Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia
Introduction
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by lifelong elevation of LDL-cholesterol concentrations, tendon xanthomas, and early-onset of coronary heart disease (CHD) [1]. The underlying molecular defect consists of mutations in the gene encoding for the LDL receptor (LDLR) protein. Detection of functional mutations of the LDLR gene provides an unequivocal diagnosis of the condition [2].
Despite its strong genetic background, FH shows a great variability in phenotypic expression in terms of the lipid profile, frequency of xanthomas, and onset and severity of CHD [1], [3], [4]. To date, more than 1000 LDLR mutations have been reported [5] (http://www.ucl.ac.uk/ldlr/Current), and differences between null allele and defective allele mutations have been found for the lipid phenotype, response to statins, and CHD risk, as reviewed up to 2004 [4] and confirmed by more recent reports of large series of molecularly diagnosed FH children [6], [7] and adults [7], [8], [9], [10]. Regarding the association between LDLR mutation type and CHD risk, most studies reviewed by Austin et al. [4] involved small patient groups. Recent reports of large series of molecularly diagnosed FH patients from different geographical locations have provided inconsistent results, as both null [7], [9] and positive associations [8], [10] have been described.
Sonographically defined carotid intima-media thickness (IMT) is a well-established surrogate marker for cardiovascular risk [11] that was shown to be significantly higher in FH patients than in both age-and sex-matched normolipidemic [12], [13] and hypercholesterolemic [14], [15] controls. In FH, IMT was associated with family history of early-onset CHD [15], presence of CHD [16], [17], and lipoprotein concentrations [13], [15], [16], [18]. Carotid IMT was categorized by the type of LDLR defect in two studies of 79 [13] and 122 [14] FH adults and one study of 193 FH children [6]. A trend towards an increased unadjusted IMT was reported in FH patients carrying null alleles compared to those with defective alleles [13], [14], while FH children with null alleles had significantly higher IMT than those with defective alleles, independently of LDL-cholesterol levels [6]. Carotid plaque burden was evaluated in one study [13] and found to be unrelated to LDLR mutational class. Thus, similarly to its influence on CHD risk [7], [8], [9], [10], the effect of mutation severity on carotid atherosclerosis is insufficiently defined.
In a study of 146 adult FH patients, we recently showed that femoral IMT is increased in relation to mutational class [19]. We hypothesized that a similar association would be detected for carotid IMT in a sufficiently powered study. Thus, we evaluated both carotid IMT and plaque in 436 FH patients carrying functional LDLR mutations.
Section snippets
Subjects
In a cross-sectional study, 436 consecutive patients (223 men and 213 women, mean age 44 ± 14 years) with a molecular diagnosis of FH underwent carotid ultrasound according to a predefined protocol in three Lipid Clinics in Northern Spain during a 5-year period (March 2003 to April 2008). All patients were referred by primary care physicians to their reference Lipid Clinic for diagnosis of severe hypercholesterolemia and were recruited at Hospital Miguel Servet in Zaragoza (n = 180), Hospital
Clinical features and lipid profiles
Of the 436 FH patients, 376 were asymptomatic and 60 had a documented history of CHD (45 myocardial infarction and 15 angina). Table 1 shows the clinical characteristics and lipid concentrations of the FH and control groups. Predictably, FH subjects showed a higher number and potency of cardiovascular risk factors than healthy controls.
At the time of carotid ultrasound, 86 patients were treatment-naive and 350 patients (80%) had been treated previously with lipid-lowering drugs (348 statins, 2
Discussion
The major novel finding of this study is that adults with a molecular diagnosis of FH characterized by null allele (receptor-negative) mutations of the LDLR gene show a more severe clinical phenotype and worse advanced carotid atherosclerosis than those with receptor-defective mutations, independently of age, gender, lipid and nonlipid risk factors, and the CYS. Inasmuch as sonographically assessed carotid atherosclerosis is an intermediate marker that has predictive value of future CHD events
Conflicts of interest
None.
Acknowledgements
This work was supported by grants from the Spanish Ministry of Health (RTIC G03/181, PI05/0075, PI05/0134, and PI06/0365) and Fundació Privada Catalana de Nutrició i Lípids, Barcelona, Spain. Mireia Junyent is supported by a Fulbright grant from the Spanish Ministry of Education and Science (reference 2007-1086). We thank Emili Corbella for expert statistical advice. CIBEROBN is an initiative of ISCIII, Spain.
Disclosures: Diego Tejedor is employed by Progenika Biopharma, the company that
References (31)
- et al.
Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent–offspring study
Atherosclerosis
(2005) - et al.
Cardiovascular disease in familial hypercholesterolaemia: influence of low-density lipoprotein receptor mutation type and classic risk factors
Atherosclerosis
(2008) - et al.
Positive family history for coronary heart disease and ‘midband lipoproteins’ are potential risk factors of carotid atherosclerosis in familial hypercholesterolemia
Atherosclerosis
(2002) - et al.
Differences in intima-media thickness in the carotid and femoral arteries in familial hypercholesterolemic heterozygotes with and without clinical manifestations of cardiovascular disease
Atherosclerosis
(1999) - et al.
Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomized, double-blind trial
Lancet
(2001) - et al.
Effects of intronic mutations in the LDLR gene on pre-mRNA splicing: comparison of wet-lab and bioinformatics analyses
Mol Genet Metab
(2009) - et al.
Tendon xanthomas in familial hypercholesterolemia are associated with a differential inflammatory response of macrophages to oxidized LDL
FEBS Lett
(2005) - et al.
Familial hypercholesterolemia
- et al.
Diagnosing familial hypercholesterolaemia: the relevance of genetic testing
Eur Heart J
(2006) - et al.
Phenotypic variability in familial hypercholesterolemia: an update
Curr Opin Lipidol
(2002)
Familial hypercholesterolemia and coronary heart disease: a HuGE association
Am J Epidemiol
Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database
Ann Hum Genet
Low-density lipoprotein receptor genotype and response to pravastatin in children with familial hypercholesterolemia. Substudy of an intima-media thickness trial
Circulation
Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk
J Med Genet
Influence of LDL-receptor mutation type on age at first cardiovascular event in patients with familial hypercholesterolaemia
Eur Heart J
Cited by (43)
Intima-media thickness in treated and untreated patients with and without familial hypercholesterolemia: A systematic review and meta-analysis
2022, Journal of Clinical LipidologyCitation Excerpt :Analysis of the pooled data showed a significant difference in mean carotid IMT between FH patients and controls of 0.16 mm (95% CI 0.03 to 0.30; P=0.02). Six studies also assessed carotid plaques, and 5 of these showed a significantly more often occurrence of plaques in patients with FH as compared to unaffected controls.34,40,43,44,53 One study showed more often plaques in FH patient, but this was not significant.49
Why patients with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels
2021, Trends in Cardiovascular MedicineMaternally inherited hypercholesterolemia does not modify the cardiovascular phenotype in familial hypercholesterolemia
2021, AtherosclerosisCitation Excerpt :However, a characteristic of HeFH is the great variability in clinical presentation, including LDLc concentrations, and the presence of tendon xanthomas or coronary artery disease [4]. This variability is multifactorial and has been associated with the gene responsible for FH, with a more severe phenotype in carriers of LDLR mutations than in those with a mutation in APOB, PCSK9, or APOE [5,6]; the type of causal mutation, with worse phenotype in null-allele carriers than in defective allele carriers [7]; the interaction with other genes, such as ABCA1 or PSCK9 [8,9]; and the presence of CVD risk factors common to the general population, such as smoking, diabetes, low high-density lipoprotein cholesterol (HDLc), and high lipoprotein(a) (Lp(a)) levels [10]. Despite all this, the origin of this clinical variation in HeFH remains unknown [1,4].
Detecting familial hypercholesterolemia by serum lipid profile screening in a hospital setting: Clinical, genetic and atherosclerotic burden profile
2018, Nutrition, Metabolism and Cardiovascular DiseasesIntegrated guidance on the care of familial hypercholesterolemia from the International FH Foundation
2014, Journal of Clinical Lipidology