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1.
J Clin Invest ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33630758

RESUMO

Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains a common variant rs9349379 (A > G) associated with CAD. As PHACTR1 is an actin-binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk-allele to CAD via impaired efferocytosis. We show here that rs9349379-G/G was associated with lower levels of PHACTR1 and impaired efferocytosis in human monocyte-derived macrophages and human atherosclerotic lesional macrophages compared with rs9349379-A/A. Silencing PHACTR1 in human and mouse macrophages compromised AC engulfment, and mice in which hematopoietic Phactr1 was genetically targeted in Western diet-fed Ldlr-/- mice showed impaired lesional efferocytosis, increased plaque necrosis, and thinner fibrous caps-all signs of vulnerable plaques in humans. Mechanistically, PHACTR1 prevented dephosphorylation of myosin light chain (MLC), which was necessary for AC engulfment. In summary, rs9349379-G lowers PHACTR1, which, by lowering phospho-MLC, compromised efferocytosis. Thus, rs9349379-G may contribute to CAD risk, at least in part, by impairing atherosclerotic lesional macrophage efferocytosis.

3.
Circ Genom Precis Med ; 13(5): 417-423, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32862661

RESUMO

BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8-as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in ABCG5 or ABCG8. RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in ABCG5 and 2 pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 was ≈0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; P=1.1×10-6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

4.
PLoS One ; 15(8): e0237430, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841307

RESUMO

BACKGROUND & AIMS: Given ongoing challenges in non-invasive non-alcoholic liver disease (NAFLD) diagnosis, we sought to validate an ALT-based NAFLD phenotype using measures readily available in electronic health records (EHRs) and population-based studies by leveraging the clinical and genetic data in the Million Veteran Program (MVP), a multi-ethnic mega-biobank of US Veterans. METHODS: MVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for women without other causes of liver disease were compared to controls with normal ALT. Genetic variants spanning eight NAFLD risk or ALT-associated loci (LYPLAL1, GCKR, HSD17B13, TRIB1, PPP1R3B, ERLIN1, TM6SF2, PNPLA3) were tested for NAFLD associations with sensitivity analyses adjusting for metabolic risk factors and alcohol consumption. A manual EHR review assessed performance characteristics of the NAFLD phenotype with imaging and biopsy data as gold standards. Genetic associations with advanced fibrosis were explored using FIB4, NAFLD Fibrosis Score and platelet counts. RESULTS: Among 322,259 MVP participants, 19% met non-invasive criteria for NAFLD. Trans-ethnic meta-analysis replicated associations with previously reported genetic variants in all but LYPLAL1 and GCKR loci (P<6x10-3), without attenuation when adjusted for metabolic risk factors and alcohol consumption. At the previously reported LYPLAL1 locus, the established genetic variant did not appear to be associated with NAFLD, however the regional association plot showed a significant association with NAFLD 279kb downstream. In the EHR validation, the ALT-based NAFLD phenotype yielded a positive predictive value 0.89 and 0.84 for liver biopsy and abdominal imaging, respectively (inter-rater reliability (Cohen's kappa = 0.98)). HSD17B13 and PNPLA3 loci were associated with advanced fibrosis. CONCLUSIONS: We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.


Assuntos
Alanina Transaminase/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , 17-Hidroxiesteroide Desidrogenases/genética , Abdome/diagnóstico por imagem , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Alanina Transaminase/genética , Registros Eletrônicos de Saúde , Feminino , Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Humanos , Lipase/genética , Fígado/patologia , Lisofosfolipase/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etnologia , Hepatopatia Gordurosa não Alcoólica/genética , Fenótipo , Fatores de Risco , Veteranos
5.
Nat Genet ; 52(7): 680-691, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541925

RESUMO

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.


Assuntos
Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Afro-Americanos , Cromossomos Humanos X , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/genética , Europa (Continente) , Feminino , Estudos de Associação Genética , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Polimorfismo de Nucleotídeo Único , Medição de Risco
6.
Nat Med ; 26(6): 869-877, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32461697

RESUMO

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5-8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação com Perda de Função/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Linhagem Celular , Células-Tronco Embrionárias/metabolismo , Feminino , Mutação com Ganho de Função/genética , Heterozigoto , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Longevidade/genética , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Fenótipo
7.
PLoS Genet ; 16(4): e1008629, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32282858

RESUMO

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.


Assuntos
Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Predisposição Genética para Doença , Cirrose Hepática/genética , Cirrose Hepática/prevenção & controle , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto/genética , Oxirredutases/genética , Alelos , LDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Conjuntos de Dados como Assunto , Fígado Gorduroso/sangue , Fígado Gorduroso/enzimologia , Feminino , Homozigoto , Humanos , Fígado/enzimologia , Cirrose Hepática/sangue , Cirrose Hepática/enzimologia , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/enzimologia , Cirrose Hepática Alcoólica/genética , Cirrose Hepática Alcoólica/prevenção & controle , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade
8.
J Clin Invest ; 130(2): 575-581, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31929188

RESUMO

Technological advances in rapid data acquisition have transformed medical biology into a data mining field, where new data sets are routinely dissected and analyzed by statistical models of ever-increasing complexity. Many hypotheses can be generated and tested within a single large data set, and even small effects can be statistically discriminated from a sea of noise. On the other hand, the development of therapeutic interventions moves at a much slower pace. They are determined from carefully randomized and well-controlled experiments with explicitly stated outcomes as the principal mechanism by which a single hypothesis is tested. In this paradigm, only a small fraction of interventions can be tested, and an even smaller fraction are ultimately deemed therapeutically successful. In this Review, we propose strategies to leverage large-cohort data to inform the selection of targets and the design of randomized trials of novel therapeutics. Ultimately, the incorporation of big data and experimental medicine approaches should aim to reduce the failure rate of clinical trials as well as expedite and lower the cost of drug development.


Assuntos
Big Data , Pesquisa Biomédica , Estudos de Coortes , Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos
9.
Circulation ; 141(2): 124-131, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31707836

RESUMO

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1ß expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk. METHODS: We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with DNMT3A or TET2 CHIP. We used the IL6R p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by IL6R p.Asp358Ala. RESULTS: We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04-1.56], P=0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21-2.09], P<0.001). IL6R p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29-0.73], P<0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89-1.01], P=0.08; Pinteraction=0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by IL6R p.Asp358Ala (Pinteraction=0.036). CONCLUSIONS: CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.


Assuntos
Doenças Cardiovasculares/patologia , Interleucina-6/metabolismo , Receptores de Interleucina-6/genética , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Evolução Clonal , Feminino , Hematopoese , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Transdução de Sinais
10.
Nat Genet ; 51(11): 1574-1579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Doenças Vasculares/genética , Tromboembolia Venosa/genética , Idoso , Animais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Fatores de Risco , Reino Unido/epidemiologia , Doenças Vasculares/epidemiologia , Doenças Vasculares/patologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/patologia
11.
Circulation ; 140(12): 1031-1040, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31337231

RESUMO

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.


Assuntos
Afro-Americanos , Apolipoproteína L1/genética , Doença da Artéria Coronariana/genética , Genótipo , Infarto do Miocárdio/genética , Doença Arterial Periférica/genética , Adulto , Alelos , Doença da Artéria Coronariana/epidemiologia , Registros Eletrônicos de Saúde , Feminino , Predisposição Genética para Doença , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Doença Arterial Periférica/epidemiologia , Polimorfismo Genético , Estudos Retrospectivos , Risco , Estados Unidos/epidemiologia , Veteranos
12.
Nat Med ; 25(8): 1274-1279, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285632

RESUMO

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.


Assuntos
Estudo de Associação Genômica Ampla , Doença Arterial Periférica/genética , Idoso , LDL-Colesterol/genética , Fator V/genética , Inibidores do Fator Xa/uso terapêutico , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Receptores de LDL/genética , Veteranos
13.
Circ Genom Precis Med ; 12(5): e002376, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30939045

RESUMO

Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10-5) and 53% lower triglyceride level ( P=2×10-4). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10-7), a 30% decrease in triglycerides ( P=5×10-4), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.


Assuntos
Apolipoproteínas B/genética , LDL-Colesterol/sangue , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Adulto , Idoso , Apolipoproteínas B/sangue , Estudos de Casos e Controles , Doença das Coronárias/sangue , Doença das Coronárias/prevenção & controle , Feminino , Variação Genética , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/sangue
15.
J Proteome Res ; 18(6): 2397-2410, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-30887811

RESUMO

Direct infusion high-resolution mass spectrometry (DIHRMS) is a novel, high-throughput approach to rapidly and accurately profile hundreds of lipids in human serum without prior chromatography, facilitating in-depth lipid phenotyping for large epidemiological studies to reveal the detailed associations of individual lipids with coronary heart disease (CHD) risk factors. Intact lipid profiling by DIHRMS was performed on 5662 serum samples from healthy participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS). We developed a novel semi-targeted peak-picking algorithm to detect mass-to-charge ratios in positive and negative ionization modes. We analyzed lipid partial correlations, assessed the association of lipid principal components with established CHD risk factors and genetic variants, and examined differences between lipids for a common genetic polymorphism. The DIHRMS method provided information on 360 lipids (including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and sterol lipids), with a median coefficient of variation of 11.6% (range: 5.4-51.9). The lipids were highly correlated and exhibited a range of associations with clinical chemistry biomarkers and lifestyle factors. This platform can provide many novel insights into the effects of physiology and lifestyle on lipid metabolism, genetic determinants of lipids, and the relationship between individual lipids and CHD risk factors.


Assuntos
Biomarcadores/sangue , Doença das Coronárias/genética , Lipídeos/genética , Doença das Coronárias/sangue , Doença das Coronárias/patologia , Feminino , Variação Genética , Glicerofosfolipídeos/sangue , Humanos , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Esfingolipídeos/sangue , Esfingolipídeos/genética , Esteróis/sangue
16.
Diabetes ; 68(1): 226-234, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30389748

RESUMO

A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic ß-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, P = 3.4 × 10-17), Ile195Thr (-0.15 SD, P = 1.0 × 10-9), Ile482Val (-0.019 SD, P = 1.6 × 10-5), and rs72927479 (-0.035 SD, P = 2.6 × 10-12). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10-13). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; P = 0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.


Assuntos
Receptores de Ativinas Tipo I/genética , Diabetes Mellitus Tipo 2/genética , Análise de Sequência de DNA/métodos , Algoritmos , Exoma/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos
17.
Nat Genet ; 50(11): 1514-1523, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30275531

RESUMO

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).


Assuntos
Grupos Étnicos/genética , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Veteranos/estatística & dados numéricos , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Grupos Étnicos/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/genética , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Hispano-Americanos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
JAMA Cardiol ; 3(7): 619-627, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29926099

RESUMO

Importance: Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective: To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants: A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures: Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures: Coronary heart disease. Results: Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance: The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).


Assuntos
Doença das Coronárias/genética , Hipolipemiantes/uso terapêutico , Lipoproteína(a)/sangue , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Biomarcadores/sangue , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Doença das Coronárias/sangue , Doença das Coronárias/prevenção & controle , Feminino , Seguimentos , Variação Genética , Humanos , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Fatores de Risco
19.
Nat Commun ; 9(1): 1613, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29691411

RESUMO

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.


Assuntos
Doença/genética , Proteínas/genética , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Frequência do Gene , Testes Genéticos , Variação Genética , Humanos , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Fenótipo , Proteínas/metabolismo , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/fisiopatologia , Reino Unido
20.
Circulation ; 137(3): 222-232, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-28982690

RESUMO

BACKGROUND: Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy. METHODS: We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [NOS3] and Guanylate Cyclase 1, Soluble, Alpha 3 [GUCY1A3]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815). RESULTS: A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P=5.5*10-26], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P=0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P=5.6*10-5) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P=0.01). CONCLUSIONS: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.


Assuntos
Pressão Sanguínea/genética , Doença das Coronárias/genética , Mutação , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico/metabolismo , Doença Arterial Periférica/genética , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética , Guanilil Ciclase Solúvel/genética , Acidente Vascular Cerebral/genética , Doença das Coronárias/enzimologia , Doença das Coronárias/epidemiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Óxido Nítrico Sintase Tipo III/metabolismo , Doença Arterial Periférica/enzimologia , Doença Arterial Periférica/epidemiologia , Fenótipo , Fatores de Proteção , Fatores de Risco , Guanilil Ciclase Solúvel/metabolismo , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/epidemiologia
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