RESUMO
BACKGROUND AND AIMS: We recently identified lysosomal acid lipase (LAL) deficiency, a recessive disease caused by mutations in LIPA, in 3 patients with a clinical diagnosis of familial hypercholesterolemia (FH). We aimed to determine the prevalence of LIPA mutations among individuals with a clinical FH diagnosis. METHODS: In 276 patients with phenotypic FH, in whom no genetic basis for their phenotype was found, LIPA was sequenced. All variants were assessed for pathogenicity using a literature search and in silico prediction models. RESULTS: We included 213 adults and 63 children with mean (±SD) LDL-C levels of 7.8 ± 1.3 and 4.4 ± 1.5 mmol/L, respectively. Twenty-one variants were identified. Six patients were heterozygous carrier of a (potentially) pathogenic mutation. No homozygous LIPA mutation carriers were identified. CONCLUSIONS: Our data show that LAL deficiency was not missed as diagnosis in our study population but the frequency of heterozygous LIPA mutations implies that the FH population might be relatively enriched with LIPA mutation carriers.
Assuntos
Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Mutação , Esterol Esterase/genética , Doença de Wolman/genética , Adolescente , Adulto , Idoso , Criança , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Triglicerídeos/sangue , Doença de WolmanRESUMO
BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.
Assuntos
Anticorpos Monoclonais/administração & dosagem , LDL-Colesterol/sangue , Doença da Artéria Coronariana , Hiperlipoproteinemia Tipo II , Mutação , Pró-Proteína Convertases , Serina Endopeptidases , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Método Duplo-Cego , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/antagonistas & inibidores , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismoRESUMO
AIMS: Autosomal-dominant hypercholesterolaemia (ADH) is a heterogeneous common disorder, and uncovering the molecular determinants that underlie ADH is a major focus of cardiovascular research. However, despite rapid technical advances, efforts to identify novel ADH genes have yet not been very successful and are largely challenged by phenotypic and genetic heterogeneity of this disease. We aimed to investigate the impact of this phenotypic heterogeneity on successfully finding new genes that are involved in ADH. METHODS AND RESULTS: For the ADH phenotype, subjects are considered as affected according to plasma cholesterol levels above the 95th percentile for age and gender. The disease penetrance is generally set at 0.9. These parameters were evaluated in 10000 carriers of true pathogenic APOB and LDLR mutations and 20000 relatives negative for the familial mutations. Application of the above parameters in almost a thousand families included in this study would have identified the causal variant in only 38% of all families. An average penetrance of 0.9 or higher, with a cut-point at the 95th percentile, was only observed for LDLR nonsense mutations. For APOB and LDLR missense mutations, a disease penetrance of 0.9 or higher is only expected, when total cholesterol and low-density lipoprotein cholesterol cut-points between the 75th and 90th percentile are used to determine an individual's disease status. CONCLUSIONS: Although pathogenic LDLR and APOB mutations do follow Mendelian patterns of inheritance, the extensive variation in genotype and phenotype for well-known ADH-causing mutations emphasises that current criteria and strategies indeed are likely to hamper the identification of novel genes related to ADH. These findings provide a basis for the revision of our assessment on who is affected and who is not and emphasise the essence of pedigree information and mapping data before exome sequencing is applied in order to increase success rates of finding new genes related to ADH.
Assuntos
Estudos de Associação Genética/métodos , Hiperlipoproteinemia Tipo II/genética , Apolipoproteínas B/genética , LDL-Colesterol/genética , Feminino , Heterozigoto , Humanos , Masculino , Mutação/genética , Linhagem , Penetrância , Curva ROC , Receptores de LDL/genéticaRESUMO
AIMS: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands. METHODS AND RESULTS: The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be â¼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event. CONCLUSION: The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.
Assuntos
Hiperlipoproteinemia Tipo II/epidemiologia , Adolescente , Adulto , Idoso , Apolipoproteína B-100/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Heterozigoto , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/genética , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação/genética , Países Baixos/epidemiologia , Fenótipo , Prevalência , Prognóstico , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Serina Endopeptidases/genética , Adulto JovemRESUMO
RATIONALE: Autosomal-dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and increased risk for coronary vascular disease. ADH is caused by mutations in the low-density lipoprotein receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin 9. A number of patients, however, suffer from familial hypercholesterolemia 4 (FH4), defined as ADH in absence of mutations in these genes and thereafter use the abbreviation FH4. OBJECTIVE: To identify a fourth locus associated with ADH. METHODS AND RESULTS: Parametric linkage analysis combined with exome sequencing in a FH4 family resulted in the identification of the variant p.Glu97Asp in signal transducing adaptor family member 1 (STAP1), encoding signal transducing adaptor family member 1. Sanger sequencing of STAP1 in 400 additional unrelated FH4 probands identified a second p.Glu97Asp carrier and 3 additional missense variants, p.Leu69Ser, p.Ile71Thr, and p.Asp207Asn. STAP1 carriers (n=40) showed significantly higher plasma total cholesterol and low-density lipoprotein cholesterol levels compared with nonaffected relatives (n=91). CONCLUSIONS: We mapped a novel ADH locus at 4p13 and identified 4 variants in STAP1 that associate with ADH.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Hiperlipoproteinemia Tipo II/genética , Mutação/genética , Adulto , Apolipoproteínas B/genética , Feminino , Ligação Genética , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/fisiopatologia , Metabolismo dos Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Serina Endopeptidases/genéticaRESUMO
AIMS: Recent genome-wide association studies suggest that IDOL (also known as MYLIP) contributes to variation in circulating levels of low-density lipoprotein cholesterol (LDL-C). IDOL, an E3-ubiquitin ligase, is a recently identified post-transcriptional regulator of LDLR abundance. Briefly, IDOL promotes degradation of the LDLR thereby limiting LDL uptake. Yet the exact role of IDOL in human lipoprotein metabolism is unclear. Therefore, this study aimed at identifying and functionally characterizing IDOL variants in the Dutch population and to assess their contribution to circulating levels of LDL-C. METHODS AND RESULTS: We sequenced the IDOL coding region in 677 individuals with LDL-C above the 95th percentile adjusted for age and gender (high-LDL-C cohort) in which no mutations in the LDLR, APOB, and PCSK9 could be identified. In addition, IDOL was sequenced in 560 individuals with baseline LDL-C levels below the 20th percentile adjusted for age and gender (low-LDL-C cohort). We identified a total of 14 IDOL variants (5 synonymous, 8 non-synonymous, and 1 non-sense). Functional characterization of these variants demonstrated that the p.Arg266X variant represents a complete loss of IDOL function unable to promote ubiquitylation and subsequent degradation of the LDLR. Consistent with loss of IDOL function, this variant was identified in individuals with low circulating LDL-C. CONCLUSION: Our results support the notion that IDOL contributes to variation in circulating levels of LDL-C. Strategies to inhibit IDOL activity may therefore provide a novel therapeutic venue to treating dyslipidaemia.
Assuntos
Códon sem Sentido/genética , Hiperlipoproteinemia Tipo II/genética , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Mutação de Sentido Incorreto/genética , Ubiquitina-Proteína Ligases/fisiologia , Adulto , LDL-Colesterol/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Linhagem , Fenótipo , Receptores de LDL/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Aims Autosomal dominant hypercholesterolaemia (ADH) is a major risk factor for coronary artery disease. This disorder is caused by mutations in the genes coding for the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9). However, in 41% of the cases, we cannot find mutations in these genes. In this study, new genetic approaches were used for the identification and validation of new variants that cause ADH. Methods and results Using exome sequencing, we unexpectedly identified a novel APOB mutation, p.R3059C, in a small-sized ADH family. Since this mutation was located outside the regularly screened APOB region, we extended our routine sequencing strategy and identified another novel APOB mutation (p.K3394N) in a second family. In vitro analyses show that both mutations attenuate binding to the LDLR significantly. Despite this, both mutations were not always associated with ADH in both families, which prompted us to validate causality through using a novel genetic approach. Conclusion This study shows that advances in genetics help increasing our understanding of the causes of ADH. We identified two novel functional APOB mutations located outside the routinely analysed APOB region, suggesting that screening for mutations causing ADH should encompass the entire APOB coding sequence involved in LDL binding to help identifying and treating patients at increased cardiovascular risk.
Assuntos
Apolipoproteínas B/genética , Exoma/genética , Hiperlipoproteinemia Tipo II/genética , Mutação/genética , Feminino , Ligação Genética/genética , Testes Genéticos/métodos , Humanos , Lipoproteínas LDL/genética , Masculino , Linhagem , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Análise de Sequência de DNA/métodos , Serina Endopeptidases/genéticaRESUMO
Autosomal Dominant Hypercholesterolemia (ADH) is caused by LDLR and APOB mutations. However, genetically diagnosed ADH patients do not always exhibit the expected hypercholesterolemic phenotype. Of 4,669 genetically diagnosed ADH patients, identified through the national identification screening program for ADH, 75 patients (1.6%) had LDL-cholesterol (LDL-C) levels below the 50th percentile for age and gender prior to lipid-lowering therapy. The genes encoding APOB, PCSK9, and ANGPTL3 were sequenced in these subjects to address whether monogenic dominant loss-of-function mutations underlie this paradoxical phenotype. APOB mutations, resulting in truncated APOB, were found in five (6.7%) probands, reducing LDL-C by 56%. Rare variants in PCSK9, and ANGPTL3 completely correcting the hypercholesterolemic phenotype were not found. The common variants p.N902N, c.3842+82T>A, p.D2312D, and p.E4181K in APOB, and c.1863+94A>G in PCSK9 were significantly more prevalent in our cohort compared to the general European population. Interestingly, 40% of our probands carried at least one minor allele for all four common APOB variants compared to 1.5% in the general European population. While we found a low prevalence of rare variants in our cohort, our data suggest that regions in proximity of the analyzed loci, and linked to specific common haplotypes, might harbor additional variants that correct an ADH phenotype.
Assuntos
Angiopoietinas/genética , Apolipoproteínas B/genética , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Mutação , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Adulto , Proteína 3 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Adulto JovemRESUMO
BACKGROUND: Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. Mutations in the genes encoding for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) underlie ADH. Nevertheless, a proportion of individuals who exhibit the ADH phenotype do not carry mutations in any of these 3 genes. Estimates of the percentage of such cases among the ADH phenotype vary widely. We therefore investigated a large pediatric population with an unequivocal ADH phenotype to assess the molecular basis of hereditary hypercholesterolemia and to define the percentage of individuals with unexplained dyslipidemia. METHODS AND RESULTS: We enrolled individuals with low-density lipoprotein cholesterol levels above the 95th percentile for age and gender and an autosomal dominant inheritance pattern of hypercholesterolemia from a large referred pediatric cohort of 1430 children. We excluded children with thyroid dysfunction, nephrotic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, and obesity (body mass index >75th percentile for age and gender), as well as children referred via a cascade screening program and those from families with a known molecular diagnosis. Of the 269 children who remained after the exclusion criteria were applied, 255 (95%) carried a functional mutation (LDLR, 95%; APOB, 5%). CONCLUSION: In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Adolescente , Apolipoproteínas B/sangue , Apolipoproteínas B/genética , Criança , Pré-Escolar , LDL-Colesterol/sangue , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Mutação , Fenótipo , Receptores de LDL/genéticaRESUMO
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Negro ou Afro-Americano/genética , Animais , Povo Asiático/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/terapia , Europa (Continente)/etnologia , Feminino , Genótipo , Humanos , Fígado/metabolismo , Masculino , Camundongos , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Reprodutibilidade dos Testes , Triglicerídeos/sangue , População Branca/genética , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
Patients with familial hypercholesterolemia (FH) have elevated LDL-C levels, usually above the 90th percentile (P90) for age and gender. However, large-scale genetic cascade screening for FH showed that 15% of the LDL-receptor (LDLR) or Apolipoprotein B (APOB) mutation carriers have LDL-C levels below P75. Nonpathogenicity of sequence changes may explain this phenomenon. To assess pathogenicity of a mutation we proposed three criteria: (1) mean LDL-C 4P75 in untreated mutation carriers; (2) higher mean LDL-C level in untreated carriers than in untreated noncarriers; and (3) higher percentage of medication users in carriers than in noncarriers at screening. We considered a mutation nonpathogenic when none of the three criteria were met. We applied these criteria to mutations that had been determined in more than 50 untreated adults. Segregation analysis was performed to confirm nonpathogenicity. Forty-six mutations had been tested in more than 50 untreated subjects, and three were nonpathogenic according to our criteria: one in LDLR (c.108C4A, exon 2) and two in APOB (c.13154T4C and c.13181T4C, both in exon 29). Segregation analysis also indicated nonpathogenicity. According to our criteria, three sequence variants were nonpathogenic. The criteria may help to identify nonpathogenic sequence changes in genetic cascade screening programs.
Assuntos
Apolipoproteínas B/genética , Hiperlipoproteinemia Tipo II/genética , Mutação , Receptores de LDL/genética , Adulto , Idoso , LDL-Colesterol/sangue , Estudos de Coortes , Feminino , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Autosomal-dominant hypercholesterolemia (ADH) has been identified as a major risk factor for coronary vascular disease (CVD) and is associated with mutations in the low-density lipoprotein receptor (LDLR) and the apolipoprotein B (APOB) gene. Since 1991 DNA samples from clinically diagnosed ADH patients have been routinely analyzed for the presence of LDLR and APOB gene mutations. As of 2001, 1,641 index patients (164 index patients per year) had been identified, while from 2001 onward a more sensitive, high-throughput system was used, resulting in the identification of 1,177 new index patients (average=294 index patients per year). Of these 1,177 index cases, 131 different causative genetic variants in the LDLR gene and six different causative mutations in the APOB gene were new for the Dutch population. Of these 131 mutations, 83 LDLR and four APOB gene mutations had not been reported before. The inclusion of all 2,818 index cases into the national screening program for familial hypercholesterolemia (FH) resulted in the identification of 7,079 relatives who carried a mutation that causes ADH. Screening of the LDLR and APOB genes in clinically diagnosed FH patients resulted in approximately 77% of the patients being identified as carriers of a causative mutation. The population of patients with ADH was divided into three genetically distinct groups: carriers of an LDLR mutation (FH), carriers of an APOB mutation (FDB), and non-LDLR/non-APOB patients (FH3). No differences were found with regard to untreated cholesterol levels, response to therapy, and onset of CVD. However, all groups were at an increased risk for CVD. Therefore, to ultimately identify all individuals with ADH, the identification of new genes and mutations in the genes that cause ADH is of crucial importance for the ongoing national program to identify patients with ADH by genetic cascade screening.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Mutação , Adulto , Apolipoproteínas B/genética , Análise Mutacional de DNA , Feminino , Rearranjo Gênico , Testes Genéticos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Receptores de LDL/genética , Fatores de Risco , Doenças Vasculares/genéticaRESUMO
Inherited, or autosomal dominant, hypercholesterolaemia, with an average global prevalence of one in 500 individuals, is one of the most frequent inherited metabolic disorders. The disorder is associated with a high risk for premature cardiovascular disease (CVD) and death as a consequence of accelerated atherosclerosis. Although the molecular genetic basis is largely elucidated and effective medical treatment, in the form of inhibitors of intracellular cholesterol synthesis, is available, the disorder is severely underdiagnosed and undertreated. On the other hand, with the well-understood aetiology, the accurate diagnosis, the availability of sensitive predictive makers and efficacious therapy, this disorder can serve as a model for disease management: from early presymptomatic diagnosis, accurate prognosis, optimal treatment and large-scale screening to population-based prevention of CVD.
Assuntos
Dislipidemias/genética , Dislipidemias/terapia , Genes Dominantes , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , HumanosAssuntos
LDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Hiperlipoproteinemia Tipo II/genética , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Variação Genética/genética , Humanos , Prognóstico , Pró-Proteína Convertase 9 , Pró-Proteína Convertases , Fatores de Risco , Triglicerídeos/sangueRESUMO
Patients with familial hypercholesterolemia (FH) or familial defective apolipoprotein B (FDB) have severely increased low-density lipoprotein (LDL)-cholesterol levels and increased risk for premature coronary artery disease (CAD). Previous data on FDB patients were collected in patients referred to lipid clinics and were therefore subject to referral bias. We assessed the clinical phenotype of FDB in a population free from selection on CAD to compare the atherosclerotic burden with that of heterozygous FH. The study population was actively recruited in a large-scale screening program for inherited hypercholesterolemia in which FH and FDB heterozygotes were diagnosed by standard molecular techniques. Patients with FH and FDB had significantly higher plasma total cholesterol and LDL-cholesterol levels compared with their unaffected relatives. As with previous findings in FH, in FDB 19% of the carriers and 17% of the noncarriers of apoB mutations would have been misdiagnosed by cholesterol measurement alone, taking the age- and sex-specific 95th percentile as the diagnostic criterion. In FH patients the CAD risk was 8.5 relative to unaffected family members, whereas FDB patients had a 2.7-fold higher risk of CAD than unaffected relatives. FDB patients, free from clinical selection bias, do show lower total and LDL-cholesterol levels and lower CAD risk compared with FH heterozygotes. However, FDB patients are still exposed to a substantially higher CAD risk compared with unaffected relatives.