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Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.
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Doença da Artéria Coronariana , Animais , Humanos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Epistasia Genética , Fenótipo , Lipídeos/sangue , Sistema ABO de Grupos SanguíneosRESUMO
BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.
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Angioedema , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Estudo de Associação Genômica Ampla , Angioedema/induzido quimicamente , Angioedema/genética , BradicininaRESUMO
AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.
Assuntos
Estenose da Valva Aórtica , Dislipidemias , Humanos , Estudo de Associação Genômica Ampla/métodos , Adiposidade/genética , Predisposição Genética para Doença , Estenose da Valva Aórtica/genética , Obesidade , Fatores de Risco , Inflamação , Dislipidemias/complicações , Dislipidemias/genética , Apolipoproteínas/genética , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND & AIMS: Fatty liver disease has been associated with higher all-cause as well as liver-related, ischemic heart disease (IHD)-related and extrahepatic cancer-related mortality in observational epidemiological studies. We tested the hypothesis that fatty liver disease is a causal risk factor for higher mortality. METHODS: We genotyped seven genetic variants known to be associated with fatty liver disease (in PNPLA3, TM6SF2, HSD17B13, MTARC1, MBOAT7, GCKR, and GPAM) in 110 913 individuals from the Danish general population. Hepatic steatosis was measured by hepatic computed tomography in n = 6965. Using a Mendelian randomization framework, we tested whether genetically proxied hepatic steatosis and/or elevated plasma alanine transaminase (ALT) was associated with liver-related mortality. RESULTS: During a median follow-up of 9.5 years, 16 119 individuals died. In observational analyses, baseline elevated plasma ALT was associated with higher all-cause (1.26-fold), liver-related (9-fold), and extrahepatic cancer-related (1.25-fold) mortality. In genetic analyses, the risk alleles in PNPLA3, TM6SF2, and HSD17B13 were individually associated with higher liver-related mortality. The largest effects were seen for the PNPLA3 and TM6SF2 risk alleles, for which homozygous carriers had 3-fold and 6-fold, respectively, higher liver-related mortality than non-carriers. None of the risk alleles, individually or combined into risk scores, were robustly associated with all-cause, IHD-related, or extrahepatic cancer-related mortality. In instrumental variable analyses, genetically proxied hepatic steatosis and higher plasma ALT were associated with liver-related mortality. CONCLUSIONS: Human genetic data support that fatty liver disease is a causal driver of liver-related mortality.
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Neoplasias , Hepatopatia Gordurosa não Alcoólica , Humanos , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Fatores de Risco , Fígado , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIMS: To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs). METHODS AND RESULTS: A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17-1.24; P = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits. CONCLUSION: This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.
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Angioedema , Inibidores da Enzima Conversora de Angiotensina , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Tosse/induzido quimicamente , Tosse/genética , Tosse/tratamento farmacológico , Estudo de Associação Genômica Ampla , Angioedema/induzido quimicamente , Loci Gênicos , Fatores de RiscoRESUMO
AIMS: Left atrial (LA) volume and function impose significant impact on cardiovascular pathogenesis if compromised. We aimed at investigating the genetic architecture of LA volume and function using cardiac magnetic resonance imaging data. METHODS AND RESULTS: We used the UK Biobank, which is a large prospective population study with available phenotypic and genetic data. On a subset of 35 658 European individuals, we performed genome-wide association studies on five volumetric and functional LA variables, generated using a machine learning algorithm. In total, we identified 18 novel genetic loci, mapped to genes with known roles in cardiomyopathy (e.g. MYO18B, TTN, DSP, ANKRD1) and arrhythmia (e.g. TTN, CASQ2, MYO18B, C9orf3). We observed high genetic correlation between LA volume and function and stroke, which was most pronounced for LA passive emptying fraction (rg = 0.40, P = 4 × 10-6). To investigate whether the genetic risk of atrial fibrillation (AF) is associated with LA traits that precede overt AF, we produced a polygenetic risk score for AF. We found that polygenetic risk for AF is associated with increased LA volume and decreased LA function in participants without AF [LAmax 0.25 (mL/m2)/standard deviation (SD), 95% confidence interval (CI) (0.15; 0.36), P = 5.13 × 10-6; LAmin 0.21 (mL/m2)/SD, 95% CI (0.15; 0.28), P = 1.86 × 10-10; LA active emptying fraction -0.35%/SD, 95% CI (-0.43; -0.26), P = 3.14 × 10-14]. CONCLUSION: We report on 18 genetic loci associated with LA volume and function and show evidence for several plausible candidate genes important for LA structure.
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Apêndice Atrial , Fibrilação Atrial , Fibrilação Atrial/genética , Função do Átrio Esquerdo , Estudo de Associação Genômica Ampla , Átrios do Coração/diagnóstico por imagem , Humanos , Estudos ProspectivosRESUMO
OBJECTIVES: To determine whether electrocardiogram (ECG) markers are associated with incident non-Alzheimer's dementia (non-AD) and whether these markers also improve risk prediction for non-AD. MATERIALS AND METHODS: We retrospectively included 170,605 primary care patients aged 60 years or older referred for an ECG by their general practitioner and followed them for a median of 7.6 years. Using Cox regression, we reported hazard ratios (HRs) for electrocardiogram markers. Subsequently, we evaluated if addition of these electrocardiogram markers to a clinical model improved risk prediction for non-AD using change in area under the receiver-operator characteristics curve (AUC). RESULTS: The 5-year cumulative incidence of non-AD was 3.4 %. Increased heart rate (HR=1.06 pr. 10 bpm [95% confidence interval: 1.04-1.08], p<0.001), shorter QRS duration (HR=1.07 pr. 10 ms [1.05-1.09], p<0.001), elevated J-amplitude (HR=1.16 pr. mm [1.08-1.24], p<0.001), decreased T-peak amplitude (HR=1.02 pr. mm [1.01-1.04], p=0.002), and increased QTc (HR=1.08 pr. 20 ms [1.05-1.10], p<0.001) were associated with an increased rate of non-AD. Atrial fibrillation on the ECG (HR=1.18 [1.08-1.28], p<0.001) Sokolow-Lyon index > 35 mm (HR=1.31 [1.18-1.46], p<0.001) and borderline (HR=1.18 [1.11-1.26], p<0.001) or abnormal (HR=1.40 [1.27-1.55], p<0.001) QRS-T angle were also associated with an increased rate of non-AD. Upon addition of ECG markers to the Cox model, 5-year and 10-year C-statistic (AUC) improved significantly (delta-AUC, 0.36 [0.18-0.50] and 0.20 [0.03-0.35] %-points, respectively). CONCLUSIONS: ECG markers typical of an elevated cardiovascular risk profile were associated with non-AD and improved both 5-year and 10-year risk predictions for non-AD.
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Demência , Eletrocardiografia , Demência/diagnóstico , Humanos , Atenção Primária à Saúde , Estudos Retrospectivos , Fatores de RiscoRESUMO
AIM: To investigate the effect of diabetes duration on glycaemic control, measured using mean glycated haemoglobin (HbA1c) level, and mortality risk within different age, sex and clinically relevant, comorbidity-defined subgroups in an elderly population with type 2 diabetes (T2D). METHODS: We studied older (≥65 years) primary care patients with T2D, who had three successive annual measurements of HbA1c taken between 2005 and 2013. The primary exposure was the mean of all three HbA1c measurements. Follow-up began on the date of the third measurement. Individual mean HbA1c levels were categorized into clinically relevant groups (<6.5% [<48 mmol/mol]; 6.5%-6.9% [48-52 mmol/mol]; 7%-7.9% [53-63 mmol/mol]; 8%-8.9% [64-74 mmol/mol]; and ≥9% [≥75 mmol/mol]). We used multiple Cox regression to study the effect of glycaemic control on the hazard of all-cause mortality, adjusted for age, sex, use of concomitant medication, and age- and disease-related comorbidities. RESULTS: A total of 9734 individuals were included. During a median (interquartile range) follow-up of 7.3 (4.6-8.7) years, 3320 individuals died. We found that the effect of mean HbA1c on all-cause mortality depended on the duration of diabetes (P for interaction <.001). For individuals with short diabetes duration (<5 years), the risk of death increased with poorer glycaemic control (increasing HbA1c), whereas for individuals with longstanding diabetes (≥5 years), we found a J-shaped association, where a mean HbA1c level between 6.5% and 7.9% [48 and 63 mmol/mol] was associated with the lowest risk of death. For individuals with longstanding diabetes, both low (<6.5% [<48 mmol/mol]; hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.07-1.37, P = .002) and high mean HbA1c levels (≥9.0% [≥75 mmol/mol]; HR 1.60, 95% CI 1.28-1.99, P < .001) were associated with an increased risk of death. We also calculated 5-year absolute risks of all-cause mortality, separately for short and long diabetes duration, and found similar risk patterns across different age groups, sex and comorbidity strata. CONCLUSIONS: In elderly individuals with T2D, the effect of glycaemic control (measured by HbA1c) on all-cause mortality depended on the duration of diabetes. Of particular clinical importance, we found that strict glycaemic control was associated with an increased risk of death among individuals with long (≥ 5 years) diabetes duration. Conversely, for individuals with short diabetes duration, strict glycaemic control was associated with the lowest risk of death. These results indicate that tight glycemic control may be beneficial in people with short duration of diabetes, whereas a less stringent target may be warranted with longer diabetes exposure.
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Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/patologia , Controle Glicêmico , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Causas de Morte , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/terapia , Progressão da Doença , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Mortalidade , Fatores de Risco , Fatores de TempoRESUMO
PURPOSE: We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality compared with noncarriers. METHODS: All BrS-associated variants were identified using the Human Gene Mutation Database (HGMD). Individuals were randomly selected from a general population study using whole-exome sequencing data (n = 870) and genotype array data (n = 6,161) and screened for BrS-associated variants. Electrocardiograms (ECG) were analyzed electronically, and data on syncope, ventricular arrhythmias, and mortality were obtained from administrative health-care registries. RESULTS: In HGMD, 382 BrS-associated genetic variants were identified. Of these, 28 variants were identified in the study cohort. None of the carriers presented with type 1 BrS ECG pattern. Mean J-point elevation in V1 and V2 were within normal guideline limits for carriers and noncarriers. There was no difference in syncope susceptibility (carriers 8/624; noncarriers 98/5,562; P = 0.51), ventricular arrhythmia (carriers 4/620; noncarriers 9/5,524; P = 0.24), or overall mortality (hazard ratio 0.93, 95% CI 0.63-1.4). CONCLUSIONS: Our data indicate that a significant number of BrS-associated variants are not the monogenic cause of BrS.Genet Med advance online publication 06 October 2016.
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Arritmias Cardíacas/epidemiologia , Síndrome de Brugada/genética , Síndrome de Brugada/mortalidade , Variação Genética , Coração/fisiopatologia , Síncope/epidemiologia , Adulto , Arritmias Cardíacas/etiologia , Síndrome de Brugada/complicações , Síndrome de Brugada/fisiopatologia , Dinamarca/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Distribuição Aleatória , Sistema de Registros , Síncope/etiologia , Sequenciamento do Exoma/métodosRESUMO
AIMS: We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers. METHODS AND RESULTS: All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) and 95 of 5861 (1.6%) individuals, respectively, had experienced syncope during follow-up (P = 0.80). There was no significant difference in overall mortality rates between carriers [7/217 (3.2%)] and non-carriers [301/6453 (4.7%)] (P = 0.24). CONCLUSION: We present QTc data and register data, indicating that 26 cLQTS-associated variants neither had any effect on the QTc intervals nor on syncope propensity or overall mortality. Based on the frequency of individual gene variants, we suggest that the 10 variants frequently identified, assumed to relate to cLQTS, are less likely to associate with a dominant monogenic form of the disease.
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Síndrome do QT Longo/genética , Mutação/genética , Dinamarca/epidemiologia , Eletrocardiografia , Feminino , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Frequência Cardíaca/fisiologia , Heterozigoto , Humanos , Síndrome do QT Longo/congênito , Síndrome do QT Longo/mortalidade , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Fatores de Risco , Síncope/genéticaRESUMO
POPDC2 encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia and morpholino knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy. Using homology modelling we show that the identified POPDC2 variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies we demonstrated that, while co-expression of wild-type POPDC2 with TREK-1 increased TREK-1 current density, POPDC2 variants found in the patients failed to increase TREK-1 current density. While patient muscle biopsy did not show clear myopathic disease, it showed significant reduction of the expression of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in any of the two proteins. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and 2 was most prevalent in AV node, AV node pacemaker and AV bundle cells. Sinoatrial node cells expressed POPDC2 abundantly, but expression of POPDC1 was sparse. Together, these results concur with predisposition to AV node disease in humans with loss-of-function variants in POPDC1 and POPDC2 and presence of sinus node disease in POPDC2, but not in POPDC1 related disease in human. Using population-level genetic data of more than 1 million individuals we showed that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for POPDC2 as the cause of a novel Mendelian autosomal recessive cardiac syndrome, consistent with previous work showing that mice and zebrafish deficient in functional POPDC2 display sinus and AV node dysfunction.
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We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cirrose Hepática , Humanos , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/genética , Alanina Transaminase/sangue , Polimorfismo de Nucleotídeo Único , Masculino , Lipase/genética , Feminino , gama-Glutamiltransferase/genética , Proteínas de Membrana/genética , Estudos de Coortes , Estudos de Casos e Controles , Herança Multifatorial/genética , Fatores de Risco , Variação GenéticaRESUMO
Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. Design, Setting, and Participants: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. Exposure: Genotype. Main Outcomes and Measures: Pericarditis. Results: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10-16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10-8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein ß (encoded by CEBPB). Conclusions and Relevance: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1-blocking drugs.
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Estudo de Associação Genômica Ampla , Humanos , Masculino , Adolescente , Feminino , Genótipo , Fenótipo , Frequência do Gene , FinlândiaRESUMO
Importance: An animal (mouse) study indicated that deficiency of proprotein convertase subtilisin/kexin type 9 (PCSK9) causes cardiac remodeling and heart failure (HF). Cardiac remodeling after PCSK9-inhibitor treatment is a concern for patients and for development of treatment directed against PCSK9. Objective: To determine whether genetic variants in the PCSK9 gene are associated with altered cardiac structure, cardiac function, and HF in humans. Design, Setting, Participants: This was a nested case-control study within the UK Biobank. Between March 13, 2006, and October 1, 2010, the UK Biobank enrolled 502â¯480 individuals aged 40 to 69 years. This study focused on a subset of those individuals, who completed cardiac magnetic resonance (CMR) imaging and had available genetic data. Analyses were conducted between November 2, 2021, and October 28, 2022. Exposures: Carrier status of predicted loss-of-function (pLoF) PCSK9 variants, R46L missense variant, and a genetic risk score (GRS). Main Outcomes and Measures: A total of 11 CMR imaging measurements, generated using a machine learning algorithm, and HF diagnosis. Results: In up to 35â¯135 individuals with CMR images, 18â¯252 (52%) were female individuals, and mean (SD) age was 55.0 (7.4) years. No significant association between PCSK9 carrier status and CMR indices were found for left ventricular mass (pLoF: ß = -1.01; 95% CI, -2.99 to 0.98; P = .32; R46L: ß = -0.18; 95% CI, -0.55 to 0.19; P = .35; GRS: ß = -0.19; 95% CI, -0.50 to 0.11; P = .22) and left ventricular ejection fraction (pLoF: ß = 0.43; 95% CI, -1.32 to 2.18; P = .63; R46L: ß = -0.19; 95% CI, -0.52 to 0.14; P = .26; GRS: ß = -0.08; 95% CI, -0.35 to 0.20; P = .58) or HF (pLoF: odds ratio [OR], 1.14; 95% CI, 0.56-2.05; P = .69; R46L: OR, 0.99; 95% CI, 0.90-1.10; P = .91; GRS: OR, 1.04; 95% CI, 0.96-1.13; P = .32). Conclusions and Relevance: Results of this case-control study suggest that there was no association between PCSK9 genetic variants and altered cardiac structure, cardiac function, or HF in humans.
Assuntos
Insuficiência Cardíaca , Pró-Proteína Convertase 9 , Humanos , Feminino , Animais , Camundongos , Masculino , Pró-Proteína Convertase 9/genética , Estudos de Casos e Controles , Volume Sistólico , Remodelação Ventricular/genética , Função Ventricular Esquerda , Insuficiência Cardíaca/genéticaRESUMO
OBJECTIVE: The association between common electrocardiogram (ECG) markers and Alzheimer's disease has been scarcely investigated, and it is unknown if ECG markers can improve risk prediction. Thus, we aimed to examine the association between common ECG markers and Alzheimer's disease in a large population. METHODS: We studied the association between ECG markers and Alzheimer's disease using Cox models with adjustment for age, sex, and comorbidities using a large primary care population of patients aged 60 years or more. RESULTS: We followed 172,236 subjects for a median of 7.5 years. Increased PR interval (hazard ratio for PR > 188 ms: 0.76 [95% confidence interval: 0.69-0.83, p < 0.001) and increased QTc interval (hazard ratio for QTc = [426;439]: 0.90 [0.83-0.98], p = 0.02) were associated with a decreased rate of Alzheimer's disease. A positive Sokolow-Lyon index >35 mm (1.22 [1.13-1.33], p < 0.001) and increased T-wave amplitude >4.1 mm (1.15 [1.04-1.27]) were associated with an increased rate of Alzheimer's disease. Upon addition of ECG markers to a reference model, 10-year prediction area under the receiver-operator characteristics curve (AUC) improved by 0.39 [0.06-0.67] %-points. The 10-year absolute risk of Alzheimer's disease was 6.5% and 5.2% for an 82-year old female and a male, respectively, with a favorable ECG, and 12% and 9.2%, respectively, with an unfavorable ECG, almost twice as high. CONCLUSIONS: We identified several common ECG markers which were associated with Alzheimer's disease, and which improved risk prediction for Alzheimer's disease.
Assuntos
Doença de Alzheimer , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Eletrocardiografia , Comorbidade , Biomarcadores , Atenção Primária à SaúdeRESUMO
We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5. We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).
Assuntos
Trombose , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/genética , Tromboembolia Venosa/epidemiologia , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Fatores de RiscoRESUMO
OBJECTIVE: To evaluate the association between PCSK9 predicted loss-of-function (pLoF) variants and glycemic traits, hepatobiliary function, and neurocognitive traits. RESEARCH DESIGN AND METHODS: We identified carriers of PCSK9 pLoF variants in UK Biobank exome sequencing data. We assessed the aggregate effects of these variants on lipid and lipoprotein traits, which served as a positive control. Association of PCSK9 pLoF carrier status and glycemic traits, hepatobiliary function, and neurocognitive traits was then evaluated as a measure for adverse effects. RESULTS: We identified 374 individuals carrying one of 41 unique PCSK9 pLoF variants. As expected, we found that PCSK9 pLoF carriers had significantly lower LDL cholesterol C levels (P = 7.4 × 10-55) and apolipoprotein B levels (P = 7.6 × 10-50) than did noncarriers. However, we found no significant associations between pLoF carrier status and glycemic traits, hepatobiliary function, and neurocognitive traits (P > 0.05). CONCLUSIONS: Our results do not support adverse effects of PCSK9 pLoF variants on glycemic traits, hepatobiliary function, or neurocognitive traits.
Assuntos
Apolipoproteínas B , Pró-Proteína Convertase 9 , Heterozigoto , Humanos , Fenótipo , Pró-Proteína Convertase 9/genéticaRESUMO
Background Results from animal models and observational studies have raised concerns regarding the potential cataractogenic effects of statin treatment. We investigated whether common and rare genetic variants in HMGCR are associated with cataract risk, to gauge the likely long-term effects of statin treatment on lenticular opacities. Methods and Results We used genotyping data and exome sequencing data of unrelated European individuals in the UK Biobank to test the association between genetically proxied inhibition of HMGCR and cataract risk. First, we constructed an HMGCR genetic score consisting of 5 common variants weighted by their association with low-density lipoprotein cholesterol. Second, we analyzed exome sequencing data to identify carriers of predicted loss-of-function mutations in HMGCR. Common and rare variants in aggregate were then tested for association with cataract and cataract surgery. In an analysis of >402 000 individuals, a 38.7 mg/dL (1 mmol/L) reduction in low-density lipoprotein C by the HMGCR genetic score was associated with higher risk for cataract (odds ratio, 1.14 [95% CI, 1.00-1.39], P=0.045) and cataract surgery (odds ratio, 1.25 [95% CI, 1.06-1.48], P=0.009). Among 169 172 individuals with HMGCR sequencing data, we identified 32 participants (0.02%), who carried a rare HMGCR predicted loss-of-function variant. Compared with noncarriers, heterozygous carriers of HMGCR predicted loss-of-function had a higher risk of developing cataract (odds ratio, 4.54 [95% CI, 1.96-10.53], P=0.001) and cataract surgery (odds ratio, 5.27 [95% CI, 2.27-12.25], P=5.37×10-4). In exploratory analyses, we found no significant association between genetically proxied inhibition of PCSK9, NPC1L1, or circulating low-density lipoprotein cholesterol levels (P>0.05 for all) and cataract risk. Conclusions We found that genetically proxied inhibition of the HMGCR gene mimicking long-term statin treatment associated with higher risk of cataract. Clinical trials with longer follow-up are needed to confirm these findings.