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Kindt I.,Foundation for the Identification of Persons with Inherited Hypercholesterolemia
Netherlands Heart Journal

Background In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations.Methods Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified FH patients in each postal code area was calculated and visualised in different maps. Results A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous tients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. Conclusions Phenotypes with regard to LDL-C evels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was bserved. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherlands. © The Author(s) 2011. Source

Broekhuizen K.,VU University Amsterdam | van Poppel M.N.M.,VU University Amsterdam | Koppes L.L.,TNO | Kindt I.,Foundation for the Identification of Persons with Inherited Hypercholesterolemia | And 2 more authors.

Objective: To evaluate the efficacy of an individualised tailored lifestyle intervention on physical activity, dietary intake, smoking and compliance to statin therapy in people with Familial Hypercholesterolemia (FH). Methods: Adults with FH (n = 340) were randomly assigned to a usual care control group or an intervention group. The intervention consisted of web-based tailored lifestyle advice and face-to-face counselling. Physical activity, fat, fruit and vegetable intake, smoking and compliance to statin therapy were self-reported at baseline and after 12 months. Regression analyses were conducted to examine between-group differences. Intervention reach, dose and fidelity were assessed. Results: In both groups, non-significant improvements in all lifestyle behaviours were found. Post-hoc analyses showed a significant decrease in saturated fat intake among women in the intervention group (β = -1.03; CI -1.98/-0.03). In the intervention group, 95% received a log on account, of which 49% logged on and completed one module. Nearly all participants received face-to-face counselling and on average, 4.2 telephone booster calls. Intervention fidelity was low. Conclusions: Individually tailored feedback is not superior to no intervention regarding changes in multiple lifestyle behaviours in people with FH. A higher received dose of computer-tailored interventions should be achieved by uplifting the website and reducing the burden of screening questionnaires. Counsellor training should be more extensive. Trial Registration: Dutch Trial Register NTR1899. © 2012 Broekhuizen et al. Source

Huijgen R.,University of Amsterdam | Vissers M.N.,University of Amsterdam | Kindt I.,Foundation for the Identification of Persons with Inherited Hypercholesterolemia | Trip M.D.,University of Amsterdam | And 3 more authors.
Circulation: Cardiovascular Genetics

Background - Genetic cascade screening for heterozygous familial hypercholesterolemia (FH) revealed that 15% of individuals given this diagnosis do not exhibit elevated low-density lipoprotein cholesterol (LDL-C) levels. We assessed whether cardiovascular risk for these individuals differs from that of hypercholesterolemic FH heterozygotes and unaffected relatives. Methods and Results - Individuals aged 18 to 55 years were recruited within 18 months after genetic screening. Three groups were studied: subjects given a molecular diagnosis of FH and with LDL-C levels at genetic screening below the 75th percentile (FH-low), subjects with FH and an LDL-C level above the 90th percentile (FH-high), and subjects without FH (no-FH). We measured carotid intima-media thickness (IMT) by ultrasonography. Differences in carotid IMT among the groups were assessed using multivariate linear regression analyses. Mean carotid IMT of 114 subjects in the FH-low group (0.623 mm; 95% CI, 0.609 to 0.638 mm) was significantly smaller than that of 162 subjects in the FH-high group (0.664 mm; 95% CI, 0.648 to 0.679 mm; P<0.001) and did not significantly differ from the mean carotid IMT in 145 subjects in the no-FH group (0.628 mm; 95% CI, 0.613 to 0.642 mm; P=0.67). Conclusions - Our findings suggest that the risk of cardiovascular disease in patients with FH to a large extent is related to LDL-C levels and not to the presence of a mutation per se. Consequently, this study cautiously suggests that individuals with an FH genotype without expression of hypercholesterolemia may not require a pharmaceutical intervention that is as aggressive as the standard for subjects with FH. © 2011 American Heart Association, Inc. Source

Huijgen R.,University of Amsterdam | Kindt I.,Foundation for the Identification of Persons with Inherited Hypercholesterolemia | Fouchier S.W.,University of Amsterdam | Defesche J.C.,University of Amsterdam | And 3 more authors.
Human Mutation

Patients with familial hypercholesterolemia (FH) have elevated LDL-C levels, usually above the 90th percentile (P90) for age and gender. However, large-scale genetic cascade screening for FH showed that 15% of the LDL-receptor (LDLR) or Apolipoprotein B (APOB) mutation carriers have LDL-C levels below P75. Nonpathogenicity of sequence changes may explain this phenomenon. To assess pathogenicity of a mutation we proposed three criteria: (1) mean LDL-C >P75 in untreated mutation carriers; (2) higher mean LDL-C level in untreated carriers than in untreated noncarriers; and (3) higher percentage of medication users in carriers than in noncarriers at screening. We considered a mutation nonpathogenic when none of the three criteria were met. We applied these criteria to mutations that had been determined in more than 50 untreated adults. Segregation analysis was performed to confirm nonpathogenicity. Forty-six mutations had been tested in more than 50 untreated subjects, and three were nonpathogenic according to our criteria: one in LDLR (c.108C>A, exon 2) and two in APOB (c.13154T>C and c.13181T>C, both in exon 29). Segregation analysis also indicated nonpathogenicity. According to our criteria, three sequence variants were nonpathogenic. The criteria may help to identify nonpathogenic sequence changes in genetic cascade screening programs. © 2010 Wiley-Liss, Inc. Source

Huijgen R.,University of Amsterdam | Hutten B.A.,University of Amsterdam | Kindt I.,Foundation for the Identification of Persons with Inherited Hypercholesterolemia | Vissers M.N.,University of Amsterdam | Kastelein J.J.P.,University of Amsterdam
Circulation: Cardiovascular Genetics

Background- Screening for familial hypercholesterolemia (FH) within affected families is often based on cutoff values for low-density lipoprotein cholesterol (LDL-C). However, the diagnostic accuracy of LDL-C levels is influenced by the magnitude of the LDL-C overlap between FH patients and unaffected relatives. The purpose of the current study was to assess to what extent this overlap is influenced by the severity of specific FH mutations. Methods and Results- Individuals were eligible if they underwent family screening for FH between 2003 and 2010. The entire cohort was then compared with those who were investigated for the presence of the most severe mutations (class 1). The area under the receiver operating characteristics curve and the sensitivity of the 90th percentile of LDL-C were calculated for both cohorts. We included 26 406 individuals, of whom 9169 (35%) carried an FH-causing mutation. In the entire cohort at baseline, mean LDL-C was 4.63±1.44 mmol/L for FH carriers (n=5372) and 2.96±0.96 mmol/L for unaffected relatives (n=15 148); P<0.001. The corresponding operating characteristics curve (95% CI) was 86.6% (85.9%-87.2%), and the cutoff level of LDL-C above the 90th percentile showed a sensitivity of 68.5%. The operating characteristics curve and sensitivity significantly improved when the 5933 individuals tested for class 1 mutations were assessed separately; 96.2% (95.3%-97.1%) and 91.3%, respectively. Conclusions- In summary, the overlap in terms of LDL-C levels between those with molecularly proven FH and unaffected relatives is to a large extent because of the high prevalence of modestly severe LDL-receptor mutations in the Netherlands. © 2012 American Heart Association, Inc. Source

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