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The long delay before genomic technologies become available in low- and middle-income countries is a concern from both scientific and ethical standpoints. Polygenic risk scores (PRSs), a relatively recent advance in genomics, could have a substantial impact on promoting health by improving disease risk prediction and guiding preventive strategies. However, clinical use of PRSs in their current forms might widen global health disparities, as their portability to diverse groups is limited. This Perspective highlights the need for global collaboration to develop and implement PRSs that perform equitably across the world. Such collaboration requires capacity building and the generation of new data in low-resource settings, the sharing of harmonized genotype and phenotype data securely across borders, novel population genetics and statistical methods to improve PRS performance, and thoughtful clinical implementation in diverse settings. All this needs to occur while considering the ethical, legal and social implications, with support from regulatory and funding agencies and policymakers.
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BACKGROUND: Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause. METHODS: We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRSCHD) with multiple measures of coronary artery disease (CAD) severity. We assessed the interplay between PRSCHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes. We performed mediation analyses to explore whether CAD severity mediated the association of PRSCHD with prevalent coronary heart disease and incident myocardial infarction. RESULTS: A 1-SD increase in PRSCHD was associated with multiple measures of CAD severity, including the log Gensini score (ß, 0.31 [95% CI, 0.28-0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRSCHD (ß, 0.21 [95% CI, 0.03-0.38]). PRSCHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13-1.27]; P=5×10-10), and the Gensini score mediated 90% of this association. CONCLUSIONS: PRSCHD was associated with multiple measures of CAD severity. The association of PRSCHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.
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Background: The MI-GENES clinical trial (NCT01936675), in which participants at intermediate risk of coronary heart disease (CHD) were randomized to receive a Framingham risk score (FRSg, n=103), or an integrated risk score (IRSg, n=104) that additionally included a polygenic risk score (PRS), demonstrated that after 6 months, participants randomized to IRSg had higher statin initiation and lower low-density lipoprotein cholesterol (LDL-C). Objectives: In a post hoc 10-year follow-up analysis of the MI-GENES trial, we investigated whether disclosure of a PRS for CHD was associated with a reduction in adverse cardiovascular events. Methods: Participants were followed from randomization beginning in October 2013 until September 2023 to ascertain adverse cardiovascular events, testing for CHD, and changes in risk factors, by blinded review of electronic health records. The primary outcome was the time from randomization to the occurrence of the first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction, coronary revascularization, and non-fatal stroke. Statistical analyses were conducted using Cox proportional hazards regression and linear mixed-effects models. Results: We followed all 203 participants who completed the MI-GENES trial, 100 in FRSg and 103 in IRSg (mean age at the end of follow-up: 68.2±5.2, 48% male). During a median follow-up of 9.5 years, 9 MACEs occurred in FRSg and 2 in IRSg (hazard ratio (HR), 0.20; 95% confidence interval (CI), 0.04 to 0.94; P=0.042). In FRSg, 47 (47%) underwent at least one test for CHD, compared to 30 (29%) in IRSg (HR, 0.51; 95% CI, 0.32 to 0.81; P=0.004). IRSg participants had a longer duration of statin therapy during the first four years post-randomization and a greater reduction in LDL-C for up to 3 years post-randomization. No significant differences between the two groups were observed for hemoglobin A1C, systolic and diastolic blood pressures, weight, and smoking cessation rate during follow-up. Conclusions: The disclosure of an IRS that included a PRS to individuals at intermediate risk for CHD was associated with a lower incidence of MACE after a decade of follow-up, likely due to a higher rate of initiation and longer duration of statin therapy, leading to lower LDL-C levels.
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Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. Mechanisms leading to preeclampsia are unclear; however, there is evidence of high heritability. We evaluated the association of polygenic scores (PGS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture. Non-Hispanic Black and White reproductive age females with pregnancy indications and genotypes were obtained from Vanderbilt University's BioVU, Electronic Medical Records and Genomics network, and Penn Medicine Biobank. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PGS were acquired from Giri et al. Associations between preeclampsia and each PGS were evaluated separately by race and data source before subsequent meta-analysis. Ten-fold cross validation was used for prediction modeling. In 3504 Black and 5009 White included individuals, the rate of preeclampsia was 15.49%. In cross-ancestry meta-analysis, all PGSs were associated with preeclampsia (ORDBP = 1.10, 95% CI 1.02-1.17, p = 7.68 × 10-3; ORSBP = 1.16, 95% CI 1.09-1.23, p = 2.23 × 10-6; ORPP = 1.14, 95% CI 1.07-1.27, p = 9.86 × 10-5). Addition of PGSs to clinical prediction models did not improve predictive performance. Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia.
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Presión Sanguínea , Preeclampsia , Humanos , Preeclampsia/genética , Femenino , Embarazo , Presión Sanguínea/genética , Adulto , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Población Blanca/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: African Americans (AAs) face cardiovascular health (CVH) disparities linked to systemic racism. The 2020 police killing of Mr. George Floyd in Minneapolis, Minnesota, alongside the COVID-19 pandemic, exacerbated adverse psychosocial factors affecting CVH outcomes among AAs. This manuscript describes the study protocol and participant characteristics in an ancillary study exploring the relationship between biopsychosocial factors and CVH among AAs. METHODS: Using a community-based participatory approach, a mixed-methods ancillary study of 58 AA participants from an overarching randomized control trial (RCT) was conducted. Baseline RCT health assessments (November 2020) provided sociodemographic, medical, and clinical data. Subsequent health assessments (February-December 2022) measured sleep quality, psychosocial factors (e.g., high-effort coping), biomarkers (e.g., cortisol), and cardiovascular diagnostics (e.g., cardio-ankle vascular index). CVH was assessed using the American Heart Association Life's Simple 7 (LS7) (range 0 to 14, poor to ideal) and Life's Essential 8 (LE8) scores (range 0 to 100, low to high). Correlations between these scores will be examined. Focus group discussions via videoconferencing (March to April 2022) assessed psychosocial and structural barriers, along with the impact of COVID-19 and George Floyd's killing on daily life. RESULTS: Participants were predominantly female (67%), with a mean age of 54.6 [11.9] years, high cardiometabolic risk (93% had overweight/obesity and 70% hypertension), and moderate LE8 scores (mean 57.4, SD 11.5). CONCLUSION: This study will enhance understanding of the associations between biopsychosocial factors and CVH among AAs in Minnesota. Findings may inform risk estimation, patient care, and healthcare policies to address CVD disparities in marginalized populations.
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Negro o Afroamericano , COVID-19 , Enfermedades Cardiovasculares , Investigación Participativa Basada en la Comunidad , Racismo , Determinantes Sociales de la Salud , Estrés Psicológico , Humanos , Negro o Afroamericano/psicología , Femenino , Masculino , Racismo/psicología , Persona de Mediana Edad , Enfermedades Cardiovasculares/etnología , COVID-19/epidemiología , COVID-19/etnología , Estrés Psicológico/etnología , Estrés Psicológico/epidemiología , Adulto , Anciano , Disparidades en el Estado de Salud , Proyectos de Investigación , Minnesota/epidemiologíaRESUMEN
Importance: Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling. Objective: To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes. Design, Setting, and Participants: This was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023. Exposures: CHIP (variant allele frequency [VAF] ≥2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF ≥10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro-B-type natriuretic peptide), and echocardiographic indices. Main Outcome Measure: Incident AF. Results: A total of 199â¯982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195â¯851 [97.9%]; mean [SD] age, 56 [8] years; 108â¯370 female [55%]; 87â¯481 male [45%]; 3154 Black [2%], 183â¯747 White [94%], and 7971 other race [4%]), 11â¯328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197â¯209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197â¯209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index. Conclusions and Relevance: Large TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.
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Fibrilación Atrial , Hematopoyesis Clonal , Proteínas de Unión al ADN , Dioxigenasas , Proteínas Proto-Oncogénicas , Proteínas Represoras , Humanos , Femenino , Masculino , Fibrilación Atrial/genética , Hematopoyesis Clonal/genética , Proteínas Represoras/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genética , Estudios Prospectivos , Anciano , ADN Metiltransferasa 3A , ADN (Citosina-5-)-Metiltransferasas/genética , Biomarcadores/sangre , Biomarcadores/metabolismo , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Troponina T/genética , Troponina T/sangre , Troponina T/metabolismo , Ecocardiografía , Reino Unido/epidemiologíaRESUMEN
Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed effects of covariate stratification and interaction on body mass index (BMI) PGS (PGSBMI) across four cohorts of European (N=491,111) and African (N=21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R2 differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R2 being nearly double between best and worst performing quintiles for certain covariates. 28 covariates had significant PGSBMI-covariate interaction effects, modifying PGSBMI effects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R2 differences among strata and interaction effects - across all covariates, their main effects on BMI were correlated with their maximum R2 differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGSBMI individuals have highest R2 and increase in PGS effect. Using quantile regression, we show the effect of PGSBMI increases as BMI itself increases, and that these differences in effects are directly related to differences in R2 when stratifying by different covariates. Given significant and replicable evidence for context-specific PGSBMI performance and effects, we investigated ways to increase model performance taking into account non-linear effects. Machine learning models (neural networks) increased relative model R2 (mean 23%) across datasets. Finally, creating PGSBMI directly from GxAge GWAS effects increased relative R2 by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGSBMI performance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.
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Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10-5) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.
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Predisposición Genética a la Enfermedad , Leucopenia , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Humanos , Recuento de Leucocitos , Masculino , Femenino , Leucopenia/genética , Leucopenia/sangre , Persona de Mediana Edad , Anciano , Adulto , Inmunosupresores/uso terapéuticoRESUMEN
Severe hypercholesterolemia/possible familial hypercholesterolemia (FH) is relatively common but underdiagnosed and undertreated. We investigated whether implementing clinical decision support (CDS) was associated with lower low-density lipoprotein cholesterol (LDL-C) in patients with severe hypercholesterolemia/possible FH (LDL-C ≥ 190 mg/dL). As part of a pre-post implementation study, a CDS alert was deployed in the electronic health record (EHR) in a large health system comprising 3 main sites, 16 hospitals and 53 clinics. Data were collected for 3 months before ('silent mode') and after ('active mode') its implementation. Clinicians were only able to view the alert in the EHR during active mode. We matched individuals 1:1 in both modes, based on age, sex, and baseline lipid lowering therapy (LLT). The primary outcome was difference in LDL-C between the two groups and the secondary outcome was initiation/intensification of LLT after alert trigger. We identified 800 matched patients in each mode (mean ± SD age 56.1 ± 11.8 y vs. 55.9 ± 11.8 y; 36.0% male in both groups; mean ± SD initial LDL-C 211.3 ± 27.4 mg/dL vs. 209.8 ± 23.9 mg/dL; 11.2% on LLT at baseline in each group). LDL-C levels were 6.6 mg/dL lower (95% CI, -10.7 to -2.5; P = 0.002) in active vs. silent mode. The odds of high-intensity statin use (OR, 1.78; 95% CI, 1.41-2.23; P < 0.001) and LLT initiation/intensification (OR, 1.30, 95% CI, 1.06-1.58, P = 0.01) were higher in active vs. silent mode. Implementation of a CDS was associated with lowering of LDL-C levels in patients with severe hypercholesterolemia/possible FH, likely due to higher rates of clinician led LLT initiation/intensification.
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BACKGROUND: Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (CHD; PRSCHD) for 5 genetic ancestry groups. METHODS: We derived ancestry-specific and multi-ancestry PRSCHD based on pruning and thresholding (PRSPT) and ancestry-based continuous shrinkage priors (PRSCSx) applied to summary statistics from the largest multi-ancestry genome-wide association study meta-analysis for CHD to date, including 1.1 million participants from 5 major genetic ancestry groups. Following training and optimization in the Million Veteran Program, we evaluated the best-performing PRSCHD in 176,988 individuals across 9 diverse cohorts. RESULTS: Multi-ancestry PRSPT and PRSCSx outperformed ancestry-specific PRSPT and PRSCSx across a range of tuning values. Two best-performing multi-ancestry PRSCHD (ie, PRSPTmult and PRSCSxmult) and 1 ancestry-specific (PRSCSxEUR) were taken forward for validation. PRSPTmult demonstrated the strongest association with CHD in individuals of South Asian ancestry and European ancestry (odds ratio per 1 SD [95% CI, 2.75 [2.41-3.14], 1.65 [1.59-1.72]), followed by East Asian ancestry (1.56 [1.50-1.61]), Hispanic/Latino ancestry (1.38 [1.24-1.54]), and African ancestry (1.16 [1.11-1.21]). PRSCSxmult showed the strongest associations in South Asian ancestry (2.67 [2.38-3.00]) and European ancestry (1.65 [1.59-1.71]), lower in East Asian ancestry (1.59 [1.54-1.64]), Hispanic/Latino ancestry (1.51 [1.35-1.69]), and the lowest in African ancestry (1.20 [1.15-1.26]). CONCLUSIONS: The use of summary statistics from a large multi-ancestry genome-wide meta-analysis improved the performance of PRSCHD in most ancestry groups compared with single-ancestry methods. Despite the use of one of the largest and most diverse sets of training and validation cohorts to date, improvement of predictive performance was limited in African ancestry. This highlights the need for larger genome-wide association study datasets of underrepresented populations to enhance the performance of PRSCHD.
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Enfermedad Coronaria , Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Humanos , Enfermedad Coronaria/genética , Masculino , Femenino , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Persona de Mediana Edad , Puntuación de Riesgo GenéticoRESUMEN
Background: Peripheral artery disease (PAD) impacts more than 200 million people worldwide. The understanding of the genetics of the disease and its clinical implications continue to evolve. This systematic review provides a comprehensive summary of all DNA variants that have been studied in association with the diagnosis and progression of PAD, with a meta-analysis of the ones replicated in the literature. Methods: A systematic review of all studies examining DNA variants associated with the diagnosis and progression of PAD was performed. Candidate gene and genome-wide association studies (GWAS) were included. A meta-analysis of 13 variants derived from earlier smaller candidate gene studies of the diagnosis of PAD was performed. The literature on the progression of PAD was limited, and a meta-analysis was not feasible because of the heterogeneity in the criteria used to characterize it. Results: A total of 231 DNA variants in 112 papers were studied for the association with the diagnosis of PAD. There were significant variations in the definition of PAD and the selection of controls in the various studies. GWAS have established 19 variants associated with the diagnosis of PAD that were replicated in several large patient cohorts. Only variants in intercellular adhesion molecule-1 (rs5498), IL-6 (rs1800795), and hepatic lipase (rs2070895) showed significant association with the diagnosis of PAD. However, these variants were not noted in the published GWAS. Conclusions: Genetic research in the diagnosis of PAD has significant heterogeneity, but recent GWAS have demonstrated variants consistently associated with the disease. More research focusing on the progression of PAD is needed to identify patients at risk of adverse events and develop strategies that would improve their outcomes.
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Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.
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Enfermedad Crónica , Puntuación de Riesgo Genético , Salud Poblacional , Adulto , Niño , Humanos , Comunicación , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Estados UnidosRESUMEN
Background: The joint effects of polygenic risk and social determinants of health (SDOH) on coronary heart disease (CHD) in the United States are unknown. Methods: In 67,256 All of Us (AoU) participants with available SDOH data, we ascertained self-reported race/ethnicity and calculated a polygenic risk score for CHD (PRS CHD ). We used 90 SDOH survey questions to develop an SDOH score for CHD (SDOH CHD ). We assessed the distribution of SDOH CHD across self-reported races and US states. We tested the joint association of SDOH CHD and PRS CHD with CHD in regression models that included clinical risk factors. Results: SDOH CHD was highest in self-reported black and Hispanic people. Self-reporting as black was associated with higher odds of CHD but not after adjustment for SDOH CHD . Median SDOH CHD values varied by US state and were associated with heart disease mortality. A 1-SD increase in SDOH CHD was associated with CHD (OR=1.36; 95% CI, 1.29 to 1.46) and incident CHD (HR=1.73; 95% CI, 1.27 to 2.35) in models that included PRS CHD and clinical risk factors. Among people in the top 20% of PRS CHD , CHD prevalence was 4.8% and 7.8% in the bottom and top 20% of SDOH CHD , respectively. Conclusions: Increased odds of CHD in self-reported black people are likely due to higher SDOH burden. SDOH and PRS were independently associated with CHD in the US. Our findings emphasize the need to consider both PRS and SDOH for equitable disease risk assessment.
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Polygenic scores (PGS) for coronary heart disease (CHD) are constructed using GWAS summary statistics for CHD. However, pleiotropy is pervasive in biology and disease-associated variants often share etiologic pathways with multiple traits. Therefore, incorporating GWAS summary statistics of additional traits could improve the performance of PGS for CHD. Using lasso regression models, we developed two multi-PGS for CHD: 1) multiPGSCHD, utilizing GWAS summary statistics for CHD, its risk factors, and other ASCVD as training data and the UK Biobank for tuning, and 2) extendedPGSCHD, using existing PGS for a broader range of traits in the PGS Catalog as training data and the Atherosclerosis Risk in Communities Study (ARIC) cohort for tuning. We evaluated the performance of multiPGSCHD and extendedPGSCHD in the Mayo Clinic Biobank, an independent cohort of 43,578 adults of European ancestry which included 4,479 CHD cases and 39,099 controls. In the Mayo Clinic Biobank, a 1 SD increase in multiPGSCHD and extendedPGSCHD was associated with a 1.66-fold (95% CI: 1.60-1.71) and 1.70-fold (95% CI: 1.64-1.76) increased odds of CHD, respectively, in models that included age, sex, and 10 PCs, whereas an already published PGS for CHD (CHD_PRSCS) increased the odds by 1.50 (95% CI: 1.45-1.56). In the highest deciles of extendedPGSCHD, multiPGSCHD, and CHD_PRSCS, 18.4%, 17.5%, and 16.3% of patients had CHD, respectively.
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Enfermedad Coronaria , Adulto , Humanos , Enfermedad Coronaria/genética , Factores de Riesgo , FenotipoRESUMEN
Ebstein's anomaly, a rare congenital heart disease, is distinguished by the failure of embryological delamination of the tricuspid valve leaflets from the underlying primitive right ventricle myocardium. Gaining insight into the genetic basis of Ebstein's anomaly allows a more precise definition of its pathogenesis. In this study, two distinct cohorts from the Chinese Han population were included: a case-control cohort consisting of 82 unrelated cases and 125 controls without cardiac phenotypes and a trio cohort comprising 36 parent-offspring trios. Whole-exome sequencing data from all 315 participants were utilized to identify qualifying variants, encompassing rare (minor allele frequency < 0.1% from East Asians in the gnomAD database) functional variants and high-confidence (HC) loss-of-function (LoF) variants. Various statistical models, including burden tests and variance-component models, were employed to identify rare variants, genes, and biological pathways associated with Ebstein's anomaly. Significant associations were noted between Ebstein's anomaly and rare HC LoF variants found in genes related to the matrisome, a collection of extracellular matrix (ECM) components. Specifically, 47 genes with HC LoF variants were exclusively or predominantly identified in cases, while nine genes showed such variants in the probands. Over half of unrelated cases (n = 42) and approximately one-third of probands (n = 12) were found to carry one or two LoF variants in these prioritized genes. These results highlight the role of the matrisome in the pathogenesis of Ebstein's anomaly, contributing to a better understanding of the genetic architecture underlying this condition. Our findings hold the potential to impact the genetic diagnosis and treatment approaches for Ebstein's anomaly.
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Anomalía de Ebstein , Cardiopatías Congénitas , Humanos , Anomalía de Ebstein/genética , Válvula Tricúspide/patología , Cardiopatías Congénitas/complicaciones , Miocardio/patología , Ventrículos Cardíacos/patologíaRESUMEN
Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.
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Predisposición Genética a la Enfermedad , Humanos , Factores de Riesgo , Herencia Multifactorial , Medicina de Precisión , Estudio de Asociación del Genoma CompletoRESUMEN
BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code-based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code-based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.
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Fibrilación Atrial , Enfermedad de la Arteria Coronaria , Insuficiencia Cardíaca Sistólica , Femenino , Humanos , Masculino , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/genética , Fibrilación Atrial/complicaciones , Genómica , Atrios Cardíacos/diagnóstico por imagen , Factores de Riesgo , Análisis de la Aleatorización MendelianaRESUMEN
African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.