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1.
Nat Genet ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462485

RESUMO

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10-10 < P < 5 × 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

2.
Diabetes ; 69(12): 2806-2818, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32917775

RESUMO

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

3.
Sci Rep ; 10(1): 8233, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427856

RESUMO

Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aß) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (ß = 0.638, P = 3.33 × 10-4) and HAGH (ß = 0.481, P = 7.20 × 10-4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (ß = 1.365, P = 3.97 × 10-3) and HAGH proteins (ß = 0.506, P = 9.31 × 10-7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10-3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10-9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.


Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteína E4/metabolismo , Caderinas/metabolismo , Triagem de Portadores Genéticos , Tioléster Hidrolases/metabolismo , Apolipoproteína E4/genética , Biomarcadores/sangue , Humanos
4.
PLoS One ; 15(5): e0230815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379818

RESUMO

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.


Assuntos
Glicemia/análise , Fumar Cigarros/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Genótipo , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Fumar Cigarros/etnologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Viabilidade , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
5.
Nat Med ; 26(1): 110-117, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31932804

RESUMO

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).


Assuntos
Estudos Epidemiológicos , Microbioma Gastrointestinal/genética , Metaboloma/genética , Preparações Farmacêuticas , Índice de Massa Corporal , Fatores de Confusão Epidemiológicos , Endofenótipos , Humanos , Fígado/metabolismo , Modelos Biológicos , Mapas de Interação de Proteínas
6.
Biol Psychiatry ; 87(5): 409-418, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31635762

RESUMO

BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons. METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms. CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.

7.
EBioMedicine ; 51: 102520, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31877415

RESUMO

BACKGROUND: Metabolic syndrome (MetS), the clustering of metabolic risk factors, is associated with cardiovascular disease risk. We sought to determine if dysregulation of the lipidome may contribute to metabolic risk factors. METHODS: We measured 154 circulating lipid species in 658 participants from the Framingham Heart Study (FHS) using liquid chromatography-tandem mass spectrometry and tested for associations with obesity, dysglycemia, and dyslipidemia. Independent external validation was sought in three independent cohorts. Follow-up data from the FHS were used to test for lipid metabolites associated with longitudinal changes in metabolic risk factors. RESULTS: Thirty-nine lipids were associated with obesity and eight with dysglycemia in the FHS. Of 32 lipids that were available for replication for obesity and six for dyslipidemia, 28 (88%) replicated for obesity and five (83%) for dysglycemia. Four lipids were associated with longitudinal changes in body mass index and four were associated with changes in fasting blood glucose in the FHS. CONCLUSIONS: We identified and replicated several novel lipid biomarkers of key metabolic traits. The lipid moieties identified in this study are involved in biological pathways of metabolic risk and can be explored for prognostic and therapeutic utility.


Assuntos
Biomarcadores , Metabolismo dos Lipídeos , Lipidômica , Lipídeos/sangue , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Adulto , Idoso , Animais , Estudos Transversais , Suscetibilidade a Doenças , Feminino , Humanos , Lipidômica/métodos , Estudos Longitudinais , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
9.
Sci Rep ; 9(1): 11623, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406173

RESUMO

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.


Assuntos
Homocisteína/metabolismo , Leucócitos/ultraestrutura , Metabolismo dos Lipídeos , Metabolômica/métodos , Telômero , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encurtamento do Telômero
10.
Nat Commun ; 10(1): 3346, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431621

RESUMO

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18-109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.


Assuntos
Metabolômica/métodos , Mortalidade , Análise de Sobrevida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Fatores de Risco , Adulto Jovem
11.
Circ Genom Precis Med ; 12(7): e002384, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31306056

RESUMO

BACKGROUND: Lipids are increasingly involved in cardiovascular risk prediction as potential proarrhythmic influencers. However, knowledge is limited about the specific mechanisms connecting lipid alterations with atrial conduction. METHODS: To shed light on this issue, we conducted a broad assessment of 151 sphingo- and phospholipids, measured using mass spectrometry, for association with atrial conduction, measured by P wave duration (PWD) from standard electrocardiograms, in the MICROS study (Microisolates in South Tyrol) (n=839). Causal pathways involving lipidomics, body mass index (BMI), and PWD were assessed using 2-sample Mendelian randomization analyses based on published genome-wide association studies of lipidomics (n=4034) and BMI (n=734 481), and genetic association analysis of PWD in 5 population-based studies (n=24 236). RESULTS: We identified an association with relative phosphatidylcholine 38:3 (%PC 38:3) concentration, which was replicated in the ORCADES (Orkney Complex Disease Study; n=951), with a pooled association across studies of 2.59 (95% CI, 1.3-3.9; P=1.1×10-4) ms PWD per mol% increase. While being independent of cholesterol, triglycerides, and glucose levels, the %PC 38:3-PWD association was mediated by BMI. Results supported a causal effect of BMI on both PWD ( P=8.3×10-5) and %PC 38:3 ( P=0.014). CONCLUSIONS: Increased %PC 38:3 levels are consistently associated with longer PWD, partly because of the confounding effect of BMI. The causal effect of BMI on PWD reinforces evidence of BMI's involvement into atrial electrical activity.


Assuntos
Artérias/fisiopatologia , Índice de Massa Corporal , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Lipídeos/química , Adulto , Idoso , Artérias/metabolismo , Eletrocardiografia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Metabolismo dos Lipídeos , Lipidômica , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fatores de Risco
12.
Am J Hum Genet ; 105(1): 15-28, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178129

RESUMO

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


Assuntos
Adiponectina/genética , Tecido Adiposo/patologia , Exoma/genética , Predisposição Genética para Doença , Lipídeos/análise , Obesidade/etiologia , Polimorfismo de Nucleotídeo Único , Tecido Adiposo/metabolismo , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Fenótipo , Locos de Características Quantitativas , Adulto Jovem
13.
Neurology ; 92(16): e1899-e1911, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30944236

RESUMO

OBJECTIVE: To identify a plasma metabolomic biomarker signature for migraine. METHODS: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. RESULTS: Decreases in the level of apolipoprotein A1 (ß -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (ß -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (ß -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. CONCLUSIONS: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.


Assuntos
Lipoproteínas HDL/metabolismo , Transtornos de Enxaqueca/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Ácidos Graxos Ômega-3/sangue , Feminino , Humanos , Masculino , Metaboloma , Metabolômica , Pessoa de Meia-Idade , Ressonância Magnética Nuclear Biomolecular , Espectroscopia de Prótons por Ressonância Magnética , Fatores Sexuais
14.
Ophthalmology ; 126(3): 393-406, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30315903

RESUMO

PURPOSE: Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. DESIGN: Pooled analysis of cross-sectional data. PARTICIPANTS: Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. METHODS: AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. MAIN OUTCOME MEASURES: AMD features and stage; lipid measurements. RESULTS: HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10-7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10-6 and P = 1.6 × 10-4). CONCLUSIONS: Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.


Assuntos
HDL-Colesterol/sangue , Degeneração Macular/sangue , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , LDL-Colesterol/sangue , Estudos Transversais , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , União Europeia , Feminino , Humanos , Metabolismo dos Lipídeos , Degeneração Macular/epidemiologia , Degeneração Macular/genética , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/sangue
15.
Nat Commun ; 9(1): 4228, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315176

RESUMO

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10-56) and SLC2A9 (p = 4.5 × 10-7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10-3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.


Assuntos
Exoma/genética , Ácido Úrico/sangue , Predisposição Genética para Doença , Proteínas Facilitadoras de Transporte de Glucose/química , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Testes de Função Renal , Metanálise como Assunto , Transportadores de Ânions Orgânicos/química , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/química , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Estrutura Secundária de Proteína
16.
Nat Genet ; 50(4): 559-571, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29632382

RESUMO

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.


Assuntos
Diabetes Mellitus Tipo 2/genética , Alelos , Mapeamento Cromossômico/estatística & dados numéricos , Diabetes Mellitus Tipo 2/classificação , Diabetes Mellitus Tipo 2/fisiopatologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , Sequenciamento Completo do Exoma/estatística & dados numéricos
17.
Atherosclerosis ; 272: 60-65, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29550646

RESUMO

BACKGROUND AND AIMS: Increasing evidence shows that intracranial carotid artery atherosclerosis may develop under the influence of a differential metabolic risk factor profile than atherosclerosis in the extracranial part of the carotid artery. To further elucidate these differences, we investigated associations of a wide range of circulating metabolites with intracranial and extracranial carotid artery atherosclerosis. METHODS: From the population-based Rotterdam Study, blood samples from 1111 participants were used to determine a wide range of metabolites by proton nuclear magnetic resonance (NMR). Moreover, these participants underwent non-contrast computed tomography of the neck and head to quantify the amount of extra- and intracranial carotid artery calcification (ECAC and ICAC), as a proxy of atherosclerosis. We assessed associations of the metabolites with ICAC and ECAC and compared the metabolic association patterns of the two. RESULTS: We found that one standard deviation (SD) increase in concentration of 3-hydroxybutyrate, a ketone body, was significantly associated with a 0.11 SD increase in ICAC volume (p = 1.8 × 10-4). When we compared the metabolic association pattern of ICAC with that of ECAC, we observed differences in glycolysis-related metabolite measures, lipoprotein subfractions, and amino acids. Interestingly, glycoprotein acetyls were associated with calcification in both studied vessel beds. These associations were most prominent in men. CONCLUSIONS: We found that a higher circulating level of 3-hydroxybutyrate was associated with an increase in ICAC. Furthermore, we found differences in metabolic association patterns of ICAC and ECAC, providing further evidence for location-specific differences in the etiology of atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Doenças das Artérias Carótidas/metabolismo , Arteriosclerose Intracraniana/metabolismo , Ácido 3-Hidroxibutírico/sangue , Idoso , Aterosclerose/complicações , Calcinose , Doenças das Artérias Carótidas/complicações , Artéria Carótida Interna/metabolismo , Estudos de Coortes , Feminino , Glicólise , Glicoproteínas/sangue , Humanos , Arteriosclerose Intracraniana/complicações , Corpos Cetônicos/sangue , Lipoproteínas/sangue , Espectroscopia de Ressonância Magnética , Masculino , Metaboloma , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco , Acidente Vascular Cerebral/complicações , Tomografia Computadorizada por Raios X , Calcificação Vascular/complicações
18.
Alzheimers Dement ; 14(6): 723-733, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29519576

RESUMO

INTRODUCTION: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. METHODS: We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented. RESULTS: Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer's disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched-chain amino acids were also associated with decreased Alzheimer's disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer's disease risk. DISCUSSION: Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology.


Assuntos
Doença de Alzheimer/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Demência , Metabolômica/métodos , Adulto , Idoso , Doença de Alzheimer/patologia , Biomarcadores/metabolismo , Demência/metabolismo , Demência/patologia , Humanos , Lipoproteínas/metabolismo , Imagem por Ressonância Magnética , Espectrometria de Massas , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Fatores de Risco
19.
BMC Med Genomics ; 11(1): 22, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29506515

RESUMO

BACKGROUND: Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. METHODS: The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. RESULTS: We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. CONCLUSIONS: We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.


Assuntos
Ligação Genética , Hipertrofia Ventricular Esquerda/genética , MAP Quinase Quinase Quinases/genética , Análise de Sequência com Séries de Oligonucleotídeos , Sequenciamento Completo do Exoma , Eletrocardiografia , Feminino , Genótipo , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
20.
Alzheimers Dement ; 14(6): 707-722, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29316447

RESUMO

INTRODUCTION: Identifying circulating metabolites that are associated with cognition and dementia may improve our understanding of the pathogenesis of dementia and provide crucial readouts for preventive and therapeutic interventions. METHODS: We studied 299 metabolites in relation to cognition (general cognitive ability) in two discovery cohorts (N total = 5658). Metabolites significantly associated with cognition after adjusting for multiple testing were replicated in four independent cohorts (N total = 6652), and the associations with dementia and Alzheimer's disease (N = 25,872) and lifestyle factors (N = 5168) were examined. RESULTS: We discovered and replicated 15 metabolites associated with cognition including subfractions of high-density lipoprotein, docosahexaenoic acid, ornithine, glutamine, and glycoprotein acetyls. These associations were independent of classical risk factors including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, and apolipoprotein E (APOE) genotypes. Six of the cognition-associated metabolites were related to the risk of dementia and lifestyle factors. DISCUSSION: Circulating metabolites were consistently associated with cognition, dementia, and lifestyle factors, opening new avenues for prevention of cognitive decline and dementia.


Assuntos
Biomarcadores/metabolismo , Disfunção Cognitiva/metabolismo , Demência/metabolismo , Adulto , Idoso , Doença de Alzheimer/metabolismo , Estudos de Coortes , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores de Risco
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