The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients

Jansen, Angelique C.M.; Cohen, Emily; Tanck, Michael W.T.; Trip, Mieke D.; Lansberg, Peter; Liem, Anho; Lennep, Henk W. O. Roeters van; Sijbrands, Eric J.G.; Kastelein, John J.P.

doi:10.1111/j.1365-2796.2004.01405.x

Cited by 263 publications

(177 citation statements)

References 30 publications

(53 reference statements)

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“…5 Previously, we performed a retrospective multicentre cohort study of 2400 FH patients, of whom 782 patients (32.6%) had at least one cardiovascular event during an average follow up of 66 years. 6 In this cohort, we demonstrated that LDL-C levels are more important than the LDLR mutation type in determining the age of onset of CAD. 7 We also showed that classical risk factors including male gender, smoking, hypertension, type 2 diabetes, low levels of high-density lipoprotein cholesterol (HDL-C) and elevated lipoprotein(a) levels were independent risk factors for the development of CAD.…”

Section: Introductionmentioning

confidence: 59%

“…As previously reported, established risk factors do associate with the risk of CAD in FH patients. 8,22 However, none of the tested CAD-associated SNPs significantly modified the risk of CAD in our FH cohort in analyses unadjusted or adjusted for established cardiovascular risk factors. The lowest observed P-value of association was for a SNP in the SMARCA44 gene, near the LDLR gene (in adjusted analysis; P ¼ 0.021 ); however, it showed a paradoxically protective effect.…”

Section: Discussionmentioning

confidence: 78%

“…The study design and study population have been described elsewhere. 6 Briefly, DNA samples from patient who, based on clinically oriented algorithms are anticipated to suffer from FH are being sent in to the central core molecular diagnostic laboratory by physicians working at one of the nationwide lipid clinics. LDLR gene variation was genotyped according to previously published methods.…”

Section: Study Design and Study Populationmentioning

confidence: 99%

“…However, these factors combined explained only 18.7% of the variation in CVD occurrence. 8 Thus, a considerable part of the variability in CVD occurrence remains to be disentangled and common genetic variation might provide one of the explanations.…”

Section: Introductionmentioning

confidence: 99%

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Common genetic variants do not associate with CAD in familial hypercholesterolemia

et al. 2013

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In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G4T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49-0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.

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Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 78%

Section: Study Design and Study Populationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Common genetic variants do not associate with CAD in familial hypercholesterolemia

et al. 2013

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“…13 Cross-tabulation and stepwise forward regression analysis of genome-wide significant polymorphisms in the LDLR gene region were performed using SPSS version 15 To replicate our results, we compared the genotype frequencies of the ten most significant polymorphisms between a second cohort of 2189 patients with clinical FH and another population-based control sample consisting of 2157 subjects of the Rotterdam study (RS-II). 12,14 The above-described Illumina chips were used to genotype the subjects of the RS-II. In the second FH cohort, the polymorphisms were genotyped using TaqMan (Applied Biosystems, Foster City, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Low-density lipoprotein receptor mutations generate synthetic genome-wide associations

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et al. 2012

Eur J Hum Genet

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Genome-wide association (GWA) studies have discovered multiple common genetic risk variants related to common diseases. It has been proposed that a number of these signals of common polymorphisms are based on synthetic associations that are generated by rare causative variants. We investigated if mutations in the low-density lipoprotein receptor (LDLR) gene causing familial hypercholesterolemia (FH, OMIM #143890) produce such signals. We genotyped 480 254 polymorphisms in 464 FH patients and in 5945 subjects from the general population. A total of 28 polymorphisms located up to 2.4 Mb from the LDLR gene were genome-wide significantly associated with FH (Po10 À8 ). We replicated the 10 top signals in 2189 patients with a clinical diagnosis of FH and in 2157 subjects of a second sample of the general population (Po0.000087). Our findings confirm that rare variants are able to cause synthetic genome-wide significant associations, and that they exert this effect at relatively large distances from the causal mutation.

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Association of the Interaction Between Familial Hypercholesterolemia Variants and Adherence to a Healthy Lifestyle With Risk of Coronary Artery Disease

et al. 2022

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IMPORTANCE Familial hypercholesterolemia variants impair clearance of cholesterol from the circulation and increase risk of coronary artery disease (CAD). The extent to which adherence to a healthy lifestyle is associated with a lower risk of CAD in carriers and noncarriers of variants warrants further study. OBJECTIVETo assess the association of the interaction between familial hypercholesterolemia variants and adherence to a healthy lifestyle with risk of CAD. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study used 2 independent data sets with gene sequencing and lifestyle data from the UK Biobank: a case-control study of 4896 cases and 5279 controls and a cohort study of 39 920 participants. Participants were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. The case-control study included participants with CAD and controls at enrollment. The cohort study used a convenience sample of individuals with available gene sequencing data. Statistical analysis was performed from April 2, 2019, to January 20, 2022. EXPOSURES Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist and adherence to a healthy lifestyle based on a 4-point scoring system (1 point for each of the following: healthy diet, regular exercise, not smoking, and absence of obesity). MAIN OUTCOMES AND MEASURES Coronary artery disease, defined as myocardial infarction inthe case-control study, and myocardial infarction, ischemic heart disease, or coronary revascularization procedure in the cohort study. RESULTSThe case-control study included 10 175 participants (6828 men [67.1%]; mean [SD] age, 58.6 [7.2] years), and the cohort study included 39 920 participants (18 802 men [47.1%]; mean [SD] age at the end of follow-up, 66.4 [8.0] years). A variant was identified in 35 of 4896 cases (0.7%) and 12 of 5279 controls (0.2%), corresponding to an odds ratio of 3.0 (95% CI, 1.6-5.9), and a variant was identified in 108 individuals (0.3%) in the cohort study, in which the hazard ratio for CAD was 3.8 (95% CI, 2.5-5.8). However, this risk appeared to vary according to lifestyle categories in both carriers and noncarriers of familial hypercholesterolemia variants, without a significant interaction between carrier status and lifestyle (odds ratio, 1.2 [95% CI, 0.6-2.5]; P = .62). Among carriers, a favorable lifestyle conferred 86% lower risk of CAD compared with an unfavorable lifestyle (hazard ratio, 0.14 [95% CI, 0.04-0.41]). The estimated risk of CAD by the age of 75 years varied according to lifestyle, ranging from 10.2% among noncarriers with a favorable lifestyle to 24.0% among noncarriers with an unfavorable lifestyle and ranging from 34.5% among carriers with a favorable lifestyle to 66.2% among carriers with an unfavorable lifestyle.

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The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients

Cited by 263 publications

References 30 publications

Common genetic variants do not associate with CAD in familial hypercholesterolemia

Common genetic variants do not associate with CAD in familial hypercholesterolemia

Low-density lipoprotein receptor mutations generate synthetic genome-wide associations

Association of the Interaction Between Familial Hypercholesterolemia Variants and Adherence to a Healthy Lifestyle With Risk of Coronary Artery Disease

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