the present study were to: (1) quantify biological age based on a physiological biomarker composite model; (2) and evaluate its association with death and age-related disease onset in the setting of an elderly population. Using structural equation modeling we computed biological age for 1699 individuals recruited from the first and second waves of the Rotterdam study. The algorithm included nine physiological parameters (c-reactive protein, creatinine, albumin, total cholesterol, cytomegalovirus optical density, urea nitrogen, alkaline phosphatase, forced expiratory volume and systolic blood pressure). We assessed the association between biological age, all-cause mortality, all-cause morbidity and specific age-related diseases over a median follow-up of 11 years. Biological age, compared to chronological age or the traditional biomarkers of age-related diseases, showed a stronger association with all-cause mortality (HR 1.15 vs. 1.13 and 1.10), all-cause morbidity (HR 1.06 vs. 1.05 and 1.03), stroke (HR 1.17 vs. 1.08 and 1.04), cancer (HR 1.07 vs. 1.04 and 1.02) and diabetes mellitus (HR 1.12 vs. 1.01 and 0.98). Individuals who were biologically younger exhibited a healthier life-style as reflected in their lower BMI (P < 0.001) and lower incidence of stroke (P < 0.001), cancer (P < 0.01) and diabetes mellitus (P = 0.02). Collectively, our findings suggest that biological age based on the biomarker composite model of nine physiological parameters is a useful construct to assess individuals 65 years and older at increased risk for specific age-related diseases.


Assuntos
Envelhecimento/fisiologia , Biomarcadores/sangue , Adulto , Idade de Início , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/mortalidade , Causas de Morte , Creatinina , Diabetes Mellitus/mortalidade , Feminino , Humanos , Longevidade , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Morbidade , Mortalidade , Estudos Prospectivos
7.
BMC Med ; 17(1): 63, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30871536

RESUMO

BACKGROUND: Whether cognitive decline is related to a higher risk of death independent of the initial cognitive function is inconclusive. Evidence of the association between cognitive decline and mortality among Chinese older people is limited. We aimed to examine whether cognitive decline, assessed by the rate of decrease in the Mini-Mental State Examination (MMSE) score, was associated with mortality independent of initial cognitive function (baseline MMSE score) among Chinese older people. METHODS: We established two successive and non-overlapping cohorts of older adults nested within the Chinese Longitudinal Healthy Longevity Survey (CLHLS), an ongoing, open, community-based cohort survey conducted every 2-3 years. Cognitive function was measured using the Chinese version of the MMSE. A total of 11,732 older adults who completed two consecutive cognitive function examinations were included and followed for 3 years. A Cox proportional hazards model was used to examine the association of cognitive decline with mortality after adjusting for sociodemographic characteristics, health behaviours, comorbidities and initial cognitive function. RESULTS: The mean age was 82.5 years old, and 44.9% (5264/11732) of participants were men. After adjusting for baseline MMSE scores and other covariates, the rate of change in MMSE scores over 3 years was monotonically and positively associated with subsequent 3-year mortality. Compared to those with stable cognitive function, participants with rapid cognitive decline (decline faster than average, a reduction of MMSE scores > 1.62 points/year) had a 75% higher risk of death (hazard ratio = 1.75, 95% confidence interval 1.57-1.95). The association between cognitive decline and mortality was stronger among relatively younger Chinese older people (aged 65-79 years versus 80 years and over) and those with normal cognitive function at baseline (MMSE scores ≥ 24 versus < 24 points), respectively, but did not differ by cohort and sex. CONCLUSION: Faster cognitive decline was associated with higher mortality independent of initial cognitive function, especially among those aged 65-79 years and those with normal cognitive function at baseline. The association was consistent across two successive cohorts. Our findings indicate the practical significance of monitoring cognitive change in older adults.

8.
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.

9.
PLoS Med ; 16(2): e1002741, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30716101

RESUMO

BACKGROUND: Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk factors on this risk. METHODS AND FINDINGS: Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%-95.1%) for men and 92.8% (95% CI 91.8%-93.8%) for women. These risks remained high (>90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3-11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2-6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent. CONCLUSIONS: Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs.


Assuntos
Expectativa de Vida/tendências , Multimorbidade/tendências , Doenças não Transmissíveis/epidemiologia , Vigilância da População , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Doenças não Transmissíveis/terapia , Vigilância da População/métodos , Estudos Prospectivos , Fatores de Risco
10.
Neuroimage ; 189: 432-444, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30659958

RESUMO

Structural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are gaining interest as potentially more subtle markers of neurodegeneration. However, brain structure and function are also affected by 'normal' brain ageing. More information is needed on how functional connectivity relates to aging, particularly in the absence of overt neurodegenerative disease. We investigated the association of age with resting-state functional connectivity in 2878 non-demented persons between 50 and 95 years of age (54.1% women) from the population-based Rotterdam Study. We obtained nine well-known resting state networks using data-driven methodology. Within the anterior default mode network, ventral attention network, and sensorimotor network, functional connectivity was significantly lower with older age. In contrast, functional connectivity was higher with older age within the visual network. Between resting state networks, we found patterns of both increases and decreases in connectivity in approximate equal proportions. Our results reinforce the notion that the aging brain undergoes a reorganization process, and serves as a solid basis for exploring functional connectivity as a preclinical marker of neurodegenerative disease.

11.
Nat Genet ; 51(2): 245-257, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643258

RESUMO

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.


Assuntos
Comportamento/fisiologia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudos de Casos e Controles , Feminino , Genética Comportamental/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
12.
Behav Sleep Med ; 17(1): 31-40, 2019 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28107032

RESUMO

OBJECTIVE/BACKGROUND: About 15% of grievers experience complicated grief. We determined cross-sectional and longitudinal relations of grief and complicated grief with sleep duration and quality in the general population of elderly adults. PARTICIPANTS: We included 5,421 men and women from the prospective population-based Rotterdam Study. METHODS: The Inventory of Complicated Grief was used to define grief and complicated grief. We assessed sleep with the Pittsburgh Sleep Quality Index. RESULTS: After 6 years, 3,511 (80% of survivors) underwent the follow-up interview. Complicated grief was cross-sectionally associated with shorter sleep duration and lower sleep quality. These associations were explained by the presence of depressive symptoms. The prospective analyses showed that sleep duration and sleep quality did not decline further during follow-up of persons who experienced grief or complicated grief. CONCLUSION: In community-dwelling, middle-aged and older adults, persons with normal and complicated grief had both a shorter sleep duration and a lower sleep quality, mainly explained by depressive symptoms. However, prospective analyses showed that sleep quality and sleep duration do not decline further in persons with normal grief and complicated grief.


Assuntos
Depressão/complicações , Pesar , Transtornos do Sono-Vigília/etiologia , Idoso , Estudos Transversais , Depressão/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Transtornos do Sono-Vigília/patologia
13.
Circulation ; 139(5): 620-635, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30586737

RESUMO

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. RESULTS: We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

14.
Nat Commun ; 9(1): 5141, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510157

RESUMO

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

15.
Eur J Epidemiol ; 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30519805
16.
J Diabetes ; 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30520249

RESUMO

BACKGROUND: Metabolic syndrome (MetS) and its components share genetic basis with type 2 diabetes (T2D). However, whether MetS and its components play a role in mediating the T2D genetic susceptibility is not completely understood. METHODS: We assessed the mediation effects of MetS and its components on the genetic susceptibility for 18 GWAS-identified T2D-associated variants using a two-stage strategy based on parametric models involving 7110 Chinese participants (of which, 2,436 T2D patients) across 2,885 families. For all the analyses, both an unweighted genetic risk score and individual variant were fitted. Multilevel logistic regression was used to account for the intra-familial correlation. RESULTS: We found that MetS significantly mediated the effect of MTNR1B polymorphism on T2D risk (OR of average causal mediation effect [ORACME ]: 1.004; 95% CI: 1.001-1.008; p-value: 0.018). In addition, low level of high-density lipoprotein cholesterol (HDL-c) mediated the genetic effects of MTNR1B (1.012; 1.007-1.015; <0.001), SLC30A8 (1.001; 1.000-1.007; 0.040), BCL11A (1.009; 1.007-1.016; <0.001), PROX1 (1.005; 1.003-1.011; <0.001) and ADAMTS9 (1.006; 1.001-1.009; 0.022), whereas increased fasting blood glucose (FBG) significantly mediated the genetic effect of BCL11A (1.017; 1.003-1.021, 0.012). CONCLUSIONS: Our findings provide evidence on that MetS and its two components (HDL-c, and FBG), might be involved in mediating the genetic predisposition to T2D. Our results emphasize the importance of maintaining normal HDL-c and FBG levels in the prevention of T2D. This article is protected by copyright. All rights reserved.

18.
Am J Ophthalmol ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30312575

RESUMO

PURPOSE: What patients should eat to reduce their risk of age-related macular degeneration (AMD) is still unclear. We investigated the effect of a diet recommended by Health Councils on AMD. DESIGN: Prospective population-based cohort study. METHODS: 4202 participants from the Rotterdam Study aged 55+ years, free of AMD at baseline, were included and followed up for 9.1±5.8 years. Incident AMD was graded on fundus photographs. Dietary data were collected using a validated 170-item food frequency questionnaire, and food intakes were categorized into food patterns based on guidelines from Health Councils. Associations with incident AMD were analyzed using Cox-proportional hazards models, and adjusted for age, sex, total energy intake, smoking, body mass index, hypertension, education, and income. RESULTS: A total of 754 persons developed incident AMD. Intake of the recommended amounts of vegetables (≥200gr/day), fruit (2x/day), and fish (2x/week) was 30.6%, 54.9% and 12.5%, respectively. In particular the intake of fish (2x/week) decreased the risk of incident AMD; hazard ratio (HR) 0.76 [95% Confidence Interval (CI) 0.60-0.97]). Intake of the recommended amounts of all three food groups was only 3.7%, but adherence to this pattern showed a further reduction of the risk of incident AMD (HR 0.58 [95%CI 0.36-0.93]). Younger age, higher income, and nonsmoking were associated with this food pattern, but risk lowering effects remained significant after additional adjustment for these factors. CONCLUSION: A diet of 200 grams of vegetables/day, 2x fruit/day, and 2x fish/week is associated with a significantly reduced risk of AMD.

19.
Am J Epidemiol ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30299452

RESUMO

Reliable population estimates of life-expectancy with dementia are required for shaping health care policy. 10,348 persons from the population-based Rotterdam Study were followed from 1990-2015 for dementia and death. We created multi-state lifetables, and assessed the effect of postponing disease onset. During 120,673 person-years, 1,666 persons developed dementia, and 6,150 died. Overall life-expectancy of women ranged from 18.0 years (95% confidence interval:17.8-18.2) at age 65 to 2.3 years (2.2-2.3) at age 95. Of total life-expectancy at age 65, 5.7%, i.e. 1.0 year (1.0-1.1), was lived with dementia, increasing with age to 42.1% (1.0 year,0.9-1.0) of life-expectancy at age 95. For men, overall life-expectancy ranged from 15.6 years (15.4-15.9) at age 65 to 1.8 years (1.7-1.8) at age 95, of which 3.7% (0.6 year,0.5-0.6) and 35.3% (0.6 year,0.5-0.7) was lived with dementia, respectively. Postponing dementia onset by 1-3 years resulted in 25-57% reductions in years lived with dementia. Survival after dementia diagnosis ranged from 6.7 (95%CI 5.3-8.1) years when diagnosed before age 70, to 2.6 years (2.3-2.9) >90 years. Dementia places a large burden on individuals and society in terms of healthy life-years lost, but this is potentially highly amendable by preventive interventions at the population level.

20.
Eur Heart J ; 39(44): 3961-3969, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30169657

RESUMO

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

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