Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia

Mahtab Sharifi, Elizabeth Higginson, Sven Bos, Angela Gallivan, Darren Harvey, Ka Wah Li, Amali Abeysekera, Angela Haddon, Helen Ashby, Kate E. Shipman, Jackie A. Cooper, Marta Futema, Jeanine E. Roeters van Lennep, Eric J.G. Sijbrands, Mourad Labib, Devaki Nair, Steve E. Humphries*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

63 Citations (Scopus)
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Abstract

Background and aims 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. 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. 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. 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. Results 86 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]. 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.

Original languageEnglish
Pages (from-to)405-411
Number of pages7
JournalAtherosclerosis
Volume263
Early online date13 May 2017
DOIs
Publication statusPublished - Aug 2017

Bibliographical note

Funding Information:
The study was supported by a grant from the British Heart Foundation (grant RC 93008). SEH and JAC acknowledge BHF support (RG 2008/008) and also funding from the Department of Health's NIHR Biomedical Research Centers funding scheme. MS was supported by the BHF and the Royal Free Hospital Charity. MF is funded by the ‘Fondation Leducq’ grant (14 CVD03). EJGS was supported by Dutch Heart Foundation (Grant 2006T102). DN has received grants from Pfizer (Pfizer Foundation award 2008), Solvay, Merck Sharp & Dohme and AstraZeneca. DN has advisory board membership for Merck Sharp & Dohme, Sanofi and Amgen.

Publisher Copyright:
© 2017 The Authors

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