Genetic Determinants of Cardiovascular Disease Risk in Familial Hypercholesterolemia

Abstract

Objective-To investigate the contribution of polymorphisms in multiple candidate genes to cardiovascular disease (CVD) risk in a large cohort of patients with heterozygous familial hypercholesterolemia (FH). (FH) is a common hereditary disease, characterized by elevated levels of plasma low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease (CVD). 1 Characteristically, the mean age of onset of CVD is between 40 and 45 years in male FH patients and in female FH patients 10 years later. 1,2 Nevertheless, the phenotypic expression of this disorder, in terms of onset and severity of atherosclerotic vascular disease, varies considerably. 3 Unfortunately, a paucity of solid data exists on factors that contribute to these phenotypic differences. Previous studies have mostly focused on classical CVD risk factors and the functional variety among LDL receptor mutations. 4 -6 Although both influence the occurrence of CVD, they can only partially explain the observed large differences. We recently studied the contribution of classical risk factors to CVD in a large cohort of FH patients and demonstrated that Ͻ20% of the variation in CVD occurrence could be explained by these risk factors alone. 7 Therefore, other still unknown and possibly genetic factors play an undeniable role in the development of CVD in these patients. Genetic differences affect susceptibility to disease and whereas premature atherosclerosis can be linked in rare cases to single-gene disorders, most individuals do not carry such DNA defects. The "common disorder, common variant" theory predicts that the majority of population-attributable variation in susceptibility to prevalent disease is caused by variants that occur in high frequency in multiple genes. 8 Such genetic variation may also play an important role in the development of CVD in FH. This is substantiated by the fact that clustering of CVD occurs in FH kindred. 9 Unfortunately, large-scale association studies involving multiple polymorphisms are lacking in FH. Our objective, therefore, was to investigate the contribution of polymorphisms in multiple candidate genes to CVD risk in a large cohort of patients with heterozygous FH. Methods and Results-We Methods Study Design and Study PopulationThe present investigation was a retrospective, multicenter, cohort study. The study design and study population have been described elsewhere. 7 Briefly, lipid clinics in the Netherlands submit DNA samples from clinically suspected FH patients to a central laboratory for LDL receptor mutation analysis. 10 We randomly selected hypercholesterolemic patients from this DNA bank database with the aid of a computer program (Microsoft Excel). These patients had been referred from 27 lipid clinics throughout the Netherlands ( Figure I, available online at http://atvb.ahajournals.org).Phenotypic data (including detailed information on CVD) were acquired by reviewing patient's medical records by a trained team of data collectors. 7 Guidelines for data collection from medical records were ...

No certain predictors for mutation status in a Danish cohort with familial hypercholesterolemia: A descriptive study

“…Thus, in order to identify most mutation carriers, even patients with only possible FH must be genotyped as recently suggested by Damgaard et al [19]: They tested the ability of three clinical diagnosis tools to predict mutation status in FH individuals but did only find a tenuous relationship of genotype to phenotype. These findings warrant continued investigation to reveal which factors to include to optimize the mutation screening procedure as in a recent work by Jansen et al, who screened for a wide variety of gene mutations [20].…”

“…Other loci causing clinical FH has been reported [12,22] and the mutation prevalence at these loci will be interesting, as recent studies seems to imply an explanation for the discordance observed [23]. Furthermore, additional mutations in the gene coding for lipoprotein lipase (LPL) has been reported capable of deteriorating the FH phenotype [24], and lately, mutation in the prothrombin gene has been suggested [20]. Of note, the Bonferroni test and the AUC plot ( Fig.…”

Common genetic variants do not associate with CAD in familial hypercholesterolemia

“…14 However, in that publication, the threshold to reach statistical significance was rather lenient. In this paper, a P-value o0.001 was considered statistically significant; however, applying the Bonferroni correction, which is common practice nowadays would suggest a P-value o0.00076.…”

“…An additive genetic model was applied in the Cox model and classical cardiovascular risks were used as covariates. 21 We corrected for factors that had previously been shown to be associated with CAD risk in this population: age, gender, smoking, type 2 diabetes, hypertension and body mass index (BMI). Analyses were performed for the loci previously reported to be associated with CAD.…”

Cox proportional hazards models have more statistical power than logistic regression models in cross-sectional genetic association studies

“…10 Three polymorphisms had only wild-type alleles in our population and were therefore excluded from the present analyses. All patients gave informed consent and the ethics institutional review board of each participating hospital approved the protocol.…”