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1.
Diabetes Care ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277303

RESUMO

OBJECTIVE: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. RESEARCH DESIGN AND METHODS: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment. RESULTS: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08-1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17-1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs. CONCLUSIONS: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.

2.
Nat Metab ; 2(10): 1135-1148, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33067605

RESUMO

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.

5.
Am J Hum Genet ; 107(4): 612-621, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32888428

RESUMO

Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.


Assuntos
Artrite Reumatoide/genética , Hipersensibilidade a Drogas/genética , Antígenos HLA-B/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Psoríase/genética , Adulto , Alelos , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Cromossomos Humanos Par 6/química , Hipersensibilidade a Drogas/complicações , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Registros Eletrônicos de Saúde , Europa (Continente) , Feminino , Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Antígenos HLA-B/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Penicilinas/efeitos adversos , Proteína Tirosina Fosfatase não Receptora Tipo 22/imunologia , Psoríase/complicações , Psoríase/imunologia , Autorrelato , Linfócitos T/imunologia , Linfócitos T/patologia , Estados Unidos
6.
PLoS Comput Biol ; 16(8): e1008044, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797044

RESUMO

Genetic studies have recently highlighted the importance of fat distribution, as well as overall adiposity, in the pathogenesis of obesity-associated diseases. Using a large study (n = 1,288) from 4 independent cohorts, we aimed to investigate the relationship between mean adipocyte area and obesity-related traits, and identify genetic factors associated with adipocyte cell size. To perform the first large-scale study of automatic adipocyte phenotyping using both histological and genetic data, we developed a deep learning-based method, the Adipocyte U-Net, to rapidly derive mean adipocyte area estimates from histology images. We validate our method using three state-of-the-art approaches; CellProfiler, Adiposoft and floating adipocytes fractions, all run blindly on two external cohorts. We observe high concordance between our method and the state-of-the-art approaches (Adipocyte U-net vs. CellProfiler: R2visceral = 0.94, P < 2.2 × 10-16, R2subcutaneous = 0.91, P < 2.2 × 10-16), and faster run times (10,000 images: 6mins vs 3.5hrs). We applied the Adipocyte U-Net to 4 cohorts with histology, genetic, and phenotypic data (total N = 820). After meta-analysis, we found that mean adipocyte area positively correlated with body mass index (BMI) (Psubq = 8.13 × 10-69, ßsubq = 0.45; Pvisc = 2.5 × 10-55, ßvisc = 0.49; average R2 across cohorts = 0.49) and that adipocytes in subcutaneous depots are larger than their visceral counterparts (Pmeta = 9.8 × 10-7). Lastly, we performed the largest GWAS and subsequent meta-analysis of mean adipocyte area and intra-individual adipocyte variation (N = 820). Despite having twice the number of samples than any similar study, we found no genome-wide significant associations, suggesting that larger sample sizes and a homogenous collection of adipose tissue are likely needed to identify robust genetic associations.


Assuntos
Adipócitos , Aprendizado de Máquina , Obesidade , Adipócitos/classificação , Adipócitos/citologia , Tecido Adiposo/fisiologia , Adulto , Índice de Massa Corporal , Tamanho Celular , Biologia Computacional/métodos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Obesidade/epidemiologia , Obesidade/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
7.
Sci Transl Med ; 12(549)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581134

RESUMO

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.

8.
Nat Commun ; 11(1): 2542, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439900

RESUMO

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.


Assuntos
Arritmias Cardíacas/genética , Eletrocardiografia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Arritmias Cardíacas/fisiopatologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Endofenótipos , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Locos de Características Quantitativas/genética
10.
Mol Metab ; 34: 85-96, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32180562

RESUMO

OBJECTIVES: Lipolysis, hydrolysis of triglycerides to fatty acids in adipocytes, is tightly regulated, poorly understood, and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. The goal of this study was to identify the genetic regulators of lipolysis and elucidate their molecular mechanisms. METHODS: Adipocytes from abdominal subcutaneous adipose tissue biopsies were isolated and were incubated without (spontaneous lipolysis) or with a catecholamine (stimulated lipolysis) to analyze lipolysis. DNA was extracted and genome-wide genotyping and imputation conducted. After quality control, 939 samples with genetic and lipolysis data were available. Genome-wide association studies of spontaneous and stimulated lipolysis were conducted. Subsequent in vitro gene expression analyses were used to identify candidate genes and explore their regulation of adipose tissue biology. RESULTS: One locus on chromosome 19 demonstrated genome-wide significance with spontaneous lipolysis. 60 loci showed suggestive associations with spontaneous or stimulated lipolysis, of which many influenced both traits. In the chromosome 19 locus, only HIF3A was expressed in the adipocytes and displayed genotype-dependent gene expression. HIF3A knockdown in vitro increased lipolysis and the expression of key lipolysis-regulating genes. CONCLUSIONS: In conclusion, we identified a genetic regulator of spontaneous lipolysis and provided evidence of HIF3A as a novel key regulator of lipolysis in subcutaneous adipocytes as the mechanism through which the locus influences adipose tissue biology.

12.
Nature ; 577(7789): 179-189, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915397

RESUMO

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition.


Assuntos
Variação Genética , Animais , Testes Genéticos , Genômica , Genótipo , Humanos , Fenótipo , Doenças Raras/genética
14.
PLoS Genet ; 15(10): e1008405, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31647808

RESUMO

Obesity traits are causally implicated with risk of cardiometabolic diseases. It remains unclear whether there are similar causal effects of obesity traits on other non-communicable diseases. Also, it is largely unexplored whether there are any sex-specific differences in the causal effects of obesity traits on cardiometabolic diseases and other leading causes of death. We constructed sex-specific genetic risk scores (GRS) for three obesity traits; body mass index (BMI), waist-hip ratio (WHR), and WHR adjusted for BMI, including 565, 324, and 337 genetic variants, respectively. These GRSs were then used as instrumental variables to assess associations between the obesity traits and leading causes of mortality in the UK Biobank using Mendelian randomization. We also investigated associations with potential mediators, including smoking, glycemic and blood pressure traits. Sex-differences were subsequently assessed by Cochran's Q-test (Phet). A Mendelian randomization analysis of 228,466 women and 195,041 men showed that obesity causes coronary artery disease, stroke (particularly ischemic), chronic obstructive pulmonary disease, lung cancer, type 2 and 1 diabetes mellitus, non-alcoholic fatty liver disease, chronic liver disease, and acute and chronic renal failure. Higher BMI led to higher risk of type 2 diabetes in women than in men (Phet = 1.4×10-5). Waist-hip-ratio led to a higher risk of chronic obstructive pulmonary disease (Phet = 3.7×10-6) and higher risk of chronic renal failure (Phet = 1.0×10-4) in men than women. Obesity traits have an etiological role in the majority of the leading global causes of death. Sex differences exist in the effects of obesity traits on risk of type 2 diabetes, chronic obstructive pulmonary disease, and renal failure, which may have downstream implications for public health.


Assuntos
Causas de Morte , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Obesidade/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adiposidade/genética , Idoso , Pressão Sanguínea/genética , Índice de Massa Corporal , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Neoplasias , Obesidade/complicações , Obesidade/mortalidade , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Risco , Acidente Vascular Cerebral , Relação Cintura-Quadril
16.
EBioMedicine ; 44: 467-475, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31151930

RESUMO

BACKGROUND: Abdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored. METHODS: An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue. FINDINGS: We found that rs11614913, a SNP within pre-miR-196a-2 at the HOXC locus, is an eQTL for miR-196a expression in abdominal subcutaneous adipose tissue (ASAT). Observations in large cohorts showed that rs11614913 increased waist-to-hip ratio, which was driven specifically by an expansion in ASAT. In further experiments, rs11614913 was associated with adipocyte size. Functional studies and transcriptomic profiling of miR-196a knock-down pre-adipocytes revealed a role for miR-196a in regulating pre-adipocyte proliferation and extracellular matrix pathways. INTERPRETATION: These data identify a role for miR-196a in regulating human body fat distribution. FUND: This work was supported by the Medical Research Council and Novo Nordisk UK Research Foundation (G1001959) and Swedish Research Council. We acknowledge the OBB-NIHR Oxford Biomedical Research Centre and the British Heart Foundation (BHF) (RG/17/1/32663). Work performed at the MRC Epidemiology Unit was funded by the United Kingdom's Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1.


Assuntos
Tecido Adiposo/metabolismo , Adiposidade/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , MicroRNAs/genética , Adipócitos/metabolismo , Adulto , Alelos , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Interferência de RNA , Transdução de Sinais , Transcriptoma
18.
Nat Commun ; 10(1): 29, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604766

RESUMO

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.


Assuntos
Taxa de Filtração Glomerular/genética , Hipertensão/genética , Cálculos Renais/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Adulto , Idoso , Pressão Sanguínea/genética , Grupos Étnicos/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Código das Histonas/genética , Histonas/metabolismo , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Cálculos Renais/etnologia , Cálculos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/fisiopatologia
19.
Hum Mol Genet ; 28(1): 166-174, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239722

RESUMO

More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.


Assuntos
Adiposidade/genética , Distribuição da Gordura Corporal/métodos , Obesidade/genética , Tecido Adiposo/fisiologia , Adulto , Alelos , Índice de Massa Corporal , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Relação Cintura-Quadril
20.
Am J Hum Genet ; 104(1): 157-163, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30583798

RESUMO

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10-14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Disfunção Erétil/etiologia , Disfunção Erétil/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipotálamo/patologia , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cromossomos Humanos Par 6/genética , Simulação por Computador , Europa (Continente) , Humanos , Masculino , Proteínas Repressoras/genética
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