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Background: Achilles tendon thickening (ATT) can be ameliorated by lowering low-density lipoprotein (LDL) levels in patients with familial hypercholesterolemia (FH). The Japan Atherosclerosis Society (JAS) defines ATT as ≥8.0 mm in males and ≥7.5 mm in females. We aimed to determine the clinical impact of changes in ATT on the development of major adverse cardiovascular events (MACE). Methods: Patients with clinically diagnosed heterozygous FH (HeFH) (N = 1273; 614 males, 659 females) with ATT data from X-ray were assessed. Patients were divided into four groups: patients without ATT from baseline until follow-up (group 1), patients without ATT at baseline but developed ATT at follow-up (group 2), patients with ATT at baseline but regressed at follow-up (group 3), and patients with ATT from baseline until follow-up (group 4). Cox proportional hazard models were used to assess the factors associated with MACE, including cardiovascular death and any coronary events. Results: On follow-up (median: 10.9 years), 142 MACEs were observed, and the median ATT regressed from 7.8 to 7.6 mm. Changes in ATT were significantly associated with the occurrence of MACE in all groups, when compared to group 1 (hazard ratio [HR]: 2.73; 95 % confidence interval [CI]: 1.33-4.13 [p < 0.001], HR: 2.18, 95 % CI: 1.08-3.28, [p < 0.001], HR: 6.34, 95 % CI: 3.10-9.58, [p < 0.001], in groups 2, 3, and 4, respectively). Conclusions: Assessing ATT has diagnostic value and allows for risk stratification among patients with HeFH.
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Familial hypercholesterolemia (FH) is one of the most common autosomal codominant Mendelian diseases. The major complications of FH include tendon and cutaneous xanthomas and coronary artery disease (CAD) associated with a substantial elevation of serum low-density lipoprotein levels (LDL). Genetic counseling and genetic testing for FH is useful for its diagnosis, risk stratification, and motivation for further LDL-lowering treatments. In this study, we summarize the epidemiology of FH based on numerous genetic studies, including its pathogenic variants, genotype-phenotype correlation, prognostic factors, screening, and usefulness of genetic counseling and genetic testing. Due to the variety of treatments available for this common Mendelian disease, genetic counseling and genetic testing for FH should be implemented in daily clinical practice.
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Enfermedad de la Arteria Coronaria , Hiperlipoproteinemia Tipo II , Humanos , LDL-Colesterol/genética , Asesoramiento Genético , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Pruebas Genéticas , Enfermedad de la Arteria Coronaria/genéticaRESUMEN
Objective: Sitosterolemia is a rare autosomal recessive disease caused by the deleterious variants of adenosine 5'-triphosphate (ATP)-binding cassette sub-family G member 5 (ABCG5) or ATP-binding cassette sub-family G member 8 (ABCG8). There are only few data on the pathogenicity of ABCG5 and ABCG8. This study aimed to propose a scheme for determining variant pathogenicity and to catalog the putative pathogenic variants in sitosterolemia. Methods: This study enrolled 377 consecutive Japanese patients with hyper-low-density lipoprotein cholesterolemia (mean age: 46.5±19.8 years, with 192 men) who have targeted-sequenced data on ABCG5 or ABCG8 (among 21 Mendelian lipid genes for any dyslipidemias) and serum sitosterol levels at Kanazawa University Hospital from 2016 to 2021. Serum sitosterol levels were divided by 0.79 in patients treated with ezetimibe, accounting for the average reduction with this drug. ABCG5 or ABCG8 variants were defined as putative pathogenic if associated with serum sitosterol levels ≥5 µg/mL or homozygous if associated with serum sitosterol levels ≥10 µg/mL. Results: Twenty-three ABCG5 or ABCG8 variants (16 missense, 2 nonsense, 2 frameshift, 2 deletion, and 1 splice mutation) were identified. Based on our definition, 11 putative pathogenic variants (median sitosterol level: 10.1 [6.5-17.1] µg/mL) were found in 36 individuals and 12 benign variants (median sitosterol: 3.5 [2.5-4.1] µg/mL) in 14 individuals. Conclusion: The scheme proposed for assessing the pathogenicity of genetic variations (ABCG5 and ABCG8) is useful. Using this scheme, 11 putative pathogenic, and 12 benign variants in ABCG5 or ABCG were classified.
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Background: The studies evaluating patients' characteristics and lipid-lowering therapy for patients with homozygous familial hypercholesterolemia (HoFH) are scarce. Objectives: This study aims to evaluate the characteristics of and treatments for patients with HoFH. Methods: This study included 201 patients who were diagnosed with definite or probable HoFH from the National Database of the Japanese Ministry of Health, Labour, and Welfare. Results: The patients' median age at diagnosis was 27 years and exhibited a bimodal distribution. Approximately 70% of patients had coronary artery disease. Regarding genetic backgrounds, mutations in the low-density lipoprotein (LDL) receptor (LDLR) were identified in most of the patients, followed by proprotein convertase subtilisin/kexin type 9 (PCSK9) and double heterozygotes of LDLR. High-intensity statins were introduced to 74% of the patients, lipoprotein apheresis was performed in 21%, and PCSK9 inhibitors were administered to 50%. The mean of LDL cholesterol before and after treatment were 10.1 mmol/L and 3.9 mmol/L, respectively. Patients with coronary artery disease had significantly decreased LDL cholesterol. A quarter of the patients (n = 49, 24%) exhibited valvular diseases, particularly aortic valvular disease (n = 34, 61%). Conclusions: The national epidemiological study of patients with HoFH showed patient's clinical and genetic characteristics and LDL-lowering therapy in Japan. There was considerable diversity in the severity of phenotypes, including LDL cholesterol levels, among patients with HoFH. In Japan, the management of LDL cholesterol in HoFH is still inadequate despite the availability of intensive lipid-lowering therapies.
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Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels. This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Data of patients with FH (N = 1050, male = 490) who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model. Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56-10.40, P = 1.2 × 10-5). The event rates per 1000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively. Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.
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Síndrome Coronario Agudo , Aterosclerosis , Hiperlipoproteinemia Tipo II , Humanos , Masculino , Estudios Retrospectivos , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/epidemiología , Aterosclerosis/epidemiología , Aterosclerosis/complicaciones , Modelos de Riesgos Proporcionales , Síndrome Coronario Agudo/complicaciones , Factores de RiesgoRESUMEN
AIM: In 2022, the Japan Atherosclerosis Society (JAS) has revised its clinical diagnostic criteria of familial hypercholesterolemia (FH) and adopted the use of definite, probable, possible, and unlikely FH according to the Dutch Lipid Clinic Network (DLCN) FH criteria. However, these strata have not been validated and their impact on coronary artery disease (CAD) is yet to be elucidated. METHODS: In this study, we retrospectively examined the patients with FH aged ≥ 15 years (N=857, male=431) who were admitted to Kanazawa University Hospital between 2010 and 2022. We assessed the prevalence of patients with a pathogenic variant as FH and odds ratio (OR) of CAD among each group determined by the JAS criteria 2022 for adults. RESULTS: In total, 414, 128, 142, and 173 patients were found to have definite, probable, possible, and unlikely FH, respectively, in this population. The prevalences of patients with a pathogenic variant as FH were 77.1%, 28.7%, 13.0%, and 1.2 %, respectively, among the definite, probable, possible, and unlikely FH patients (P-trend ï¼0.001). Compared with the reference group of unlikely FH, patients with definite, probable, and possible FH were noted to have significantly higher adjusted odds of developing CAD (OR, 9.1; 95% confidence interval [CI], 3.2-12.6; Pï¼0.001 and OR, 4.2; 95% CI, 1.7-6.4; Pï¼0.001, and OR, 2.8; 95% CI, 1.2-4.4; P=0.002, respectively). CONCLUSION: The new JAS diagnostic criteria for FH have been noted to work well in terms of diagnosing definitive, probable, or possible FH patients. Thus, it is seen to be of great help in terms of risk discrimination.
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BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH. OBJECTIVE: We aimed to evaluate the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program. METHODS: We conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24. RESULTS: Fifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n = 24) or the wait-list control group (n = 26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p = 0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers. CONCLUSIONS: In addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers. REGISTRATION: Japan Registry of Clinical Trials (jRCTs04218002). URL: https://jrct.niph.go.jp/latest-detail/jRCTs042180027.
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Enfermedades Cardiovasculares , Enfermedad Coronaria , Hiperlipoproteinemia Tipo II , Humanos , LDL-Colesterol , Factores de Riesgo , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/genética , Enfermedad Coronaria/diagnóstico , Factores de Riesgo de Enfermedad CardiacaRESUMEN
BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) because of COL3A1 mutations is a rare inherited collagen vascular disease associated with spontaneous arterial dissections, aneurysms, vessel rupture, and organ rupture. A direct carotid-cavernous fistula (CCF) is the most common central nervous system vascular anomaly in vEDS; however, its treatment is challenging due to extremely fragile arteries and veins. OBSERVATIONS: A 22-year-old woman presented with pulsatile tinnitus and mild diplopia. CCF formation without trauma, cervical dissecting aneurysms, thin skin, and multiple ligament tears, as well as a genetic analysis, led to a diagnosis of vEDS. To minimize the risk of vascular injury in the thoracoperitoneal cavity, the internal jugular vein was directly punctured and the CCF was embolized transvenously using the triple-overlay road-mapping technique without arterial monitoring. The CCF was completely occluded, and the patient showed an excellent clinical course without neurological or vascular complications. LESSONS: Physicians and neurosurgeons should consider vEDS when treating younger patients with spontaneous CCF without trauma and investigate the possibility of genetic abnormalities and systemic vascular pathology. Transvenous embolization of a CCF through the transjugular route using the triple-overlay road-mapping technique can minimize the risk of vascular injury in a patient with vEDS.
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Aims: We aimed to determine if coronary artery calcium (CAC) is associated with cardiovascular disease (CVD) events, defined as CVD-related death, unstable angina, myocardial infarction, or staged revascularization among patients with heterozygous familial hypercholesterolaemia (HeFH) under primary prevention settings. Methods and results: Data of patients with FH admitted to Kanazawa University Hospital between 2000 and 2020, who underwent CAC measurement and were followed up (n = 622, male = 306, mean age = 54 years), were retrospectively reviewed. Risk factors for CVD events were determined using the Cox proportional hazard model. The median follow-up duration was 13.2 years (interquartile range: 9.8-18.4 years). We observed 132 CVD events during the follow-up period. The event rate per 1000 person-years for CAC scores of 0 [n = 283 (45.5%)], 1-100 [n = 260 (41.8%)], and >100 [n = 79 (12.7%)] was 1.2, 17.0, and 78.8, respectively. Log (CAC score + 1) was a significant predictor of the occurrence of CVD events (hazard ratio: 3.24; 95% confidence interval: 1.68-4.80; P < 0.0001) in the multivariate Cox regression analysis, independent of other factors. The risk discrimination of CVD events was enhanced by adding CAC information to other conventional risk factors (C-statistics: 0.833-0.934; P < 0.0001). Conclusion: The CAC score helps in further risk stratification in patients with HeFH.
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Background: Pathogenic mutations are associated with poor outcomes in patients with familial hypercholesterolemia (FH). However, data on the effects of a healthy lifestyle on FH phenotypes are limited. Objectives: The authors investigated the interaction between a healthy lifestyle and FH mutation with prognosis in patients with FH. Methods: We investigated the associations of the interaction between genotypes and lifestyle, with the occurrence of major adverse cardiac events (MACE), such as cardiovascular-related mortality, myocardial infarction, unstable angina, and coronary artery revascularization, in patients with FH. We assessed their lifestyle based on 4 questionnaires (healthy dietary pattern, regular exercise, not smoking, and absence of obesity). The Cox proportional hazards model was used to assess the risk for MACE. Results: The median follow-up duration was 12.6 (IQR: 9.5-17.9) years. During the follow-up duration, 179 MACE were observed. Independent of classic risk factors, FH mutation and lifestyle score were significantly associated with MACE (HR: 2.73; 95% CI: 1.03-4.43; P = 0.02; and HR: 0.69, 95% CI: 0.40-0.98, P = 0.033, respectively). The estimated risk of coronary artery disease by 75 years of age varied according to lifestyle, ranging from 21.0% among noncarriers with a favorable lifestyle to 32.1% among noncarriers with an unfavorable lifestyle and ranging from 29.0% among carriers with a favorable lifestyle to 55.4% among carriers with an unfavorable lifestyle. Conclusions: A healthy lifestyle was associated with reduced risk for MACE among patients with FH with or without genetic diagnosis.
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BACKGROUND AND AIMS: No previous study has investigated the association between attainment of low-density lipoprotein (LDL) cholesterol treatment target and better prognosis in patients with familial hypercholesterolemia (FH). The current research aimed to examine the association between attainment of LDL cholesterol treatment target and major adverse cardiac events (MACEs) in patients with FH to validate the current LDL cholesterol treatment targets in primary (<100 mg/dL) and secondary (<70 mg/dL) prevention settings. METHODS: The data of patients with FH who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed-up were retrospectively reviewed. The number of MACEs, including mortality associated with cardiovascular disease, unstable angina, and myocardial infarction per 1000 person-years, was calculated for each stratum for the attainment of LDL cholesterol target. RESULTS: The median follow-up duration was 12.6 years. In total, 132 MACEs were recorded during the follow-up period. The numbers of patients who attained the LDL cholesterol target in the primary and secondary prevention groups were 228 (31.9%) and 40 (11.9%), respectively. The event rates per 1000 person-years for LDL cholesterol levels of <100 and ≥100 mg/dL in the primary prevention group were 2.6 and 4.4, respectively. The event rates per 1000 person-years for LDL cholesterol levels of <70 and ≥70 mg/dL in the secondary prevention group were 15.3 and 27.5, respectively. CONCLUSIONS: Attainment of the LDL cholesterol target is associated with better prognosis in patients with FH. However, the attainment rate is currently inadequate among Japanese.
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Anticolesterolemiantes , Hiperlipoproteinemia Tipo II , Infarto del Miocardio , Humanos , LDL-Colesterol , Anticolesterolemiantes/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/epidemiología , Colesterol , Pronóstico , Infarto del Miocardio/complicacionesRESUMEN
BACKGROUND: Recently, the function of high-density lipoprotein (HDL), rather than the HDL cholesterol (HDL-C) level, has been attracting more attention in risk prediction for coronary artery disease (CAD).MethodsâandâResults: Patients with clinically diagnosed familial hypercholesterolemia (FH; n=108; male/female, 51/57) were assessed cross-sectionally. Serum cholesterol uptake capacity (CUC) levels were determined using our original cell-free assay. Linear regression was used to determine associations between CUC and clinical variables, including low-density lipoprotein cholesterol and the carotid plaque score. Multivariable logistic regression analysis was used to test factors associated with the presence of CAD. Among the 108 FH patients, 30 had CAD. CUC levels were significantly lower among patients with than without CAD (median [interquartile range] 119 [92-139] vs. 142 [121-165] arbitrary units [AU]; P=0.0004). In addition, CUC was significantly lower in patients with Achilles tendon thickness ≥9.0 mm than in those without Achilles tendon thickening (133 [110-157] vs. 142 [123-174] AU; P=0.047). Serum CUC levels were negatively correlated with the carotid plaque score (Spearman's r=0.37; P=0.00018). Serum CUC levels were significantly associated with CAD, after adjusting for other clinical variables (odds ratio=0.86, 95% CI=0.76-0.96, P=0.033), whereas HDL-C was not. CONCLUSIONS: HDL function, assessed by serum CUC level, rather than HDL-C level, adds risk stratification information among FH patients.
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Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Hiperlipoproteinemia Tipo II , Humanos , Masculino , Femenino , Lipoproteínas HDL , Enfermedades Cardiovasculares/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico , HDL-ColesterolRESUMEN
Background: Little is known regarding the formation of coronary and carotid plaques and their impact on cardiovascular disease in patients with familial hypercholesterolemia (FH). Objectives: This study aimed to determine: 1) if the development of coronary and carotid plaques is correlated; and 2) if these plaques are associated with major adverse cardiac events (MACEs) defined as cardiovascular-related death, unstable angina, myocardial infarction, or staged revascularization. Methods: This was a retrospective review of 622 patients with heterozygous FH (HeFH) at Kanazawa University Hospital, assessed coronary and carotid plaque scores using coronary computed tomography and carotid ultrasound within 1 year. Spearman correlation coefficients were assessed among variables. Risk factors for MACEs were determined using the Cox proportional hazard model. Results: Coronary and carotid plaque scores were significantly correlated in patients with HeFH in both sexes (Spearman's r = 0.82; P < 0.001 in males and Spearman's r = 0.87; P < 0.001 in females). We observed 132 MACEs during the median follow-up of 13.2 years. These scores were significantly associated with the occurrence of MACE (HR: 3.33; 95% CI: 1.88-4.78; P < 0.001, HR: 2.24; 95% CI: 1.28-3.20; P < 0.001, respectively). Conclusions: Coronary and carotid plaque scores were significantly correlated, and both were independently associated with MACEs. The assessments for coronary and/or carotid plaque are useful for further risk stratifications in patients with HeFH.
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Objective: The synergistic effect of lipoprotein (a) [Lp(a)] and C-reactive protein (CRP) on major adverse cardiovascular events (MACE) among patients with familial hypercholesterolemia (FH) is unknown. This study aimed to investigate the relations between Lp(a) and CRP levels and MACE in patients with FH whose Lp(a) levels are elevated. Methods: We retrospectively investigated associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of MACE among patients with FH (N = 786, male/female: 374/412). A Cox proportional hazard model was used to identify factors associated with MACE, adjusting for traditional risk factors. Patients with FH were divided into four groups, based on their Lp(a) and CRP levels, and assessed using Kaplan-Meier curves. Results: The median follow-up was 12.6 years (interquartile range [IQR], 9.5-17.9 years). During follow-up, 129 MACE were observed. Median Lp(a) and CRP levels were 21.4 (10.9-38.3) mg/dL and 0.20 (0.11-0.29) mg/dL, respectively. Under these conditions, natural log-transformed Lp(a) and CRP were not associated with MACE (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.91-1.25; P = 0.220; and HR, 1.12; CI, 0.96-1.28; P = 0.190, respectively). However, in Group 4, Lp(a) and CRP were significantly associated with MACE (HR, 2.44; CI, 1.42-3.46; P = 1.8 × 10-7). Conclusions: In patients with FH, Lp(a) was significantly associated with MACE only when the CRP level was elevated. Patients with FH whose Lp(a) and CRP levels are elevated should be treated aggressively.
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Objective: The early diagnosis and treatment initiation for children with familial hypercholesterolemia (FH) has been recommended in guidelines. However, there is limited data on the impact of early treatments on the prognosis of children with FH. To investigate if the early initiation of lipid-lowering therapies among Japanese pediatric patients with FH reduced the occurrence of cardiovascular disease (CVD) events in them. Methods: We retrospectively investigated the occurrence of CVD events (myocardial infarction, unstable angina, or coronary artery revascularization) in patients with FH (N = 1050, male/female = 490/560), including 106 children below 20 years. We compared a variety of phenotypes, including genetic backgrounds, other complications, LDL cholesterol, medical therapies, and their prognoses between the patients' diagnoses before the age of 20 years (children, mean age = 15 years) and after that age (adults, mean age = 52 years). Overall, 290 patients (27.6%) had a history of prior CVD events. Results: The median follow-up duration was 12.6 [9.5-17.9] years. The baseline LDL cholesterol level, 239 mg/dL, dropped to 112 mg/dL with the treatments. The Achilles tendon thickness was significantly lower in children than that of adults (7.2 vs. 8.9 mm, P < 0.001). Over the follow-up duration, 119 CVD events were observed. Importantly, no CVD event was observed in children despite their median LDL cholesterol level at follow-up being significantly higher than that of adults (122 vs. 111 mg/dL, P < 0.001). Conclusion: The likelihood of CVD events in those with FH diagnosed and treated in childhood is low.
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BACKGROUND: Data on the effect of variants of uncertain significance (VUS) of LDL receptor (LDLR) on familial hypercholesterolemia (FH) phenotype is limited. OBJECTIVE: To investigate the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and occurrence of major adverse cardiac events (MACEs), in FH patients (N = 1050, male/female = 490/560). METHODS: We retrospectively assessed the data of patients with FH admitted at Kanazawa University Hospital between 1990 and 2020. Based on genotype, the patients were divided into patients without variants, with VUS of LDLR, and with pathogenic variants. Cox proportional hazard model was used to identify the factors associated with MACEs. RESULTS: The median follow-up duration was 12.6 years (interquartile range: 9.5-17.9 years). Altogether, 777 patients had FH mutation and 273 had pathogenic mutation, with 92 having VUS. Over the follow-up duration, 175 MACEs were observed. LDL cholesterol level was found to be significantly higher in patients with pathogenic variants (251 mg/dL) than in patients with VUS (225 mg/dL) and without variants (203 mg/dL). Pathogenic variants and VUS are significantly associated with MACEs (hazard ratio [HR] = 1.52, 95% confidence interval [CI] = 1.02-2.02, P = 0.033 and HR = 3.18, 95% CI = 2.00-4.36, P = 1.9 × 10-5, relative to patients without any variants, respectively), independent of classical risk factors. CONCLUSION: VUS of LDLR was significantly associated with poor outcomes in FH patients. Genetic testing is useful for the diagnosis and risk stratification of FH patients.
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Variación Genética , Hiperlipoproteinemia Tipo II , Femenino , Masculino , Humanos , Estudios Retrospectivos , Hiperlipoproteinemia Tipo II/diagnóstico , Receptores de LDL/genética , LDL-Colesterol/genética , Fenotipo , MutaciónRESUMEN
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder, and a genetic analysis is important to make a definitive diagnosis. A comprehensive genetic analysis using next generation sequencing (NGS) and whole exome sequencing (WES) is feasible. However, the application of NGS in the assessment of genomic structural variations is generally limited, and a substantial number of control samples are needed for such assessments. Thus, NGS alone is unlikely to detect genomic structural variations in a "singleton." We present the case of a patient with compound HeFH (heterozygous FH), whose causative mutations in the LDLR gene could not be identified by WES, necessitating the application of the multiplex ligation-dependent probe amplification (MLPA) technique.
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Hiperlipoproteinemia Tipo II , Receptores de LDL , Pruebas Genéticas/métodos , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Mutación , Receptores de LDL/genética , Secuenciación del Exoma/métodosRESUMEN
Objective: It has been shown that pathogenic variants are associated with poor clinical outcomes in patients with familial hypercholesterolemia (FH). However, data on the effect of different types of pathogenic variants on FH phenotype is limited. Methods: We retrospectively investigated the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of major adverse cardiac events (MACEs), defined as cardiovascular death, myocardial infarction, unstable angina, or coronary artery revascularization, in patients with FH (N = 1,050, male/female = 490/560). Based on genotype, the patients were divided into the following three groups: patients without pathogenic variants, patients with missense variants, and patients with protein-truncating variants (PTVs). Cox proportional hazard model was used to identify the factors associated with MACEs. Results: The median follow-up duration was 12.6 years (interquartile range = 9.5-17.9 years). There were 665 patients with FH-mutation (277 patients with missense variants and 388 patients with PTVs) and 385 patients without FH-mutation. Over the follow-up duration, 175 MACEs were observed. We identified 89 different pathogenic variants in the 665 patients with FH. LDL cholesterol level was found to be significantly higher in patients with PTVs (256 mg/dl) than in patients with missense variants (236 mg/dl) and patients without pathogenic variants (216 mg/dl). It was also found that PTVs and missense variants are significantly associated with MACEs (hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.08-2.08, p = 0.0033 and HR = 3.24, 95% CI = 2.12-4.40, p = 3.9 × 10-6, respectively), independent of classical risk factors. Conclusion: Pathogenic variants, especially PTVs, are significantly associated with poor outcomes in patients with FH. Genetic testing is useful for the diagnosis and risk stratification of patients with FH.