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AIMS: Inflammation accompanies heart failure (HF) and elevated levels of inflammatory biomarkers are linked to new onset of HF. However, whether the prognostic relevance of inflammatory biomarkers is different in HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) is unclear. The aim of the current study is to explore the role of inflammation on the mortality risk in patients with HF. METHODS: We analysed interleukin-6 and hsCRP levels by ELISA and immunonephelometry, respectively, in HFpEF and HFrEF patients referred for coronary angiography and assessed the prognostic value in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. RESULTS: HF was present in 1086 patients (N = 506 HFpEF; N = 580 HFrEF; mean age 65 ± 10 years; 28% female). Increasing IL-6 levels were significantly associated with increased CV mortality in HFpEF [1.5 (95% CI: 1.1-2.2), P = 0.018] but not HFrEF [HR 1.3 (95% CI: 1.0-1.7), P = 0.06] patients. High-sensitive CRP followed a similar pattern but failed to reach statistical significance after full-adjustment (HFpEF: HR 1.4 95%C I: 1.0-2.0; P = 0.065; HFrEF HR: 1.0 95% CI: 0.7-1.3; P = 0.800). Interaction analysis in patients stratified by IL-6 and N terminal pro brain natriuretic peptide (NT-proBNP) above and below the median revealed a stepwise increase in CV-mortality in HFpEF (P = 0.036) but not HFrEF patients (P = 0.220). To investigate the relationship between IL-6 and NT-proBNP, we assessed the genetic IL6-Receptor variant p.Asp358Ala (rs2228145) which is linked to impaired IL-6 receptor signalling. Homozygous carriers with HFpEF but not HFrEF exhibited significantly lower NT-pro-BNP levels compared with wildtype carriers (HFpEF 779 pg/mL ± 787 vs. 1180 pg/ mL ± 1532; P = 0.008; HFrEF 2289 pg/ mL ± 3439 vs. 2326 pg/ mL ± 3386; P = 0.94), raising the hypothesis that IL-6 signalling may play a pathophysiological role in HFpEF. CONCLUSIONS: These data suggest a predictive value of elevated IL-6 for CV-mortality in HFpEF but not in HFrEF patients.
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Background Trigeminal neuralgia (TN) is a craniofacial pain characterized by sudden onset, brief, severe, recurrent shooting pain within one or more branches of the trigeminal nerve (CN V). Based on its clinical presentation, TN may be classified as purely paroxysmal or paroxysmal with concomitant continuous pain (CCP), previously known as typical and atypical, respectively. Microvascular decompression (MVD) surgery for releasing the CN V from a neurovascular conflict is an effective and safe treatment for TN. During MVD of patients manifesting TN with CCP, the involvement of an abnormal arachnoid tissue is a common finding. The etiology and pathophysiology behind the appearance of this tissue are unknown; however, it is more commonly found in this variant of the disease. Methods From January 2015 to December 2016, a total of 330 patients diagnosed with TN were evaluated at our clinic. Among them, 31 individuals (9.4%) presented with paroxysmal TN with CCP, with 16 patients (51.6%) undergoing MVD. During surgery, samples of altered arachnoid tissue were collected from five patients and subjected to Hematoxylin-Eosin staining and immunohistochemistry for S100 and CD2 Results In a long-term follow-up, 80% of patients operated by DMV remains pain free. Analysis of biopsies revealed chronic fibrosis (n=4), hyperplasia of neurothelial cells (n=3), dystrophic calcifications (n=1). Immunohistochemistry was positive for S100 (n=3) and CD20 (n=3) inflammatory markers. Conclusion Chronic inflammation in the arachnoid tissue involved in paroxysmal TN with CCP could be a contributor to the pathophysiology of this variant of the disease.
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BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics. METHODS: We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups. RESULTS: We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10-6), including the PCSK9 gene locus and five other lipid loci: APOB, TM6SF2, FADS1/FADS2, JMJD1C, and HP/HPR. The interaction analysis revealed eight loci with sex- and/or statin-interactions. At the PCSK9 gene locus, there were four independent signals, one with a significant sex-interaction showing stronger effects in men (rs693668). Regarding statin treatment, there were two significant interactions in PCSK9 missense mutations: rs11591147 had stronger effects in statin-free individuals, and rs11583680 had stronger effects in statin-treated individuals. Besides replicating known loci, we detected two novel genome-wide significant associations: one for statin-treated individuals at 6q11.1 (within KHDRBS2) and one for males at 12q24.22 (near KSR2/NOS1), both with significant interactions. In the MR of PCSK9 on LDL-C, we observed significant causal estimates within all subgroups, but significantly stronger causal effects in statin-free subjects compared to statin-treated individuals. CONCLUSIONS: We performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors.
The protein "proprotein convertase subtilisin/kexin type 9" (PCSK9) regulates the levels of low-density lipoprotein cholesterol (LDL-C) in blood, and thus, contributes to the risk of cardio-vascular diseases. Women tend to have higher PCSK9 plasma levels throughout their life, although the difference is smaller in patients under LDL-C lowering medication (e.g., statins). We investigated the interplay of genetics, statin-treatment and sex, using combined data from six European studies. We detected 11 genetic regions associated with PCSK9 levels, of which one was specific for women (at SLCO1B3, a statin-transporter gene), and three were specific for men (e.g., ALOX5, encoding a protein linked to chronic inflammatory diseases such as atherosclerosis). We also tested if statin use changed the genetic effect and found five genes only associated with PCSK9 levels in untreated participants. Variants in the gene encoding PCSK9 were most strongly associated and had heterogeneous effects in dependence on statin treatment and sex: On one hand, there were genetic variants with stronger effects in men than women. Those variants are also linked to sex-differential gene expression of PCSK9. On the other hand, there were also variants with treatment-depending effects, linked to protein structure and functionality of PCSK9. This indicates that the observed sexual and treatment-related effects on PCSK9 levels have a genetic basis. In addition, we compared the causal effects of PCSK9 on LDL-C levels between men and women and found a different response to statin treatment. This highlights the need for sex-sensitive dosages of lipid-lowering medication.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Masculino , Humanos , Feminino , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Estudo de Associação Genômica Ampla , LDL-Colesterol/genética , Oxirredutases N-Desmetilantes , Histona Desmetilases com o Domínio JumonjiRESUMO
ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.
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Moléculas de Adesão Celular , Fator VIII , Cininogênios , Lectinas Tipo C , Receptores de Superfície Celular , Fator de von Willebrand , Humanos , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo , Fator VIII/genética , Fator VIII/metabolismo , Polimorfismo de Nucleotídeo Único , Células Endoteliais da Veia Umbilical Humana/metabolismo , Análise da Randomização Mendeliana , Estudo de Associação Genômica Ampla , Trombose/genética , Trombose/sangue , Estudos de Associação Genética , Masculino , Células Endoteliais/metabolismo , FemininoRESUMO
AIMS: To investigate the prevalence of familial hypercholesterolaemia (FH) and compare the performance of clinical criteria and genetic testing in patients undergoing coronary angiography. METHODS: The prevalence of FH was determined with the Dutch Lipid Clinical Network (DLCN), US-MEDPED, Simon Broome (SB) criteria, the 'Familial Hypercholesterolaemia Case Ascertainment Tool' (FAMCAT), and a clinical algorithm. Genetic screening was conducted with a custom array from Affymetrix (CARRENAL array) harboring 944 FH mutations. RESULTS: The study cohort consisted of 3267 patients (78.6% with coronary artery disease [CAD]). FH was diagnosed in 2.8%, 2.2%, 3.9%, and 7.9% using the DLCN, US-MEDPED, SB criteria, and the FAMCAT. The clinical algorithm identified the same patients as the SB criteria. Pathogenic FH mutations were found in 1.2% (1.2% in patients with CAD, 1.0% in patients without CAD). FH was more frequently diagnosed in younger patients. With genetic testing as reference, the clinical criteria achieved areas under the ROC curve (AUCs) in the range of 0.56-0.68. Using only LDL-C corrected for statin intake, an AUC of 0.68 was achieved. CONCLUSION: FH is up to fourfold more prevalent in patients undergoing coronary angiography than in contemporary cohorts representing the general population. Different clinical criteria yield substantially different diagnosis rates, overestimating the prevalence of FH compared to genetic testing. LDL-C testing alone may be sufficient to raise the suspicion of FH, which then needs to be corroborated by genetic testing.
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X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
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Androgênios , Estudo de Associação Genômica Ampla , Humanos , Masculino , Feminino , Androgênios/genética , Rim , Cromossomos Humanos X/genética , Elementos de Resposta , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Tetraspaninas/genéticaRESUMO
BACKGROUND: Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes. METHODS: For this cohort analysis, 927 participants aged 18-69 years from the German Diabetes Study (GDS) with recent-onset type 2 diabetes were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualised for age and sex. Insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, insulin secretion was assessed by intravenous glucose tolerance test, hepatic lipid content was assessed by 1 H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 were assessed by ELISA, and peripheral and autonomic neuropathy were assessed by functional and clinical measures. Participants were followed up for up to 16 years. We also investigated heart failure and all-cause mortality in 794 individuals with type 2 diabetes undergoing invasive coronary diagnostics from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort. FINDINGS: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·0001) and insulin secretion (pdim1<0·0001, pdim2=0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, pdim1<0·0001, pdim2=0·037), pro-inflammatory biomarkers (IL-6: n=348, pdim1<0·0001, pdim2=0·013; IL-18: n=350, pdim1<0·0001, pdim2=0·38), and elevated cardiovascular risk (nevents=143, pdim1=0·14, pdim2<0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (nevents=184, pdim1=0·012, pdim2=0·044) and cardiac autonomic neuropathy (nevents=118, pdim1=0·0094, pdim2=0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (nevents=488, pdim1=0·12, pdim2=0·0032). Significant gradients differentiated individuals having heart failure with preserved ejection fraction from those who had heart failure with reduced ejection fraction. INTERPRETATION: These data define the pathophysiological underpinnings of the tree structure, which has the potential to stratify diabetes-related complications on the basis of routinely available variables and thereby expand the toolbox of precision diabetes diagnosis. FUNDING: German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, European Community, German Research Foundation, and Schmutzler Stiftung.
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Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Resistência à Insulina , Humanos , Interleucina-18 , Estudos Prospectivos , Insulina/uso terapêutico , LipídeosRESUMO
INTRODUCTION: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is an easily available parameter of vascular stiffness, but its impact on CVM in chronic dialysis patients with diabetes is unclear. METHODS: Therefore, we have examined the predictive value of baseline, predialytic PP, SBP, DBP, and MAP in the German Diabetes and Dialysis (4D) study, a prospective, randomized, double-blind trial enrolling 1,255 patients with type 2 diabetes on hemodialysis in 178 German dialysis centers. RESULTS: Mean age was 66.3 years, mean blood pressure 146/76 mm Hg, mean time suffering from diabetes 18.1 years, and mean time on maintenance dialysis 8.3 months. Considered as continuous variables, PP, MAP, SBP, and DBP could not provide a significant mortality prediction for either cardiovascular or all-cause mortality. After dividing the cohort into corresponding tertiles, we also did not detect any significant mortality prediction for PP, SBP, DBP, or MAP, both for all-cause mortality and CVM after adjusting for age and sex. Nevertheless, when comparing the HR plots of the corresponding blood pressure parameters, a pronounced U-curve was seen for PP for both all-cause mortality and CVM, with the trough range being 70-80 mm Hg. DISCUSSION: In patients with end-stage renal disease and long-lasting diabetes mellitus predialytic blood pressure parameters at study entry are not predictive for mortality, presumably because there is a very high rate of competing mortality risk factors, resulting in overall very high rates of all-cause and CVM that may no longer be significantly modulated by blood pressure control.
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Diabetes Mellitus Tipo 2 , Hipertensão , Humanos , Idoso , Pressão Sanguínea/fisiologia , Diabetes Mellitus Tipo 2/complicações , Estudos Prospectivos , Diálise Renal , Fatores de RiscoRESUMO
The structure of (R)-rasagiline mesylate [(R)-RasH+·Mes-], an active pharmaceutical ingredient used to treat Parkinson's disease, is presented. The structure was determined from laboratory and synchrotron powder diffraction data, refined using the Rietveld method, and validated and optimized using dispersion-corrected DFT calculations. The unit-cell parameters obtained in both experiments are in good agreement and the refinement with both datasets converged to good agreement factors. The final parameters obtained from laboratory data were a = 5.4905â (8), b = 6.536â (2), c = 38.953â (3)â Å, V = 1398.0â (4)â Å3 and from synchrotron powder data were a = 5.487530â (10)â Å, b = 6.528939â (12)â Å, c = 38.94313â (9)â Å, V = 1395.245â (5)â Å3 with Z = 4 and space group P212121. Preferred orientation was properly accounted for using the synchrotron radiation data, leading to a March-Dollase parameter of 1.140â (1) instead of the 0.642â (1) value obtained from laboratory data. In the structure, (R)-RasH+ moieties form layers parallel to the ab plane connected by mesylate ions through N-H...O and C-H...O hydrogen bonds. These layers stack along the c axis and are further connected by C-H...π interactions. Hirshfeld surface analysis and fingerprint plot calculations indicate that the main interactions are: H...H (50.9%), H...C/C...H (27.1%) and H...O/O...H (21.1%).
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A compilation of articles with a strong teaching element published since 2018 is presented alongside an overview of the articles in the special issue on this topic.
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BACKGROUND: Heterogeneous metabolic clusters have been identified in diabetic and prediabetic states. It is not known whether such pathophysiologic clusters impact survival in at-risk persons being evaluated for coronary heart disease. METHODS: The LURIC Study recruited patients referred for coronary angiography at a median age of 63 (IQR 56-70) with a follow-up of 16.1 (IQR 9.6, 17.7) years. Clustering of 1269 subjects without diabetes was performed with oGTT-derived glucose and insulin; fasting triglyceride, high-density lipoprotein, BMI, waist and hip circumference. Patients with T2D (n = 794) were clustered using age, BMI, glycemia, homeostasis model assessment, and islet autoantibodies. Associations of clusters with mortality were analysed using Cox regression. RESULTS: Individuals without diabetes were classified into six subphenotypes, with 884 assigned to subjects at low-risk (cluster 1,2,4) and 385 at high-risk (cluster 3,5,6) for diabetes. We found significantly increased mortality in clusters 3 (hazard ratio (HR)1.42), 5 (HR 1.43), and 6 (HR 1.46) after adjusting for age, BMI, HbA1c and sex. In the T2D group, 508 were assigned to mild age-related diabetes (MARD), 183 to severe insulin-resistant diabetes (SIRD), 84 to mild obesity-related diabetes (MOD), 19 to severe insulin-deficient diabetes (SIDD). Compared to the low-risk non-diabetes group, crude mortality was not different in MOD. Increased mortality was found for MARD (HR 2.2), SIRD (HR 2.2), and SIDD (HR 2.5). CONCLUSIONS: Metabolic clustering successfully stratifies survival even among persons undergoing invasive coronary diagnostics. Novel clustering approaches based on glucose metabolism can identify persons who require special attention as they are at risk of increased mortality.
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Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Humanos , Pessoa de Meia-Idade , Idoso , Estado Pré-Diabético/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Insulina , Autoanticorpos , Angiografia CoronáriaRESUMO
Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( SERPINA1, ZFP36L2 , and TLR10) signals contain predicted deleterious missense variants. Two loci, SOCS3 and HPN , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( FGG;FGB;FGA ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation. Key Points: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
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Background: Different observations have suggested that patients with depression have a higher risk for a number of comorbidities and mortality. The underlying causes have not been fully understood yet. Aims: The aim of our study was to investigate the association of a genetic depression risk score (GDRS) with mortality [all-cause and cardiovascular (CV)] and markers of depression (including intake of antidepressants and a history of depression) in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study involving 3,316 patients who had been referred for coronary angiography. Methods and results: The GDRS was calculated in 3,061 LURIC participants according to a previously published method and was found to be associated with all-cause (p = 0.016) and CV mortality (p = 0.0023). In Cox regression models adjusted for age, sex, body mass index, LDL-cholesterol, HDL-cholesterol, triglycerides, hypertension, smoking, and diabetes mellitus, the GDRS remained significantly associated with all-cause [1.18 (1.04-1.34, p = 0.013)] and CV [1.31 (1.11-1.55, p = 0.001)] mortality. The GDRS was not associated with the intake of antidepressants or a history of depression. However, this cohort of CV patients had not specifically been assessed for depression, leading to marked underreporting. We were unable to identify any specific biomarkers correlated with the GDRS in LURIC participants. Conclusion: A genetic predisposition for depression estimated by a GDRS was independently associated with all-cause and CV mortality in our cohort of patients who had been referred for coronary angiography. No biomarker correlating with the GDRS could be identified.
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Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Insulina/genética , Estudo de Associação Genômica Ampla , Resistência à Insulina/genética , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Glicemia/genéticaRESUMO
BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
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Proteína C , Proteína S , Proteína C/genética , Proteína S/genética , Estudo de Associação Genômica Ampla , Antitrombinas , Transcriptoma , Anticoagulantes , Antitrombina III/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Branched-chain amino acids (BCAAs) are effectors of metabolic diseases, but their impact on mortality is largely unknown. We investigated the association of BCAA with risk factors and mortality in 2,236 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study using linear and Cox regression. Adiponectin, hemoglobin, C-peptide, hemoglobin A1c, and homoarginine showed the strongest association with BCAA concentration (all p < 0.001). During a median follow-up of 10.5 years, 715 participants died, including 450 cardiovascular-related deaths. BCAA concentrations were inversely associated with the risk of all-cause and cardiovascular mortality (HR [95% CI] per 1-SD increase in log-BCAA: 0.75 [0.69-0.82] and 0.72 [0.65-0.80], respectively) after adjustment for potential confounders. BCAAs are directly associated with metabolic risk but inversely with mortality in persons with intermediate-to-high cardiovascular risk. Further studies are warranted to evaluate the diagnostic and therapeutic utility of BCAA in the context of cardiovascular diseases.
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Previous studies have reported an association between ABO type blood group and cardiovascular (CV) events and outcomes. The precise mechanisms underpinning this striking observation remain unknown, although differences in von Willebrand factor (VWF) plasma levels have been proposed as an explanation. Recently, galectin-3 was identified as an endogenous ligand of VWF and red blood cells (RBCs) and, therefore, we aimed to explore the role of galectin-3 in different blood groups. Two in vitro assays were used to assess the binding capacity of galectin-3 to RBCs and VWF in different blood groups. Additionally, plasma levels of galectin-3 were measured in different blood groups in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (2571 patients hospitalized for coronary angiography) and validated in a community-based cohort of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (3552 participants). To determine the prognostic value of galectin-3 in different blood groups, logistic regression and cox regression models were used with all-cause mortality as the primary outcome. First, we demonstrated that galectin-3 has a higher binding capacity for RBCs and VWF in non-O blood groups, compared to blood group O. Additionally, LURIC patients with non-O blood groups had substantially lower plasma levels of galectin-3 (15.0, 14.9, and 14.0 µg/L in blood groups A, B, and AB, respectively, compared to 17.1 µg/L in blood group O, p < 0.0001). Finally, the independent prognostic value of galectin-3 for all-cause mortality showed a non-significant trend towards higher mortality in non-O blood groups. Although plasma galectin-3 levels are lower in non-O blood groups, the prognostic value of galectin-3 is also present in subjects with a non-O blood group. We conclude that physical interaction between galectin-3 and blood group epitopes may modulate galectin-3, which may affect its performance as a biomarker and its biological activity.
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Galectina 3 , Fator de von Willebrand , Humanos , Fator de von Willebrand/metabolismo , Prognóstico , Sistema ABO de Grupos Sanguíneos , Rim/metabolismoRESUMO
Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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Diabetes Mellitus Tipo 2 , Proinsulina , Humanos , Proinsulina/genética , Proinsulina/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Estudo de Associação Genômica Ampla/métodos , Insulina/genética , Insulina/metabolismo , Glucose , Fatores de Transcrição/genética , Proteínas de Homeodomínio/genéticaRESUMO
BACKGROUND: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. OBJECTIVES: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. METHODS: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. RESULTS: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10-7) and EPIC arrays (p < 5.78 × 10-8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. CONCLUSION: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.
Assuntos
Metilação de DNA , Epigênese Genética , Humanos , Estudo de Associação Genômica Ampla/métodos , Loci Gênicos , Inflamação/genética , Fibrinogênio/genética , Ilhas de CpGRESUMO
Although neurohormones and Renin-Angiotensin-Aldosterone-System (RAAS) components are important predictors of cardiovascular mortality (CVM), their importance for predicting outcomes in patients with/without RAAS-blockers and different degrees of arterial stiffness is less understood. We therefore analyzed long-term data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study in 3316 patients subdivided according to pulse pressure (PP) and RAAS-blocker use. Patients on RAAS-inhibition had higher renin and noradrenaline, lower aldosterone and aldosterone/renin quotient (ARQ). Renin and noradrenaline significantly predicted CVM in patients without RAAS-blocker (HR = 1.17, 1.15) and in patients receiving angiotensin-converting-enzyme (ACE) inhibitors (HR = 1.17, 1.29), whereas aldosterone predicted CVM only in patients receiving ACE-inhibitors (HR = 1.13). CVM was predicted independently from PP by renin, noradrenaline and angiotensin II. Independently from RAAS inhibition renin decreased and ARQs increased with rising PP. Furthermore, noradrenaline increased with PP, but only without ACE-inhibition. The HR for CVM in the ACE-inhibitor group were 1.29, 1.28, 1.29 for renin in the first, second and third PP quartiles and 1.22, and 1.19 for aldosterone in the second and fourth quartile. Furthermore, we showed that noradrenaline predicts CVM in all PP quartiles in patients with ACE-inhibition. In the RAAS-blocker-free group, the HR for renin for CVM were 1.36 and 1.18 in the third and fourth PP quartiles, but neither aldosterone nor noradrenaline were predictive for CVM within the PP quartiles. Renin and noradrenaline are strong predictors of CVM regardless of RAAS blockade, whereas aldosterone is predictive only in the ACE-inhibitor group. Catecholamines but not renin are associated with rising PP.