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1.
Nat Commun ; 10(1): 3669, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413261

RESUMO

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

2.
Horm Behav ; 114: 104540, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202819

RESUMO

Parenting qualities are known to transmit across generations, but less is known about genetic processes that may modify how strongly parenting quality carries across generations. We examined in prospective data whether oxytocinergic genes of offspring moderate the intergenerational transmission of warm and accepting parent-child relationship qualities. The sample comprised 1167 Finnish parents (G2, 62% female) and their mothers (G1). At the study baseline, G1 mothers (Mage = 38) reported parent-child relationship qualities towards G2 children (age range 3-18). After 28-34 years, G2 offspring reported parent-child relationship qualities towards their own children using the same questionnaire. A cumulative genetic score was computed for G2 by summing up previously identified four alleles associated with non-optimal parenting or social impairments across OXTR (rs1042778, rs2254298, rs53576) and CD38 (rs3796863) genes. Results indicated no interaction effects of G2 cumulative genetic score on the transmission of parent-child relationship qualities. Among single polymorphisms in OXTR, the interaction effects of rs53576 and rs1042778 were found. G1 maternal emotional warmth was associated with higher G2 emotional warmth among G2 participants with the OXTR rs53576 AA/AG genotype, but not among those with the GG genotype. G1 maternal acceptance was associated with higher G2 acceptance among those G2 participants with the OXTR rs1042778 GG/GT genotype, but not among those with the TT genotype. Oxytocinergic genes may influence sensitivity to quality of parent-child relationship, although this needs replication in future studies.

3.
Sci Rep ; 9(1): 8887, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222113

RESUMO

We analyzed the associations between whole blood microRNA profiles and the indices of glucose metabolism and impaired fasting glucose and examined whether the discovered microRNAs correlate with the expression of their mRNA targets. MicroRNA and gene expression profiling were performed for the Young Finns Study participants (n = 871). Glucose, insulin, and glycated hemoglobin (HbA1c) levels were measured, the insulin resistance index (HOMA2-IR) was calculated, and the glycemic status (normoglycemic [n = 534]/impaired fasting glucose [IFG] [n = 252]/type 2 diabetes [T2D] [n = 24]) determined. Levels of hsa-miR-144-5p, -122-5p, -148a-3p, -589-5p, and hsa-let-7a-5p associated with glycemic status. hsa-miR-144-5p and -148a-3p associated with glucose levels, while hsa-miR-144-5p, -122-5p, -184, and -339-3p associated with insulin levels and HOMA2-IR, and hsa-miR-148a-3p, -15b-3p, -93-3p, -146b-5p, -221-3p, -18a-3p, -642a-5p, and -181-2-3p associated with HbA1c levels. The targets of hsa-miR-146b-5p that correlated with its levels were enriched in inflammatory pathways, and the targets of hsa-miR-221-3p were enriched in insulin signaling and T2D pathways. These pathways showed indications of co-regulation by HbA1c-associated miRNAs. There were significant differences in the microRNA profiles associated with glucose, insulin, or HOMA-IR compared to those associated with HbA1c. The HbA1c-associated miRNAs also correlated with the expression of target mRNAs in pathways important to the development of T2D.

4.
Elife ; 82019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30834892

RESUMO

Correlation among traits is a fundamental feature of biological systems that remains difficult to study. To address this problem, we developed a flexible approach that allows us to identify factors associated with inter-individual variation in correlation. We use data from three human cohorts to study the effects of genetic and environmental variation on correlations among mRNA transcripts and among NMR metabolites. We first show that environmental exposures (infection and disease) lead to a systematic loss of correlation, which we define as 'decoherence'. Using longitudinal data, we show that decoherent metabolites are better predictors of whether someone will develop metabolic syndrome than metabolites commonly used as biomarkers of this disease. Finally, we demonstrate that correlation itself is under genetic control by mapping hundreds of 'correlation quantitative trait loci (QTLs)'. Together, this work furthers our understanding of how and why coordinated biological processes break down, and points to a potential role for decoherence in disease. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

5.
Hum Mol Genet ; 28(8): 1381-1391, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30629177

RESUMO

The effect of mitochondrial DNA (mtDNA) variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mtDNA may also have a role in the development of type 2 diabetes and its precursor state, i.e. prediabetes. We examined the associations between mitochondrial single-nucleotide polymorphisms (mtSNPs) and peripheral blood transcriptomics with a focus on sex- and prediabetes-specific effects. The genome-wide blood cell expression data of 19 637 probes, 199 deep-sequenced mtSNPs and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis. Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects. This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control.


Assuntos
DNA Mitocondrial/genética , Regulação da Expressão Gênica/genética , Adulto , Sequência de Bases , Células Sanguíneas/metabolismo , Células Sanguíneas/fisiologia , DNA Mitocondrial/sangue , Diabetes Mellitus Tipo 2/genética , Feminino , Expressão Gênica , Estudos de Associação Genética/métodos , Variação Genética/genética , Genética Populacional/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Transcriptoma/genética
6.
Artigo em Inglês | MEDLINE | ID: mdl-30357825

RESUMO

BACKGROUND: Genomic analysis of the child might offer new potential to illuminate human parenting. We examined whether offspring (G2) genome-wide genotype variation (SNPs) is associated with their mother's (G1) emotional warmth and intolerance, indicating a gene-environment correlation. If this association is stronger than between G2's genes and their emotional warmth and intolerance toward their own children, then this would indicate the presence of an evocative gene-environment correlation. To further understand how G1 mother's parenting has been evoked by genetically influenced characteristics of the child (G2), we examined whether child (G2) temperament partially accounted for the association between offspring genes and parental responses. METHODS: Participants were from the Young Finns Study. G1 mothers (N = 2,349; mean age 39 years) self-reported the emotional warmth and intolerance toward G2 in 1980 when the participants were from 3 to 18 years old. G2 participants answered the same parenting scales in 2007/2012 (N = 1,378; mean age = 38 years in 2007; 59% female) when their children were on average 11 years old. Offspring temperament traits were self-reported in 1992 (G2 age range 15-30 years). Estimation of the phenotypic variance explained by the SNPs of G2 was done by genome-wide complex trait analysis with restricted maximum likelihood (GCTA-GREML). RESULTS: Results showed that the SNPs of a child (G2) explained 22.6% of the phenotypic variance of maternal intolerance (G1; p-value = .039). G2 temperament trait negative emotionality explained only 2.4% points of this association. G2 genes did not explain G1 emotional warmth or G2's own emotional warmth and intolerance. However, further analyses of a combined measure of both G1 parenting scales found genetic effects. Parent or child gender did not moderate the observed associations. CONCLUSIONS: Presented genome-wide evidence is pointing to the important role a child plays in affecting and shaping his/her family environment, though the underlying mechanisms remain unclear.

7.
Mol Psychiatry ; 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279457

RESUMO

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37-53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.

8.
Mol Psychiatry ; 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30283034

RESUMO

Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.

9.
Health Econ ; 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30240095

RESUMO

This paper contributes to the literature on the labor market consequences of obesity by using a novel instrument: genetic risk score, which reflects the predisposition to higher body mass index (BMI) across many genetic loci. We estimate instrumental variable models of the effect of BMI on labor market outcomes using Finnish data that have many strengths, for example, BMI that is measured rather than self-reported, and data on earnings and social income transfers that are from administrative tax records and are thus free of the problems associated with nonresponse, reporting error or top coding. The empirical results are sensitive to whether we use a narrower or broader genetic risk score, and to model specification. For example, models using the narrower genetic risk score as an instrument imply that a one-unit increase in BMI is associated with 6.9% lower wages, 1.8% fewer years employed, and a 3 percentage point higher probability of receiving any social income transfers. However, when we use a newer, broader genetic risk score, we cannot reject the null hypothesis of no effect. Future research using genetic risk scores should examine the sensitivity of their results to the risk score used.

10.
Sci Rep ; 8(1): 10358, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985430

RESUMO

Fatty liver (FL) disease is the most common type of chronic liver disease. We hypothesized that liver's response to the process where large droplets of triglyceride fat accumulate in liver cells is reflected also in gene pathway expression in blood. Peripheral blood genome wide gene expression analysis and ultrasonic imaging of liver were performed for 1,650 participants (316 individuals with FL and 1,334 controls) of the Young Finns Study. Gene set enrichment analysis (GSEA) was performed for the expression data. Fourteen gene sets were upregulated (false discovery rate, FDR < 0.05) in subjects with FL. These pathways related to extracellular matrix (ECM) turnover, immune response regulation, prothrombotic state and neural tissues. After adjustment for known risk factors and biomarkers of FL, we found i) integrin A4B1 signaling, ii) leukocyte transendothelial migration, iii) CD40/CD40L and iv) netrin-1 signaling pathways to be upregulated in individuals with FL (nominal p < 0.05). From these all but not ii) remained significantly upregulated when analyzing only subjects without history of heavy alcohol use. In conclusion, FL was associated with blood gene sets of ECM turnover, inflammatory response, immune system activation and prothrombotic state. These may form a systemic link between FL and the development of cardiovascular diseases.

11.
Hum Mol Genet ; 27(17): 3113-3127, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931343

RESUMO

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

12.
J Affect Disord ; 235: 480-488, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29680729

RESUMO

BACKGROUND: Lack of social support is an established risk factor across health outcomes, making it important to examine its family environmental and genetic determinants. METHODS: In a 27-year follow-up of the Young Finns Study (N = 2341), we examined with a latent growth curve model whether genes involved in the oxytocin signaling pathway-namely, oxytocin receptor gene (OXTR) variants rs1042778, rs2254298, and rs53576-moderate the effect of early-life social experiences on perceived social support across the life span. Mothers reported the emotional warmth and acceptance towards their children at baseline when the participants were from 3 to 18 years old (1980). Perceived family support and support from friends and peripheral sources were assessed in five follow-ups 18 years apart (1989-2007). RESULTS: Maternal emotional warmth and acceptance predicted the initial level of perceived social support across subscales, while the rate of change in family support was affected by the family environment only if participants carried the T-allele of OXTR rs1042778. This gene-environment interaction was not found for the rate of change in support from friends and peripheral sources and we also did not find associations between latent growth in perceived social support and OXTR variants rs53576 and rs2254298. LIMITATIONS: Selective attrition in perceived social support, maternal emotional warmth and acceptance, gender, and SES. Family environment was assessed by a non-standardized measure. CONCLUSIONS: OXTR rs1042778 polymorphism seems to contribute to changes in perceived family support in that way that some individuals (T-allele carriers) 'recover', to some extent, from the effects of early-life social experiences, whereas others (G/G genotype carriers) do not.

13.
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.

14.
Diabetologia ; 61(2): 317-330, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29098321

RESUMO

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (ß ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10-3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the ß-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses' Health Study).


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Bebidas , Glicemia/metabolismo , Jejum/sangue , Fatores de Crescimento de Fibroblastos/genética , Insulina/sangue , Edulcorantes , Feminino , Humanos , Masculino
15.
World J Surg ; 42(4): 1200-1207, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29026969

RESUMO

BACKGROUND: Individuals treated for abdominal aortic aneurysms (AAAs) are high-risk patients in whom better risk prediction could improve survival. Contemporary serum lipid parameters, such as apolipoproteins and lipoprotein subfractions, may improve or complement the prognostic value of traditional serum lipids. The aim of this study was to ascertain the extended serum lipid profiles, long-term prognosis and their association in AAA patients. METHODS: Altogether 498 patients treated for AAAs and with available serum lipid values were retrospectively analysed. Contemporary lipid parameters were estimated using a neural network model, the extended Friedewald formula. RESULTS: Younger age, smoking and urgent or emergency surgery were associated with an unfavourable, and coronary disease and previous stroke with a favourable lipid profile. In multivariable analysis-in addition to advanced age, aneurysm rupture, smoking, pulmonary disease and diabetes-high triglycerides and traditional LDL cholesterol were significant independent risk factors for mortality, HR 1.84 (95% CI 1.20-2.81) and 1.79 (95% CI 1.18-2.73), respectively, while higher EFW-IDL cholesterol was associated with better survival, HR 0.31 (95% CI 0.19-0.65). Including serum lipid parameters improved the prediction of 5-year survival (NRI = 17.7%, p = 0.016). CONCLUSIONS: Extended serum lipid parameters complement risk prediction of patients treated for AAAs. An unfavourable lipid profile is associated with treatment of AAA earlier in life and with inferior long-term survival.


Assuntos
Aneurisma da Aorta Abdominal/mortalidade , Aneurisma da Aorta Abdominal/cirurgia , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Idoso , Aneurisma da Aorta Abdominal/sangue , Colesterol/sangue , Doença da Artéria Coronariana/complicações , Feminino , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
16.
Nat Commun ; 8(1): 910, 2017 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-29030599

RESUMO

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.


Assuntos
Cadeias alfa de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Estilo de Vida , Lipoproteína(a)/genética , Longevidade/genética , Alelos , Índice de Massa Corporal , Doença das Coronárias/sangue , Doença das Coronárias/etiologia , Educação , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Resistência à Insulina/genética , Lipoproteínas HDL/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Obesidade/complicações , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Fatores Socioeconômicos
17.
Diabetes Care ; 40(10): 1386-1393, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28877915

RESUMO

OBJECTIVE: The human vitamin E-binding glycoprotein afamin is primarily expressed in the liver and has been associated with prevalent and incident metabolic syndrome. These data were in line with observations in transgenic mice. We thus investigated whether afamin concentrations are associated with prediabetes, type 2 diabetes, and insulin resistance (IR). RESEARCH DESIGN AND METHODS: Individual-level baseline (n = 20,136) and follow-up data (n = 14,017) of eight prospective cohort studies were investigated. Study-level data were combined using random-effects meta-analyses. Main outcomes were prevalent and incident type 2 diabetes, prediabetes, and IR. Discrimination and reclassification of participants was analyzed for incident type 2 diabetes. RESULTS: Mean afamin concentrations between studies ranged from 61 to 73 mg/L. The eight studies included 1,398 prevalent and 585 incident cases of type 2 diabetes. Each increase of afamin by 10 mg/L was associated with prevalent type 2 diabetes (odds ratio [OR] 1.19 [95% CI 1.12-1.26], P = 5.96 × 10-8). Afamin was positively associated with IR assessed by HOMA-IR (ß 0.110 [95% CI 0.089-0.132], P = 1.37 × 10-23). Most importantly, afamin measured at baseline was an independent predictor for 585 incident cases of type 2 diabetes (OR 1.30 [95% CI 1.23-1.38], P = 3.53 × 10-19) and showed a significant and valuable gain in risk classification accuracy when added to this extended adjustment model. CONCLUSIONS: This pooled analysis in >20,000 individuals showed that afamin is strongly associated with IR, prevalence, and incidence of type 2 diabetes independent of major metabolic risk factors or parameters. Afamin might be a promising novel marker for the identification of individuals at high risk for the development of type 2 diabetes.


Assuntos
Proteínas de Transporte/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Glicoproteínas/sangue , Síndrome Metabólica/epidemiologia , Estado Pré-Diabético/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Índice de Massa Corporal , Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Feminino , Seguimentos , Hemoglobina A Glicada/metabolismo , Humanos , Incidência , Resistência à Insulina , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Prevalência , Estudos Prospectivos , Fatores de Risco , Albumina Sérica Humana , Triglicerídeos/sangue
18.
Sci Rep ; 7(1): 12127, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28935963

RESUMO

Ascending thoracic aortic aneurysm (ATAA) is a multifactorial disease with a strong inflammatory component. Surgery is often required to prevent aortic rupture and dissection. We performed gene expression analysis (Illumina HumanHT-12 version 3 Expression BeadChip) for 32 samples from ATAA (26 without/6 with dissection), and 28 left internal thoracic arteries (controls) collected in Tampere Vascular study. We compared expression profiles and conducted pathway analysis using Ingenuity Pathway Analysis (IPA) to reveal differences between ATAA and a healthy artery wall. Almost 5000 genes were differentially expressed in ATAA samples compared to controls. The most downregulated gene was homeobox (HOX) A5 (fold change, FC = -25.3) and upregulated cadherin-2 (FC = 12.6). Several other HOX genes were also found downregulated (FCs between -25.3 and -1.5, FDR < 0.05). 43, mostly inflammatory, canonical pathways in ATAA were found to be significantly (p < 0.05, FDR < 0.05) differentially expressed. The results remained essentially the same when the 6 dissected ATAA samples were excluded from the analysis. We show for the first time on genome level that ATAA is an inflammatory process, revealing a more detailed molecular pathway level pathogenesis. We propose HOX genes as potentially important players in maintaining aortic integrity, altered expression of which might be important in the pathobiology of ATAA.

20.
Cell Rep ; 20(4): 846-853, 2017 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-28746870

RESUMO

Herein, we demonstrate that HCMV miR-UL112-5p targets ERAP1, thereby inhibiting the processing and presentation of the HCMV pp65495-503 peptide to specific CTLs. In addition, we show that the rs17481334 G variant, naturally occurring in the ERAP1 3' UTR, preserves ERAP1 from miR-UL112-5p-mediated degradation. Specifically, HCMV miR-UL112-5p binds the 3' UTR of ERAP1 A variant, but not the 3' UTR of ERAP1 G variant, and, accordingly, ERAP1 expression is reduced both at RNA and protein levels only in human fibroblasts homozygous for the A variant. Consistently, HCMV-infected GG fibroblasts were more efficient in trimming viral antigens and being lysed by HCMV-peptide-specific CTLs. Notably, a significantly decreased HCMV seropositivity was detected among GG individuals suffering from multiple sclerosis, a disease model in which HCMV is negatively associated with adult-onset disorder. Overall, our results identify a resistance mechanism to HCMV miR-UL112-5p-based immune evasion strategy with potential implications for individual susceptibility to infection and other diseases.


Assuntos
Aminopeptidases/metabolismo , Citomegalovirus/genética , Variação Genética/genética , MicroRNAs/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Regiões 3' não Traduzidas/genética , Aminopeptidases/genética , Linfócitos T CD8-Positivos/metabolismo , Infecções por Citomegalovirus/enzimologia , Infecções por Citomegalovirus/genética , Genótipo , Humanos , MicroRNAs/genética , Antígenos de Histocompatibilidade Menor/genética , Esclerose Múltipla/enzimologia , Esclerose Múltipla/genética , Ligação Proteica , RNA Mensageiro/genética , RNA Viral/genética , Linfócitos T Citotóxicos/metabolismo
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