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AIMS/HYPOTHESIS: Metabolic risk factors and plasma biomarkers for diabetes have previously been shown to change prior to a clinical diabetes diagnosis. However, these markers only cover a small subset of molecular biomarkers linked to the disease. In this study, we aimed to profile a more comprehensive set of molecular biomarkers and explore their temporal association with incident diabetes. METHODS: We performed a targeted analysis of 54 proteins and 171 metabolites and lipoprotein particles measured in three sequential samples spanning up to 11 years of follow-up in 324 individuals with incident diabetes and 359 individuals without diabetes in the Danish Blood Donor Study (DBDS) matched for sex and birth year distribution. We used linear mixed-effects models to identify temporal changes before a diabetes diagnosis, either for any incident diabetes diagnosis or for type 1 and type 2 diabetes mellitus diagnoses specifically. We further performed linear and non-linear feature selection, adding 28 polygenic risk scores to the biomarker pool. We tested the time-to-event prediction gain of the biomarkers with the highest variable importance, compared with selected clinical covariates and plasma glucose. RESULTS: We identified two proteins and 16 metabolites and lipoprotein particles whose levels changed temporally before diabetes diagnosis and for which the estimated marginal means were significant after FDR adjustment. Sixteen of these have not previously been described. Additionally, 75 biomarkers were consistently higher or lower in the years before a diabetes diagnosis. We identified a single temporal biomarker for type 1 diabetes, IL-17A/F, a cytokine that is associated with multiple other autoimmune diseases. Inclusion of 12 biomarkers improved the 10-year prediction of a diabetes diagnosis (i.e. the area under the receiver operating curve increased from 0.79 to 0.84), compared with clinical information and plasma glucose alone. CONCLUSIONS/INTERPRETATION: Systemic molecular changes manifest in plasma several years before a diabetes diagnosis. A particular subset of biomarkers shows distinct, time-dependent patterns, offering potential as predictive markers for diabetes onset. Notably, these biomarkers show shared and distinct patterns between type 1 diabetes and type 2 diabetes. After independent replication, our findings may be used to develop new clinical prediction models.
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Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. Functional annotation analysis indicated candidate genes HAND2, TBX3 and RAP2C/FRMD7 at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.
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Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Hemorragia Posparto , Humanos , Femenino , Hemorragia Posparto/genética , Embarazo , Predisposición Genética a la Enfermedad , Sitios Genéticos , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismoRESUMEN
BACKGROUND: Patients with atherosclerotic plaques containing high-risk features have an increased likelihood of events and a worse prognosis. Whether increased levels of Troponin I (TnI) and C-reactive protein (CRP) are associated with the presence of high-risk coronary atherosclerotic plaques (HRP) is not well described. We assessed the association between 1) TnI and 2) CRP with quantified coronary plaque burden, luminal diameter stenosis, and HRP in patients with low/intermediate pre-test probability of obstructive coronary artery disease (CAD) referred for coronary computed tomography angiography (CCTA). METHODS: The CCTA from 1615 patients were analyzed using a semiautomatic software for coronary artery plaque characterization. Patients with high TnI (>6 âng/L) and high CRP (>2 âmg/L) were identified. Associations of TnI and CRP with plaque burden, stenosis (≥50% luminal diameter stenosis on CCTA), and HRP were investigated. RESULTS: TnI and CRP were both positively correlated with total plaque burden (TnI rs â= â0.14, p â< â0.001; CRP rs â= â0.08, p â< â0.001). In multivariate logistic regression analyses, high TnI was associated with stenosis (OR 1.43, 95% confidence interval (CI) 1.03-1.99, p â= â0.034), the presence of HRP (OR 1.79, 95% CI: 1.17-2.74, p â= â0.008), and the subtypes of HRP; low attenuation plaque (OR 1.93, 95% CI: 1.24-3.00, p â= â0.003), and positive remodeling (OR 1.51, 95% CI: 1.07-2.13, p â= â0.018). For CRP, only stenosis and napkin ring sign correlated significantly. CONCLUSION: In patients with suspected CAD, TnI and CRP are associated with HRP features. These findings may suggest that inflammatory and particularly ischemic biomarkers might improve early risk stratification and affect patient management. GOV IDENTIFIER: NCT02264717.
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BACKGROUND: Despite recent guideline recommendations, quantitative perfusion (QP) estimates of myocardial blood flow from cardiac magnetic resonance (CMR) have only been sparsely validated. Furthermore, the additional diagnostic value of utilizing QP in addition to the traditional visual expert interpretation of stress-perfusion CMR remains unknown. The aim was to investigate the correlation between myocardial blood flow measurements estimated by CMR, positron emission tomography, and invasive coronary thermodilution. The second aim is to investigate the diagnostic performance of CMR-QP to identify obstructive coronary artery disease (CAD). METHODS: Prospectively enrolled symptomatic patients with >50% diameter stenosis on computed tomography angiography underwent dual-bolus CMR and positron emission tomography with rest and adenosine-stress myocardial blood flow measurements. Subsequently, an invasive coronary angiography (ICA) with fractional flow reserve and thermodilution-based coronary flow reserve was performed. Obstructive CAD was defined as both anatomically severe (>70% diameter stenosis on quantitative coronary angiography) or hemodynamically obstructive (ICA with fractional flow reserve ≤0.80). RESULTS: About 359 patients completed all investigations. Myocardial blood flow and reserve measurements correlated weakly between estimates from CMR-QP, positron emission tomography, and ICA-coronary flow reserve (r<0.40 for all comparisons). In the diagnosis of anatomically severe CAD, the interpretation of CMR-QP by an expert reader improved the sensitivity in comparison to visual analysis alone (82% versus 88% [P=0.03]) without compromising specificity (77% versus 74% [P=0.28]). In the diagnosis of hemodynamically obstructive CAD, the accuracy was only moderate for a visual expert read and remained unchanged when additional CMR-QP measurements were interpreted. CONCLUSIONS: CMR-QP correlates weakly to myocardial blood flow measurements by other modalities but improves diagnosis of anatomically severe CAD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481712.
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Angiografía Coronaria , Estenosis Coronaria , Reserva del Flujo Fraccional Miocárdico , Imagen de Perfusión Miocárdica , Tomografía de Emisión de Positrones , Termodilución , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Velocidad del Flujo Sanguíneo , Angiografía por Tomografía Computarizada , Angiografía Coronaria/métodos , Circulación Coronaria/fisiología , Estenosis Coronaria/fisiopatología , Estenosis Coronaria/diagnóstico por imagen , Vasos Coronarios/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Reserva del Flujo Fraccional Miocárdico/fisiología , Imagen de Perfusión Miocárdica/métodos , Tomografía de Emisión de Positrones/métodos , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Índice de Severidad de la EnfermedadRESUMEN
Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (P≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (rg=0.585, P=8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (rg=0.403, P=2.16E-03). The evolutionary persistence of female infertility-risk alleles in EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near FSHB and ARL14EP colocalised with signals for anovulatory infertility, we found no rg between female infertility and reproductive hormones (P>0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in GPC2 were at higher risk of infertility (OR=2.63, P=1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.
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BACKGROUND: The presence of coronary plaques with high-risk characteristics is strongly associated with adverse cardiac events beyond the identification of coronary stenosis. Testing by coronary computed tomography angiography (CCTA) enables the identification of high-risk plaques (HRP). Referral for CCTA is presently based on pre-test probability estimates including clinical risk factors (CRFs); however, proteomics and/or genetic information could potentially improve patient selection for CCTA and, hence, identification of HRP. We aimed to (1) identify proteomic and genetic features associated with HRP presence and (2) investigate the effect of combining CRFs, proteomics, and genetics to predict HRP presence. METHODS: Consecutive chest pain patients (n = 1462) undergoing CCTA to diagnose obstructive coronary artery disease (CAD) were included. Coronary plaques were assessed using a semi-automatic plaque analysis tool. Measurements of 368 circulating proteins were obtained with targeted Olink panels, and DNA genotyping was performed in all patients. Imputed genetic variants were used to compute a multi-trait multi-ancestry genome-wide polygenic score (GPSMult). HRP presence was defined as plaques with two or more high-risk characteristics (low attenuation, spotty calcification, positive remodeling, and napkin ring sign). Prediction of HRP presence was performed using the glmnet algorithm with repeated fivefold cross-validation, using CRFs, proteomics, and GPSMult as input features. RESULTS: HRPs were detected in 165 (11%) patients, and 15 input features were associated with HRP presence. Prediction of HRP presence based on CRFs yielded a mean area under the receiver operating curve (AUC) ± standard error of 73.2 ± 0.1, versus 69.0 ± 0.1 for proteomics and 60.1 ± 0.1 for GPSMult. Combining CRFs with GPSMult increased prediction accuracy (AUC 74.8 ± 0.1 (P = 0.004)), while the inclusion of proteomics provided no significant improvement to either the CRF (AUC 73.2 ± 0.1, P = 1.00) or the CRF + GPSMult (AUC 74.6 ± 0.1, P = 1.00) models, respectively. CONCLUSIONS: In patients with suspected CAD, incorporating genetic data with either clinical or proteomic data improves the prediction of high-risk plaque presence. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02264717 (September 2014).
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Enfermedad de la Arteria Coronaria , Placa Aterosclerótica , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/genética , Puntuación de Riesgo Genético , Proteómica , Angiografía Coronaria/métodos , Placa Aterosclerótica/genética , Placa Aterosclerótica/complicaciones , Factores de RiesgoRESUMEN
BACKGROUND: The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences. METHODS: A selection of 47 biomarkers, including markers of inflammation and vascular stress, were measured in plasma samples from 9876 Danish Blood Donor Study participants. Using regression models, we examined the association between biomarkers and sex, age, Body Mass Index (BMI), and smoking. RESULTS: Here we show that concentrations of inflammation and vascular stress biomarkers generally increase with higher age, BMI, and smoking. Sex-specific effects are observed for multiple biomarkers. CONCLUSION: This study provides comprehensive information on concentrations of 47 plasma biomarkers in healthy individuals. The study emphasizes that knowledge about biomarker concentrations in healthy individuals is critical for improved understanding of disease pathology and for tailored care and decision support tools.
Blood-based biomarkers are circulating molecules that can help to indicate health or disease. Biomarker levels may vary depending on demographic and lifestyle factors such as age, sex, smoking status, and body mass index. Here, we examine the effects of these demographic and lifestyle factors on levels of biomarkers related to activation of the immune system and cardiovascular stress. Measurements of 47 different proteins were performed on blood samples from nearly 10,000 healthy Danish blood donors. Measurement data were linked with questionnaire data to assess effects of lifestyle. We found that immune activation and vascular stress generally increased with age, BMI, and smoking. As these measurements are from healthy blood donors they can serve as a reference for expectable effects and inflammation levels in healthy individuals. Knowledge about the healthy state is important for understanding disease progression and optimizing care.
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INTRODUCTION: Migraine is a prevalent neurological headache disorder. Due to challenges associated with finding effective treatment, many individuals with migraine feel compelled to explore alternative treatment strategies, such as blood donation, hypothesized to provide migraine relief. METHODS: Through logistic, Poisson, and Cox regression methods, we examined the links between migraine and blood donation activities in two population cohorts: Danish blood donors in the Scandinavian Donations and Transfusions Database (SCANDAT-DK, N >1 million) and the Danish Blood Donor Study (N ~ 100,000). RESULTS: SCANDAT-DK analyses showed no link between migraine and the propensity to become a blood donor among males (odds ratio [OR]Males = 0.95 [95% Confidence Interval: 0.86-1.04], and a reduced propensity among females ORFemales = 0.88 [0.83-0.93]). The incidence of migraine was not reduced upon blood donation (standardized incidence ratio [SIR]Males = 0.94 [0.83-1.06]; SIRFemales = 1.04 [0.99-1.10]). Donors with migraine demonstrated longer intervals between donations (hazard ratio [HR]Males = 0.87 [0.85-0.91], HRFemales = 0.80 [0.78-0.82]), and an increased risk of donor lapse (ORMales = 1.23 [1.14-1.32]; ORFemales = 1.28 [1.22-1.33]). Results were corroborated in DBDS using self-reported migraine. Genetic predisposition to migraine associated with longer intervals in females (HRFemales = 0.98 [0.97-0.99]), but not in males. DISCUSSION: Our findings do not support the hypothesis that blood donation serves as a viable treatment strategy among migraine patients. Future prospective investigations may help to elucidate the underlying biological mechanisms by which blood donation may influence migraine pathology.
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Donación de Sangre , Trastornos Migrañosos , Masculino , Femenino , Humanos , Estudios de Cohortes , Transfusión Sanguínea , Donantes de Sangre , Trastornos Migrañosos/epidemiología , Trastornos Migrañosos/terapia , Dinamarca/epidemiologíaRESUMEN
Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits. Here we show that it also increases risk of pregnancy loss in a genome-wide association analysis on 114,761 women with reported pregnancy loss. We further show that the variant associates with more random placement of crossovers and lower recombination rate in longer chromosomes but higher in the shorter ones. These results support the hypothesis that some pregnancy losses are due to failures in recombination. They further demonstrate that variants with a substantial effect on the quality of recombination can be maintained in the population.
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Proteínas Nucleares , Complejo Sinaptonémico , Humanos , Femenino , Embarazo , Complejo Sinaptonémico/metabolismo , Proteínas Nucleares/metabolismo , Estudio de Asociación del Genoma Completo , Proteínas Cromosómicas no Histona/metabolismo , Recombinación Genética , MeiosisRESUMEN
BACKGROUND: Coronary artery calcium scoring (CACS) improves management of chest pain patients. However, it is unknown whether the benefit of CACS is dependent on the clinical likelihood (CL). OBJECTIVES: This study aims to investigate for which patients CACS has the greatest benefit when added to a CL model. METHODS: Based on data from a clinical database, the CL of obstructive coronary artery disease (CAD) was calculated for 39,837 patients referred for cardiac imaging due to symptoms suggestive of obstructive CAD. Patients were categorized according to the risk factor-weighted (RF-CL) model (very low, ≤5%; low, >5 to ≤15%; moderate >15 to ≤50%; high, >50%). CL was then recalculated incorporating the CACS result (CACS-CL). Reclassification rates and the number needed to test with CACS to reclassify patients were calculated and validated in 3 independent cohorts (n = 9,635). RESULTS: In total, 15,358 (39%) patients were down- or upclassified after including CACS. Reclassification rates were 8%, 75%, 53%, and 30% in the very low, low, moderate, and high RF-CL categories, respectively. Reclassification to very low CACS-CL occurred in 48% of reclassified patients. The number needed to test to reclassify 1 patient from low RF-CL to very low CACS-CL was 2.1 with consistency across age, sex, and cohorts. CACS-CL correlated better to obstructive CAD prevalence than RF-CL. CONCLUSIONS: Added to an RF-CL model for obstructive CAD, CACS identifies more patients unlikely to benefit from further testing. The number needed to test with CACS to reclassify patients depends on the pretest RF-CL and is lowest in patients with low (>5% to ≤15%) likelihood of CAD.
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Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Bases de Datos Factuales , Valor Predictivo de las Pruebas , Calcificación Vascular , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Masculino , Femenino , Persona de Mediana Edad , Calcificación Vascular/diagnóstico por imagen , Anciano , Medición de Riesgo , Factores de Riesgo , Reproducibilidad de los Resultados , Angiografía por Tomografía Computarizada , Pronóstico , Técnicas de Apoyo para la Decisión , Toma de Decisiones Clínicas , Índice de Severidad de la Enfermedad , Estudios RetrospectivosRESUMEN
Social trust is a heritable trait that has been linked with physical health and longevity. In this study, we performed genome-wide association studies of self-reported social trust in n = 33,882 Danish blood donors. We observed genome-wide and local evidence of genetic similarity with other brain-related phenotypes and estimated the single nucleotide polymorphism-based heritability of trust to be 6% (95% confidence interval = (2.1, 9.9)). In our discovery cohort (n = 25,819), we identified one significantly associated locus (lead variant: rs12776883) in an intronic enhancer region of PLPP4, a gene highly expressed in brain, kidneys, and testes. However, we could not replicate the signal in an independent set of donors who were phenotyped a year later (n = 8063). In the subsequent meta-analysis, we found a second significantly associated variant (rs71543507) in an intergenic enhancer region. Overall, our work confirms that social trust is heritable, and provides an initial look into the genetic factors that influence it.
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Donantes de Sangre , Estudio de Asociación del Genoma Completo , Humanos , Confianza , Fenotipo , Dinamarca , Polimorfismo de Nucleótido Simple , Predisposición Genética a la EnfermedadRESUMEN
OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
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Trastorno Bipolar , Depresión Posparto , Trastorno Depresivo Mayor , Femenino , Humanos , Animales , Ratones , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo , Depresión Posparto/genética , Predisposición Genética a la Enfermedad , Trastorno Bipolar/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Polygenic risk scores (PRS) identify at-risk individuals for many common diseases. A discussion of strengths and limitations is carried out in this review. PRS complement traditional genetic testing and have shown utility in establishing a proper diagnosis and guiding primary and secondary prevention. Some individuals with high PRS have risks similar to those with monogenic predisposition. Limitations include potential misinterpretations, problems with application across ancestries, and limited usefulness in low-heritability traits. Despite its shortcomings PRS are predicted to play major roles in the future of personal medicine and genetic testing.
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Pruebas Genéticas , Medicina , Humanos , Factores de Riesgo , Prevención Secundaria , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma CompletoRESUMEN
A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
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Estudio de Asociación del Genoma Completo , Placenta , Femenino , Humanos , Embarazo , Peso al Nacer/genética , Desarrollo Fetal/genética , Insulina , Placenta/metabolismo , MasculinoRESUMEN
BACKGROUND: Patients with de novo chest pain, referred for evaluation of possible coronary artery disease (CAD), frequently have an absence of CAD resulting in millions of tests not having any clinical impact. The objective of this study was to investigate whether polygenic risk scores and targeted proteomics improve the prediction of absence of CAD in patients with suspected CAD, when added to the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) minimal risk score (PMRS). METHODS: Genotyping and targeted plasma proteomics (N=368 proteins) were performed in 1440 patients with symptoms suspected to be caused by CAD undergoing coronary computed tomography angiography. Based on individual genotypes, a polygenic risk score for CAD (PRSCAD) was calculated. The prediction was performed using combinations of PRSCAD, proteins, and PMRS as features in models using stability selection and machine learning. RESULTS: Prediction of absence of CAD yielded an area under the curve of PRSCAD-model, 0.64±0.03; proteomic-model, 0.58±0.03; and PMRS model, 0.76±0.02. No significant correlation was found between the genetic and proteomic risk scores (Pearson correlation coefficient, -0.04; P=0.13). Optimal predictive ability was achieved by the full model (PRSCAD+protein+PMRS) yielding an area under the curve of 0.80±0.02 for absence of CAD, significantly better than the PMRS model alone (P<0.001). For reclassification purpose, the full model enabled down-classification of 49% (324 of 661) of the 5% to 15% pretest probability patients and 18% (113 of 611) of >15% pretest probability patients. CONCLUSIONS: For patients with chest pain and low-intermediate CAD risk, incorporating targeted proteomics and polygenic risk scores into the risk assessment substantially improved the ability to predict the absence of CAD. Genetics and proteomics seem to add complementary information to the clinical risk factors and improve risk stratification in this large patient group. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02264717.
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Enfermedad de la Arteria Coronaria , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/genética , Proteómica , Estudios Prospectivos , Angiografía Coronaria/métodos , Factores de Riesgo , Dolor en el Pecho/diagnóstico , Dolor en el Pecho/genéticaRESUMEN
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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Enfermedad de la Arteria Coronaria , Animales , Humanos , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/genética , Epistasis Genética , Fenotipo , Lípidos/sangre , Sistema del Grupo Sanguíneo ABORESUMEN
Missense variants in CALM genes encoding the Ca2+-binding protein calmodulin (CaM) cause severe cardiac arrhythmias. The disease mechanisms have been attributed to dysregulation of RyR2, for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and/or CaV1.2, for Long-QT Syndrome (LQTS). Recently, a novel CALM2 variant, G114R, was identified in a mother and two of her four children, all of whom died suddenly while asleep at a young age. The G114R variant impairs closure of CaV1.2 and RyR2, consistent with a CPVT and/or mild LQTS phenotype. However, the children carrying the CALM2 G114R variant displayed a phenotype commonly observed with variants in NaV1.5, i.e., Brugada Syndrome (BrS) or LQT3, where death while asleep is a common feature. We therefore hypothesized that the G114R variant specifically would interfere with NaV1.5 binding. Here, we demonstrate that CaM binding to the NaV1.5 IQ-domain is severely impaired for two CaM variants G114R and G114W. The impact was most severe at low and intermediate Ca2+ concentrations (up to 4 µM) resulting in more than a 50-fold reduction in NaV1.5 binding affinity, and a smaller 1.5 to 11-fold reduction at high Ca2+ concentrations (25-400 µM). In contrast, the arrhythmogenic CaM-N98S variant only induced a 1.5-fold reduction in NaV1.5 binding and only at 4 µM Ca2+. A non-arrhythmogenic I10T variant in CaM did not impair NaV1.5 IQ binding. These data suggest that the interaction between NaV1.5 and CaM is decreased with certain CaM variants, which may alter the cardiac sodium current, INa. Overall, these results suggest that the phenotypic spectrum of calmodulinopathies may likely expand to include BrS- and/or LQT3-like traits.
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AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.
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Calmodulina , Síndrome de QT Prolongado , Taquicardia Ventricular , Niño , Humanos , Calmodulina/genética , Muerte Súbita Cardíaca/etiología , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética , Mutación/genética , Sistema de Registros , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genéticaRESUMEN
Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation analysis indicated candidate genes, HAND2, TBX3, and RAP2C/FRMD7, at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors (PGR). Furthermore, there were strong genetic correlations with birth weight, gestational duration, and uterine fibroids. Early bleeding during pregnancy (28,898 cases and 302,894 controls) yielded no genome-wide association signals, but showed strong genetic correlation with a variety of human traits, indicative of polygenic and pleiotropic effects. Our results suggest that postpartum bleeding is related to myometrium dysregulation, whereas early bleeding is a complex trait related to underlying health and possibly socioeconomic status.