Abstract
Background and aimsFamilial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. MethodsFH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. Results86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7–0.79) vs. 0.66 mm (0.61–0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4–41.8) vs. 2.65 (0.94–7.44), p = 0.0004]. ConclusionsIn patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.
Highlights
Familial hypercholesterolemia (FH) is a common autosomal dominant disorder and a well-known cause of premature coronary heart disease (CHD) [1]
It has been shown that a significant proportion of the patients with a clinical diagnosis of FH, where no mutation is found, are likely to have a polygenic explanation for their raised low density lipoprotein-cholesterol (LDL-C) level [7,8]
Data from 252 patients were included in the study (Table 1). 86 patients (56 monogenic and 30 polygenic) had a carotid intima media thickness (IMT) measurement and 166 patients (124 monogenic and 42 polygenic) had a CAC score measurement
Summary
Familial hypercholesterolemia (FH) is a common autosomal dominant disorder and a well-known cause of premature coronary heart disease (CHD) [1]. Based on the common LDL-C raising single nucleotide polymorphisms (SNPs), a weighted SNPs score has been developed [7,8] Using this score, it appears that at least 20% of FH patients without a mutation are likely to have a polygenic explanation for their LDL-C level of over 4.9 mmol/L. Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism It is associated with higher risk of premature coronary heart disease. Methods: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Conclusions: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology
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