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PURPOSE OF REVIEW: Familial hypercholesterolemia (FH) and hyperlipoproteinemia(a) are relatively common disorders, posing a significant health burden due to increased risk of atherosclerotic cardiovascular disease (ASCVD). Development of electronic health record-based strategies with a linkage to the genetic test results has increased awareness, detection, and control of heritable lipid disorders. This review attempts to critically examine available data to provide a summary of the current evidence for lipoprotein apheresis in FH and elevated lipoprotein(a) (Lp(a)). REVIEW FINDINGS: Availability and indications for lipoprotein apheresis vary across the globe. On average, greater than 60% of atherogenic apoB-containing lipoproteins are immediately reduced following a single procedure, translating in substantial reduction of incident ASCVD events, and preventing accelerated vascular aging. Simultaneous lipid-lowering therapy targeting low-density lipoprotein (LDL) and Lp(a) enhances the efficacy of lipoprotein apheresis. Lipoprotein apheresis alters the proteomics of the lipoprotein particles, including reduction in the concentration of the oxidized-LDL and Lp(a) particles, and proinflammatory apoE bound to HDL particles and remnant lipoproteins. Other effects attributed to lipoprotein apheresis include improvement in blood rheology, endothelial function, microvascular flow, myocardial perfusion, reduction in circulating inflammatory markers. Development of lipoprotein apheresis registries provides data on benefits, challenges, and barriers to inform pertinent healthcare policies. Lipoprotein apheresis is a safe and effective procedure for lowering cholesterol in patients with combined and isolated FH and elevated Lp(a). It reduces the burden of ASCVD and improves long-term prognosis. A team approach is required by the patient, medical staff, and healthcare provider to initiate and maintain a lipoprotein apheresis program.
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Aterosclerosis , Eliminación de Componentes Sanguíneos , Hiperlipoproteinemia Tipo II , Hiperlipoproteinemias , Humanos , Hiperlipoproteinemia Tipo II/terapia , Eliminación de Componentes Sanguíneos/métodos , Colesterol , Hiperlipoproteinemias/terapia , Aterosclerosis/prevención & control , Aterosclerosis/etiología , Lipoproteína(a)RESUMEN
PURPOSE OF REVIEW: Although primarily designed for medical documentation and billing purposes, the electronic health record (EHR) has significant potential for translational research. In this article, we provide an overview of the use of the EHR for genomics research with a focus on heritable lipid disorders. RECENT FINDINGS: Linking the EHR to genomic data enables repurposing of vast phenotype data for genomic discovery. EHR data can be used to study the genetic basis of common and rare disorders, identify subphenotypes of diseases, assess pathogenicity of novel genomic variants, investigate pleiotropy, and rapidly assemble cohorts for genomic medicine clinical trials. EHR-based discovery can inform clinical practice; examples include use of polygenic risk scores for assessing disease risk and use of phenotype data to interpret rare variants. Despite limitations such as missing data, variable use of standards and poor interoperablility between disparate systems, the EHR is a powerful resource for genomic research. SUMMARY: When linked to genomic data, the EHR can be leveraged for genomic discovery, which in turn can inform clinical care, exemplifying the virtuous cycle of a learning healthcare system.
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Registros Electrónicos de Salud , Genómica , HumanosRESUMEN
Objective- It is unclear to what extent genetic susceptibility variants are shared between peripheral artery disease (PAD) and coronary heart disease (CHD), both manifestations of atherosclerotic vascular disease. We investigated whether common and low-frequency/rare variants in loci associated with CHD are also associated with PAD. Approach and Results- Targeted sequencing of 41 genomic regions associated with CHD in genome-wide association studies was performed in 1749 PAD cases (65±11 years, 61% men) and 1855 controls (60±11 years, 56% men) of European ancestry. PAD cases had a resting/postexercise ankle-brachial index ≤0.9, or history of lower extremity revascularization; controls had no history of PAD. We tested the association of common (defined as minor allele frequency ≥5%) variants with PAD assuming an additive genetic model with adjustment for age and sex. To identify low-frequency/rare variants (minor allele frequency <5%) associated with PAD, we conducted gene-level analyses using sequence kernel association test and permutation test. After Bonferroni correction, we found common variants in SH2B3, ABO, and ZEB2 to be associated with PAD ( P<4.5×10-5). At the gene level, the strongest associations were for LPL and SH2B3. Conclusions- Targeted sequencing of 41 genomic regions associated with CHD revealed several common variants/genes to be associated with PAD, highlighting the basis of shared genetic susceptibility between CHD and PAD.
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Enfermedad Coronaria/genética , Sitios Genéticos , Variación Genética , Enfermedad Arterial Periférica/genética , Análisis de Secuencia de ADN , Anciano , Estudios de Casos y Controles , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/etnología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/etnología , Fenotipo , Factores de Riesgo , Población Blanca/genéticaRESUMEN
BACKGROUND: The extent to which obesity and genetics determine postoperative complications is incompletely understood. METHODS: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity-risk single-nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. RESULTS: Individuals with overweight or obese BMI (≥25 kg/m2) had increased risk of incisional hernia (odds ratio [OR] 1.7-5.5, p < 3.1 × 10-20), and people with obesity (BMI ≥ 30 kg/m2) had increased risk of postoperative infection (OR 1.2-2.3, p < 2.5 × 10-5). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8-2.5], p = 1.4 × 10-6) and postoperative infection (OR 1.6 [95% CI 1.4-1.9], p = 3.1 × 10-6). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures. CONCLUSIONS: Clinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection.
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Análisis de la Aleatorización Mendeliana/métodos , Obesidad/complicaciones , Complicaciones Posoperatorias/genética , Adulto , Índice de Masa Corporal , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Lipoprotein(a) [Lp(a)] is acknowledged to be an independent atherothrombotic risk factor. Although genetic studies have highlighted the causal relationship between coronary disease and Lp(a), it is uncertain which strategies maximize the therapeutic benefit of patients with high Lp(a) levels. We report the challenging case of a young coronary heart disease (CHD) patient who underwent 10 percutaneous coronary interventions due to repeated acute coronary syndromes (2006-2009) despite an optimally controlled, traditional risk-factor profile. For the first time, we performed specific Lp(a) immunoadsorption in the presence of very low levels of low-density lipoprotein cholesterol (LDL-C) while the patient was on a high-dose statin regimen. There have been no previous reports of patients with high Lp(a) levels who achieved LDL-C goals when treated with an isolated Lp(a)-lowering method. Despite the very high risk of cardiovascular death, targeting Lp(a) resulted in dramatic improvement of the patient's clinical condition. Thus, we suggest that specific Lp(a) apheresis should be considered an effective new treatment strategy for patients with progressive CHD who have reached LDL-C goals but harbor elevated Lp(a) levels.
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Eliminación de Componentes Sanguíneos/métodos , Enfermedad Coronaria/terapia , Lipoproteína(a)/química , Adulto , LDL-Colesterol/sangre , Progresión de la Enfermedad , Humanos , Masculino , Factores de Riesgo , Resultado del TratamientoRESUMEN
Background: Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial atrophy which progressively extends from the epicardium towards the endocardium, resulting in wall thinning. It is one of the leading causes of sudden death in young people. Postmortem studies demonstrate that up to 70-80% of the cases have biventricular involvement. Variable penetrance and expressivity results in a wide phenotypic spectrum, challenging diagnostic accuracy of advanced multimodality imaging tools. Prompt recognition, non-invasive imaging, risk stratification for sudden cardiac death (SCD), and preventive measures are paramount to improve prognosis. Case summary: Here, we present a 22-year-old Black male who was referred to our electrophysiology clinic with palpitations, remote syncope, and a family history of SCD. Over 3 years, he developed gradually worsening symptomatic palpitations. While physical exam and transthoracic echocardiography were unremarkable, his cardiac magnetic resonance imaging was consistent with biventricular ACM. Genetic testing confirmed ACM, revealing double heterozygosity in DSG2 and PKP2. Given the elevated estimated risk of life-threatening dysrhythmias, a subcutaneous cardiac defibrillator was successfully implanted. Discussion: Frequently, patients with ACM have more than one mutation in the same gene (compound heterozygosity) or in a second gene (double heterozygosity). Genetic counselling is strongly recommended for family members of the proband. The diagnosis of ACM may be mimicked by other diseases (cardiac sarcoidosis, dilated cardiomyopathy, amyloidosis), thus genetic testing can be useful to determine the presence of the disease. The present report provides an overview of the clinical course, diagnostic criteria, risk stratification, and prognostication for patients with ACM.
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Since the 2019 National Lipid Association (NLA) Scientific Statement on Use of Lipoprotein(a) in Clinical Practice was issued, accumulating epidemiological data have clarified the relationship between lipoprotein(a) [Lp(a)] level and cardiovascular disease risk and risk reduction. Therefore, the NLA developed this focused update to guide clinicians in applying this emerging evidence in clinical practice. We now have sufficient evidence to support the recommendation to measure Lp(a) levels at least once in every adult for risk stratification. Individuals with Lp(a) levels <75â¯nmol/L (30â¯mg/dL) are considered low risk, individuals with Lp(a) levels ≥125â¯nmol/L (50â¯mg/dL) are considered high risk, and individuals with Lp(a) levels between 75 and 125â¯nmol/L (30-50â¯mg/dL) are at intermediate risk. Cascade screening of first-degree relatives of patients with elevated Lp(a) can identify additional individuals at risk who require intervention. Patients with elevated Lp(a) should receive early, more-intensive risk factor management, including lifestyle modification and lipid-lowering drug therapy in high-risk individuals, primarily to reduce low-density lipoprotein cholesterol (LDL-C) levels. The U.S. Food and Drug Administration approved an indication for lipoprotein apheresis (which reduces both Lp(a) and LDL-C) in high-risk patients with familial hypercholesterolemia and documented coronary or peripheral artery disease whose Lp(a) level remains ≥60â¯mg/dL [â¼150â¯nmol/L)] and LDL-Câ¯≥â¯100â¯mg/dL on maximally tolerated lipid-lowering therapy. Although Lp(a) is an established independent causal risk factor for cardiovascular disease, and despite the high prevalence of Lp(a) elevation (â¼1 of 5 individuals), measurement rates are low, warranting improved screening strategies for cardiovascular disease prevention.
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Enfermedades Cardiovasculares , Lipoproteína(a) , Humanos , Lipoproteína(a)/sangre , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/sangre , Factores de Riesgo , Hipolipemiantes/uso terapéuticoRESUMEN
Aims: Current guidelines recommend measuring carotid intima-media thickness (IMT) at the far wall of the common carotid artery (CCA). We aimed to precisely quantify associations of near vs. far wall CCA-IMT with the risk for atherosclerotic cardiovascular disease (CVD, defined as coronary heart disease or stroke) and their added predictive values. Methods and results: We analysed individual records of 41 941 participants from 16 prospective studies in the Proof-ATHERO consortium {mean age 61 years [standard deviation (SD) = 11]; 53% female; 16% prior CVD}. Mean baseline values of near and far wall CCA-IMT were 0.83 (SD = 0.28) and 0.82 (SD = 0.27) mm, differed by a mean of 0.02â mm (95% limits of agreement: -0.40 to 0.43), and were moderately correlated [r = 0.44; 95% confidence interval (CI): 0.39-0.49). Over a median follow-up of 9.3 years, we recorded 10 423 CVD events. We pooled study-specific hazard ratios for CVD using random-effects meta-analysis. Near and far wall CCA-IMT values were approximately linearly associated with CVD risk. The respective hazard ratios per SD higher value were 1.18 (95% CI: 1.14-1.22; I² = 30.7%) and 1.20 (1.18-1.23; I² = 5.3%) when adjusted for age, sex, and prior CVD and 1.09 (1.07-1.12; I² = 8.4%) and 1.14 (1.12-1.16; I²=1.3%) upon multivariable adjustment (all P < 0.001). Assessing CCA-IMT at both walls provided a greater C-index improvement than assessing CCA-IMT at one wall only [+0.0046 vs. +0.0023 for near (P < 0.001), +0.0037 for far wall (P = 0.006)]. Conclusions: The associations of near and far wall CCA-IMT with incident CVD were positive, approximately linear, and similarly strong. Improvement in risk discrimination was highest when CCA-IMT was measured at both walls.
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Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.
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Enfermedades de las Arterias Carótidas , Placa Aterosclerótica , Humanos , Femenino , Persona de Mediana Edad , Masculino , Grosor Intima-Media Carotídeo , Estudios Prospectivos , Factores de Riesgo , Arteria Carótida Común/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiologíaRESUMEN
The effects of vitamin D (Vit-D) deficiency and Vit-D treatment (VDT) on atrial fibrillation (AF) remain inconclusive. This study sought to determine the effects of VDT and nontreatment on AF risk in Vit-D-deficient patients without a previous history of AF. In this nested case-control study, 39,845 individuals with low 25-hydroxy-Vit-D ([25-OH]D) levels (<20 ng/ml) were divided into group-A (untreated, levels ≤20 ng/ml), group-B (treated, levels 21 to 29 ng/ml), and group-C (treated, levels ≥30 ng/ml). The risk of AF was compared utilizing propensity score-weighted Cox proportional hazard models. Among the individuals receiving VDT for ≥6 months, the risk of AF was significantly lower in group-B (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.80 to 0.98, p = 0.03] and group-C (HR 0.84, 95% CI 0.73 to 0.0.95, p = 0.007] than in group-A. A subgroup analysis of men >65 years showed individuals with hypertension had a significantly lower risk of AF in group-C than in group-B (HR 0.79, CI 0.65 to 0.94, p = 0.02) and group-A (HR 0.78, CI 0.64 to 0.96, p = 0.012). A similar result was found in men >65 years with diabetes mellitus in group-C compared with group-B (HR 0.69, CI 0.51 to 0.93, p = 0.012) and group-A (HR 0.63, CI 0.47 to 0.84, p = 0.002). In what is, to best of our knowledge, the largest observational study to date of patients with Vit-D deficiency and no previous history of AF, (25-OH)D level of >20 ng/ml with VDT for ≥6 months was associated with a significantly lower risk of AF. Additionally, men >65 years with hypertension or diabetes mellitus had a further decrease in AF risk when the (25-OH)D levels were ≥30 ng/ml.
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Fibrilación Atrial , Hipertensión , Deficiencia de Vitamina D , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Estudios de Casos y Controles , Suplementos Dietéticos , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Masculino , Factores de Riesgo , Vitamina D/análogos & derivados , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/epidemiologíaRESUMEN
The extent of intervention effects on carotid intima-media thickness (CIMT) can predict the degree of atherosclerotic cardiovascular risk-reduction. We hypothesized that regular lipoprotein apheresis over the course of 10 years might slow down progression of CIMT in patients with severe hypercholesterolemia. This case series describes 10 Caucasian patients (mean age 60 ± 9 years, 70% female, 80% statin intolerant) with a severe hypercholesterolemia phenotype treated with lipoprotein apheresis between 2005 and 2020 (mean duration, 10 ± 4 years). The median pretreatment low-density lipoprotein cholesterol (LDL-C) level was 214 mg/100 ml (95% confidence interval, 145 to 248), lipoprotein(a) (Lp[a]), 26 mg/100 ml (15 to 109; 40% with Lp(a)>60 mg/100 ml). Three patients were diagnosed with a monogenic cause. The baseline mean CIMT was 850 ± 170 µm, and maximum CIMT was 1,040 ± 220 µm across the age range of 46 to 70 years. Acute effects of lipoprotein apheresis determined as a difference before and immediately after the procedure were estimated as a median of 72 ± 8% and 75 ± 7% reduction in the LDL-C and Lp(a) levels, respectively. Using the imputed trajectories, period-specific on-treatment time-weighted averages for LDL-C and Lp(a) were 141 mg/100 ml (interquartile range, 89 to 152; 38% reduction from the baseline) and 24 mg/100 ml (interquartile range, 12 to 119; 19% reduction from baseline), respectively. The number of patients with CIMT above their "vascular age" decreased from 80% to 30% over the treatment course. In conclusion, an increase in CIMT seen with advanced age and severe hypercholesterolemia was halted with lipoprotein apheresis with an estimated annual rate of change in mean common CIMT of -4 µm/y and maximum CIMT of -3 µm/y.
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Eliminación de Componentes Sanguíneos , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Eliminación de Componentes Sanguíneos/métodos , Grosor Intima-Media Carotídeo , LDL-Colesterol , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/complicaciones , Hipercolesterolemia/terapia , Lipoproteína(a) , MasculinoRESUMEN
OBJECTIVE: The aim of the study was to examine the effects of the vitamin D (Vit-D) treatment and nontreatment on Vit-D-deficient patients without a prior history of myocardial infarction (MI). MATERIALS AND METHODS: This was a retrospective, observational, nested case-control study of patients (Nâ =â 20 025) with low 25-hydroxyvitamin D ([25-OH]D) levels (<20 ng/mL) who received care at the Veterans Health Administration from 1999 to 2018. Patients were divided into 3 groups: Group A (untreated, levels ≤20 ng/mL), Group B (treated, levels 21-29 ng/mL), and Group C (treated, levels ≥30 ng/mL). The risk of MI and all-cause mortality were compared utilizing propensity score-weighted Cox proportional hazard models. RESULTS: Among the cohort of 20 025 patients, the risk of MI was significantly lower in Group C than in Group B (hazard ratio [HR] 0.65, 95% CI 0.49-0.85, Pâ =â .002) and Group A (HR 0.73, 95% CI 0.55-0.96), Pâ =â .02). There was no difference in the risk of MI between Group B and Group A (HR 1.14, 95% CI 0.91-1.42, Pâ =â 0.24). Compared with Group A, both Group B (HR 0.59, 95% CI 0.54-0.63, Pâ <â .001) and Group C (HR 0.61, 95% CI 0.56-0.67, Pâ <â .001) had significantly lower all-cause mortality. There was no difference in all-cause mortality between Group B and Group C (HR 0.99, 95% CI 0.89-1.09, Pâ =â .78). CONCLUSIONS: In patients with Vit-D deficiency and no prior history of MI, treatment to the (25-OH)D level of >20 ng/mL and >30 ng/mL was associated with a significantly lower risk of all-cause mortality. The lower risk of MI was observed only in individuals maintaining (25-OH)D levels ≥30 ng/mL.
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BACKGROUND: Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry. METHODS: We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization-phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants. RESULTS: In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA-odds ratio and 95% CI for coronary heart disease 1.28 (1.16-1.41); cerebrovascular disease 1.14 (1.07-1.21); peripheral artery disease 1.22 (1.11-1.34); abdominal aortic aneurysm 1.28 (1.17-1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99-1.24) and cerebrovascular disease 1.06 (0.99-1.14) but similar for peripheral artery disease 1.16 (1.01-1.33) and abdominal aortic aneurysm 1.34 (1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10-1.62), mitral valve disorders 1.18 (1.09-1.27), congestive heart failure 1.12 (1.05-1.19), and chronic kidney disease 1.07 (1.01-1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94-1.25), mitral valve disorders 1.02 (0.89-1.16), congestive heart failure 1.02 (0.95-1.10), or chronic kidney disease 1.05 (0.99-1.12). Mendelian randomization-phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. CONCLUSIONS: Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.
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Población Negra/genética , Enfermedades Cardiovasculares/genética , Predisposición Genética a la Enfermedad , Lipoproteína(a)/genética , Carácter Cuantitativo Heredable , Población Blanca/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Reino UnidoRESUMEN
We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) to discover pleiotropic effects of variants in three lipoprotein metabolism genes PCSK9, APOB, and LDLR. Using high-density genotype data, we tested the associations of variants in the three genes with 1232 EHR-derived binary phecodes in 51,700 European-ancestry (EA) individuals and 585 phecodes in 10,276 African-ancestry (AA) individuals; 457 PCSK9, 730 APOB, and 720 LDLR variants were filtered by imputation quality (r 2 > 0.4), minor allele frequency (>1%), linkage disequilibrium (r 2 < 0.3), and association with LDL-C levels, yielding a set of two PCSK9, three APOB, and five LDLR variants in EA but no variants in AA. Cases and controls were defined for each phecode using the PheWAS package in R. Logistic regression assuming an additive genetic model was used with adjustment for age, sex, and the first two principal components. Significant associations were tested in additional cohorts from Vanderbilt University (n = 29,713), the Marshfield Clinic Personalized Medicine Research Project (n = 9562), and UK Biobank (n = 408,455). We identified one PCSK9, two APOB, and two LDLR variants significantly associated with an examined phecode. Only one of the variants was associated with a non-lipid disease phecode, ("myopia") but this association was not significant in the replication cohorts. In this large-scale PheWAS we did not find LDL-C-related variants in PCSK9, APOB, and LDLR to be associated with non-lipid-related phenotypes including diabetes, neurocognitive disorders, or cataracts.
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OBJECTIVE: To develop clinical decision support (CDS) for familial hypercholesterolemia (FH), based on physician input obtained by a mixed methods approach. INTRODUCTION: Awareness, detection, and control of FH-a relatively common genetic disorder-is low. Clinical decision support could address knowledge gaps and provide point-of-care guidance for the management of FH. METHODS: A 16-question survey that assessed familiarity with FH and sought input on potential content of the CDS tool was emailed to 1161 clinicians including 208 cardiologists. In addition, 4 physician focus groups were held to gather input on the structure and form of the CDS tool. This study took place between September 12, 2016, and January 16, 2017. RESULTS: The response rate to the survey was 18.1%. Clinicians were overwhelmingly (97.6%) in favor of a CDS tool that assists in managing patients with FH at the point of care and this was confirmed in the focus group discussions. Key themes emerged during the focus groups including providers' knowledge and understanding of FH, facilitators and barriers to implementing a CDS tool, and suggestions for its design and content. CONCLUSION: Clinicians were supportive of development of a CDS tool to assist with the evaluation and treatment of FH and provided feedback related to the design and implementation of such a tool.