Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia

Abstract

Background and objectives

Defects in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a highly atherogenic condition. The effect of different LDLR mutations on coronary heart disease (CHD) risk is insufficiently defined. We assessed carotid intima-media thickness (IMT), a surrogate marker of CHD, in relation to LDLR mutational class in FH.

Methods

In 436 Spanish FH patients (223 men and 213 women, age 44 ± 14 years) with known LDLR mutations, alleles were classified by standard criteria as null (n = 269), defective (n = 162), or undetermined (n = 5). LDLR defects were detected using a microarray (Lipochip^®) designed to uncover prevalent mutations in Spain and gene sequencing when no mutations were detected. Carotid IMT and plaque were assessed in FH patients and 268 healthy subjects.

Results

All carotid measurements were increased in FH patients versus controls (p < 0.05), irrespective of genotype. After adjustment for gender and age, patients with null alleles compared with defective alleles had similar mean and maximum common carotid artery (CCA) IMT, but higher maximum IMT at any carotid segment, with median values (95% confidence interval) of 1.25 mm (1.19–1.31) and 1.11 mm (1.05–1.18), respectively. Multivariate analysis showed that null alleles were independently associated with maximum CCA-IMT (β = 0.09, p = 0.033) with an impact similar to that of gender (β = 0.10, p = 0.035).

Conclusions

FH patients show advanced carotid atherosclerosis in relation to LDLR mutational class. The findings support the utility of genetic testing in FH beyond providing a secure diagnosis.

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.