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1.
Nat Hum Behav ; 3(9): 950-961, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358974

RESUMO

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

2.
Diabetes ; 68(6): 1353-1358, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30885989

RESUMO

Several amino acids (AAs) have been shown to be associated with insulin resistance and increased risk of type 2 diabetes, but no previous studies have investigated the association of AAs with insulin secretion in a longitudinal setting. Our study included 5,181 participants of the cross-sectional METabolic Syndrome In Men (METSIM) study having metabolomics data on 20 AAs. A total of 4,851 had a 7.4-year follow-up visit. Nine AAs (phenylalanine, tryptophan, tyrosine, alanine, isoleucine, leucine, valine, aspartate, and glutamate) were significantly (P < 5.8 × 10-5) associated with decreases in insulin secretion (disposition index) and the elevation of fasting or 2-h glucose levels. Five of these AAs (tyrosine, alanine, isoleucine, aspartate, and glutamate) were also found to be significantly associated with an increased risk of incident type 2 diabetes after adjustment for confounding factors. Our study is the first population-based large cohort to report that AAs are associated not only with insulin resistance but also with decreased insulin secretion.

3.
Ann Clin Transl Neurol ; 5(10): 1229-1240, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30349858

RESUMO

Objective: Apolipoprotein E (APOE) ε4 allele is a well-established risk factor in Alzheimer's disease (AD). Here, we assessed the effects of APOE polymorphism on cardiovascular, metabolic, and inflammation-related parameters in population-based cohorts. Methods: Association of cardiovascular, metabolic, and inflammation-related parameters with the APOE polymorphism in a large Finnish Metabolic Syndrome in Men (METSIM) cohort and Finnish Geriatric Intervention study to prevent cognitive impairment and disability (FINGER) were investigated. Brain-specific effects were addressed in postmortem brain samples. Results: Individuals carrying the APOE ε4 allele displayed significantly elevated serum/plasma LDL cholesterol and apolipoprotein B levels. APOE ε3ε4 and ε4ε4 significantly associated with lower levels of plasma high-sensitivity C-reactive protein (hs-CRP). Plasma amyloid-ß 42 (Aß42) and reduced hs-CRP levels showed an association independently of the APOE status. Interpretation: These data suggest that the APOE ε4 allele associates with lower levels of hs-CRP in individuals without dementia. Moreover, Aß42 may encompass anti-inflammatory effects reflected by reduced hs-CRP levels.

4.
Hum Mol Genet ; 27(9): 1664-1674, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29481666

RESUMO

Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6 million genotyped and imputed variants in 8545 non-diabetic Finnish men from the METabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966). We identified five novel loci associated with amino acid levels (P = < 5×10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10-26); ZFHX3 (chr16:73326579, minor allele frequency (MAF) = 0.42%, P = 3.6×10-9), LIPC (rs10468017, P = 1.5×10-8), and WWOX (rs9937914, P = 3.8×10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10-9). Gene-based tests identified two novel genes harboring missense variants of MAF <1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5×10-6) and BCAT2 with valine (Pgene = 7.4×10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017, MAF=0.95%, Pconditional = 5.8×10-40) with glycine levels and HAL (rs141635447, MAF = 0.46%, Pconditional = 9.4×10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend<0.001). These novel signals provide further insight into the molecular mechanisms of amino acid metabolism and potentially, their perturbations in disease.

5.
Diabetes ; 67(2): 334-342, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29141982

RESUMO

Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of the p.Pro50Thr AKT2 variant (p.P50T/AKT2) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (N = 20) and matched noncarriers (N = 25) for this allele in the population-based Metabolic Syndrome in Men (METSIM)study and invited these individuals back for positron emission tomography study with [18F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2 carriers to noncarriers, we found a 39.4% reduction in whole-body GU (P = 0.006) and a 55.6% increase in the rate of endogenous glucose production (P = 0.038). We found significant reductions in GU in multiple tissues-skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%)-and increases of 16.8-19.1% in seven tested brain regions. These data demonstrate that the p.P50T substitution of AKT2 influences insulin-mediated GU in multiple insulin-sensitive tissues and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2 carriers.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Resistência à Insulina , Mutação com Perda de Função , Proteínas Proto-Oncogênicas c-akt/genética , Absorção Fisiológica/efeitos dos fármacos , Idoso , Alelos , Substituição de Aminoácidos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/metabolismo , Diagnóstico Precoce , Finlândia , Fluordesoxiglucose F18/metabolismo , Seguimentos , Estudos de Associação Genética , Variação Genética , Heterozigoto , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas c-akt/metabolismo
6.
EBioMedicine ; 27: 151-155, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29246479

RESUMO

Branched-chain amino acids (BCAAs) metabolite, 3-Hydroxyisobutyric acid (3-HIB) has been identified as a secreted mediator of endothelial cell fatty acid transport and insulin resistance (IR) using animal models. To identify if 3-HIB is a marker of human IR and future risk of developing Type 2 diabetes (T2D), we measured plasma levels of 3-HIB and associated metabolites in around 10,000 extensively phenotyped individuals. The levels of 3-HIB were increased in obesity but not robustly associated with degree of IR after adjusting for BMI. Nevertheless, also after adjusting for obesity and plasma BCAA, 3-HIB levels were associated with future risk of incident T2D. We also examined the effect of 3-HIB on fatty acid uptake in human cells and found that both HUVEC and human cardiac endothelial cells respond to 3-HIB whereas human adipose tissue-derived endothelial cells do not respond to 3-HIB. In conclusion, we found that increased plasma level of 3-HIB is a marker of future risk of T2D and 3-HIB may be important for the regulation of metabolic flexibility in heart and muscles.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Hidroxibutiratos/sangue , Tecido Adiposo/patologia , Aminoácidos de Cadeia Ramificada/sangue , Transporte Biológico , Índice de Massa Corporal , Células Endoteliais/metabolismo , Ácidos Graxos/metabolismo , Humanos , Incidência , Metaboloma , Microvasos/patologia
7.
Nat Commun ; 8(1): 888, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-29026101

RESUMO

Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10-4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10-5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10-6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.


Assuntos
Códon sem Sentido , Diabetes Mellitus Tipo 2/genética , Fatores de Transcrição de Fator Regulador X/genética , Estudos de Coortes , Europa (Continente) , Estudos de Associação Genética , Triagem de Portadores Genéticos , Razão de Chances
8.
J Clin Endocrinol Metab ; 102(9): 3600-3609, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28911155

RESUMO

Context: Low-grade inflammation is involved in the development of type 2 diabetes and cardiovascular disease (CVD); however, prospective studies evaluating inflammatory markers as predictors of changes in insulin secretion and insulin sensitivity are lacking. Objective: We investigated the associations of glycoprotein acetyls (GlycA), interleukin-1 receptor antagonist (IL-1RA), and high-sensitivity C-reactive protein (hs-CRP) with insulin secretion, insulin sensitivity, incident type 2 diabetes, hypertension, CVD events, and total mortality in the prospective Metabolic Syndrome in Men (METSIM) study. Design: A prospective study. Participants: The cross-sectional METSIM study included 8749 nondiabetic Finnish men aged 45 to 73 years, who had been randomly selected from the population register of Kuopio, Finland. A total of 5401 men participated in the 6.8-year follow-up study. Main Outcome Measures: Changes in insulin secretion, insulin sensitivity, and cardiometabolic traits during the follow-up period and the incidence of type 2 diabetes, hypertension, CVD events, and total mortality. Results: During the follow-up period, GlycA was associated with impaired insulin secretion, hyperglycemia, incident type 2 diabetes (hazard ratio, 1.37; 95% confidence interval, 1.29 to 1.46) and CVD (hazard ratio, 1.21; 95% confidence interval, 1.12 to 1.32). IL-1RA and hs-CRP were associated with adverse changes in insulin sensitivity and obesity-related traits and with total mortality (hazard ratio, 1.13; 95% confidence interval, 1.07 to 1.20; and hazard ratio, 1.08; 95% confidence interval, 1.04 to 1.11, respectively). Conclusions: Inflammatory markers differentially predicted changes in insulin secretion and insulin sensitivity. GlycA predicted impaired insulin secretion, and IL-1RA and hs-CRP predicted changes in insulin sensitivity. Combining the three markers improved the prediction of disease outcomes, suggesting that they capture different aspects of low-grade inflammation.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/epidemiologia , Hipertensão/fisiopatologia , Resistência à Insulina , Síndrome Metabólica/fisiopatologia , Fatores Etários , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/fisiopatologia , Progressão da Doença , Finlândia/epidemiologia , Glicoproteínas/metabolismo , Humanos , Hipertensão/epidemiologia , Incidência , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Análise de Sobrevida
9.
Cell Metab ; 26(2): 281-283, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28768165

RESUMO

Plasma mannose levels are elevated in subjects with insulin resistance independently of obesity. Here, we found that elevated plasma mannose levels are strong markers of future risk of several chronic diseases including T2D, CVD, and albuminuria, and that it may contribute to their development rather than just being a novel biomarker.


Assuntos
Albuminúria/sangue , Doenças Cardiovasculares/sangue , Diabetes Mellitus Tipo 2/sangue , Resistência à Insulina , Manose/sangue , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Diabetologia ; 60(9): 1722-1730, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28573393

RESUMO

AIMS/HYPOTHESIS: Many SNPs have been associated with glycaemic traits and type 2 diabetes, but their joint effects on glycaemic traits and the underlying mechanisms leading to hyperglycaemia over time are largely unknown. We aimed to investigate the association of six genetic risk scores (GRSs) with changes in plasma glucose, insulin sensitivity, insulin secretion and incident type 2 diabetes in the prospective METabolic Syndrome In Men (METSIM) study. METHODS: We generated weighted GRSs for fasting plasma glucose ([FPG] GRSFPG, 35 SNPs), 2 h plasma glucose ([2hPG] GRS2hPG, 9 SNPs), insulin secretion (GRSIS, 17 SNPs), insulin resistance (GRSIR, 9 SNPs) and BMI (GRSBMI, 95 SNPs) and a non-weighted GRS for type 2 diabetes (GRST2D, 76 SNPs) in up to 8749 non-diabetic Finnish men. Linear regression was used to test associations of the GRSs with changes in glycaemic traits over time. RESULTS: GRST2D, GRSFPG and GRSIS were associated with an increase in FPG, GRST2D with an increase in glucose AUC and a decrease in insulin secretion, and GRS2hPG with an increase in 2hPG during the follow-up (p < 0.0017 for all models). GRST2D, GRSFPG and GRSIS were associated with incident type 2 diabetes (p < 0.008 for all models). GRSBMI and GRSIR were not significantly associated with any changes in glycaemic traits. CONCLUSIONS/INTERPRETATION: In the METSIM follow-up study, GRST2D, GRSFPG and GRSIS were associated with the worsening of FPG and an increase in incident type 2 diabetes. GRST2D was additionally associated with a decrease in insulin secretion, and GRS2hPG with an increase in 2hPG.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Adulto , Diabetes Mellitus Tipo 2/genética , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/sangue , Hiperglicemia/genética , Hiperglicemia/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Fatores de Risco
11.
Ann Neurol ; 82(1): 128-132, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28556232

RESUMO

We investigated the association of Alzheimer's disease (AD)-related rare variants APP A673T and ABCA7 rs200538373-C with the levels of ß-amyloid (Aß) and parameters of metabolic and cardiovascular health in a population-based cohort of healthy middle-aged and elderly men. Carriers of protective APP A673T variant had, on average, 28% lower levels of Aß40 and Aß42 in plasma as compared to the controls and the carriers of ABCA7 rs200538373-C. This is the first report to show decreased Aß levels in plasma in APP A673T carriers and thus provides evidence that lower Aß levels throughout life may be protective against AD. Ann Neurol 2017;82:128-132.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Transportadores de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Estudos de Casos e Controles , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fragmentos de Peptídeos/sangue , Fatores de Proteção
12.
Diabetes ; 66(8): 2296-2309, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28490609

RESUMO

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Variação Genética/fisiologia , Insulina/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/fisiologia , Alelos , Peptídeo C/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Técnicas de Genotipagem , Teste de Tolerância a Glucose/métodos , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Modelos Lineares , Fígado/metabolismo
13.
Am J Hum Genet ; 100(3): 428-443, 2017 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-28257690

RESUMO

Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 × 10-8) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.


Assuntos
Doenças Cardiovasculares/genética , Regulação da Expressão Gênica , Síndrome Metabólica/genética , Locos de Características Quantitativas , Gordura Subcutânea/metabolismo , Idoso , Animais , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Reprodutibilidade dos Testes , Transativadores/genética , Transativadores/metabolismo
14.
J Lipid Res ; 58(3): 481-493, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28119442

RESUMO

The Metabolic Syndrome in Men (METSIM) study is a population-based study including 10,197 Finnish men examined in 2005-2010. The aim of the study is to investigate nongenetic and genetic factors associated with the risk of T2D and CVD, and with cardiovascular risk factors. The protocol includes a detailed phenotyping of the participants, an oral glucose tolerance test, fasting laboratory measurements including proton NMR measurements, mass spectometry metabolomics, adipose tissue biopsies from 1,400 participants, and a stool sample. In our ongoing follow-up study, we have, to date, reexamined 6,496 participants. Extensive genotyping and exome sequencing have been performed for essentially all METSIM participants, and >2,000 METSIM participants have been whole-genome sequenced. We have identified several nongenetic markers associated with the development of diabetes and cardiovascular events, and participated in several genetic association studies to identify gene variants associated with diabetes, hyperglycemia, and cardiovascular risk factors. The generation of a phenotype and genotype resource in the METSIM study allows us to proceed toward a "systems genetics" approach, which includes statistical methods to quantitate and integrate intermediate phenotypes, such as transcript, protein, or metabolite levels, to provide a global view of the molecular architecture of complex traits.


Assuntos
Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Síndrome Metabólica/genética , Metabolômica , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Idoso , Biópsia , Glicemia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Estudos de Associação Genética , Genoma Humano , Genótipo , Teste de Tolerância a Glucose , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperglicemia/sangue , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
15.
J Clin Endocrinol Metab ; 102(2): 443-450, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27906553

RESUMO

Context: Recent studies have highlighted the role of height in complex diseases, but conflicting information has been reported on height as a predictor of changes in glycemia and risk of type 2 diabetes. Objective: Our aim was to investigate the association of height with insulin sensitivity, insulin secretion, glycemia, type 2 diabetes, and cardiovascular disease (CVD) in a large prospective population-based study. Design: The study included 8746 Finnish men (mean ± standard deviation, age 57.2 ± 7.1 years, body mass index, 26.8 ± 3.8 kg/m2) selected from a population-based Metabolic Syndrome in Men (METSIM) study. Setting: The study was conducted at Kuopio University Hospital and University of Eastern Finland. Participants: The participants were nondiabetic at the recruitment, and 5401 subjects have participated in the follow-up study. During the follow-up, a total of 693 subjects converted to type 2 diabetes and 351 were diagnosed with a new CVD event during the follow-up. Main Outcome Measures: The main outcome measures were incidence of type 2 diabetes and CVD. Results: Height measured at baseline was significantly associated with lower levels of 2-hour glucose in an oral glucose tolerance test, an increase in insulin secretion, a decrease in the risk of type 2 diabetes [hazard ratio (HR) = 0.83(confidence interval [CI] 0.77 to 0.90)] and CVD [HR = 0.75(CI 0.67 to 0.83)] during the follow-up. Conclusion: Short stature is associated with unfavorable changes in glucose metabolism and predicts an increase in the risk of type 2 diabetes and cardiovascular events.

16.
PLoS One ; 11(11): e0166584, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27851812

RESUMO

We investigated the association of the Finnish Diabetes Risk Score (FINDRISC) with insulin secretion, insulin sensitivity, and risk of type 2 diabetes, drug-treated hypertension, cardiovascular (CVD) events and total mortality in a follow-up study of the Metabolic Syndrome in Men (METSIM) cohort. The METSIM study includes 10,197 Finnish men, aged 45-73 years, and examined in 2005-2010. Of 8,749 non-diabetic participants of the METSIM study 693 developed incident type 2 diabetes, 225 started antihypertensive medication, 351 had a CVD event, and 392 died during a 8.2-year follow-up. The FINDRISC was significantly associated with decreases in insulin secretion and insulin sensitivity (P<0.0001), and with a 4.14-fold increased risk of incident type 2 diabetes, 2.43-fold increased risk of drug-treated hypertension, 1.61-fold increased risk of CVD, and 1.55-increased risk of total mortality (the FINDRISC ≥12 vs. < 12 points). In conclusion, the FINDRISC predicts impairment in insulin secretion and insulin sensitivity, the conversion to type 2 diabetes, drug-treated hypertension, CVD events and total mortality.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Hipertensão/tratamento farmacológico , Resistência à Insulina , Insulina/metabolismo , Síndrome Metabólica/epidemiologia , Idoso , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Finlândia/epidemiologia , Seguimentos , Humanos , Hipertensão/epidemiologia , Hipertensão/mortalidade , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/mortalidade , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/mortalidade , Fatores de Risco
17.
Nat Commun ; 7: 13357, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27876822

RESUMO

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.


Assuntos
Antropometria , Tamanho Corporal , Modelos Genéticos , Análise de Componente Principal , Estudo de Associação Genômica Ampla , Genótipo , Humanos
18.
Nat Genet ; 48(10): 1151-1161, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27618447

RESUMO

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.


Assuntos
Pressão Sanguínea/genética , Variação Genética , Hipertensão/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos
19.
Diabetes ; 65(10): 3200-11, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27416945

RESUMO

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.


Assuntos
Quimiocinas CC/genética , Estudo de Associação Genômica Ampla/métodos , Resistência à Insulina/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Quimiocinas CC/fisiologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/fisiologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia
20.
Sci Transl Med ; 8(341): 341ra76, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27252175

RESUMO

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.


Assuntos
Doença das Coronárias/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Alelos , Diabetes Mellitus Tipo 2/genética , Dipeptidil Peptidase 4/genética , Genótipo , Humanos , Obesidade/genética , Receptor CB2 de Canabinoide/genética , Receptor 5-HT2C de Serotonina/genética , Receptores de Somatostatina/genética , Transportador 1 de Glucose-Sódio/genética
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