For Familial Hypercholesterolemia Research Articles

EFFECT OF LDL-APHERESIS ON HDL-C FUNCTIONALITY

The Lipoprotein-apheresis (LA) devices used in North America for Familial Hypercholesterolemia (FH) reduce LDL-C (− 80%) by binding positive charged apolipoprotein B (apoB) to a negative charged environment. FH patients also have low HDL-C levels, and despite their negative charge, HDL-C is

Patient accounts of diagnostic testing for familial hypercholesterolaemia: comparing responses to genetic and non-genetic testing methods

BackgroundContinuing developments in genetic testing technology together with research revealing gene-disease associations have brought closer the potential for genetic screening of populations. A major concern, as with any screening programme, is the response of the patient to the findings of screening, whether the outcome is positive or negative. Such concern is heightened for genetic testing, which it is feared may elicit stronger reactions than non-genetic testing.MethodsThis paper draws on thematic analysis of 113 semi-structured interviews with 39 patients being tested for familial hypercholesterolaemia (FH), an inherited predisposition to early-onset heart disease. It examines the impact of disease risk assessments based on both genetic and non-genetic information, or solely non-genetic information.ResultsThe impact of diagnostic testing did not seem to vary according to whether or not genetic information was used. More generally, being given a positive or negative diagnosis of FH had minimal discernible impact on people's lives as they maintained the continuity of their beliefs and behaviour.ConclusionsThe results suggest that concerns about the use of genetic testing in this context are unfounded, a conclusion that echoes findings from studies in this and other health contexts.

Inter‐embodiment and the experience of genetic testing for familial hypercholesterolaemia

In this article we explore the concept of inter-embodiment and its potential for advancing sociological research into illness biography and genetic identity. Inter-embodiment theory views embodied knowledge as produced through relations between bodies, as opposed to originating from within the body or as the product of relations between disembodied selves. Drawing on a qualitative study in which we interviewed 38 individuals about their experiences of discovering they had high cholesterol and undergoing genetic testing for familial hypercholesterolaemia (FH), we discuss how their narratives may be understood from an inter-embodiment perspective. The participants frequently talked at length about their family histories of high cholesterol and cardiovascular disease. Through these accounts, we develop the concept of the family corpus in order to highlight the role body networks play in shaping lay constructions of genetic identity and a familial disease biography. The notion of a family corpus, we argue, is useful in understanding why genetic testing for FH was experienced as either biographical re-enforcement or as biographical disruption. We conclude by discussing the implications of our findings for future sociological research into illness biography and genetic identity.

(9) Evaluation of genotype scoring criteria for familial hypercholesterolaemia (FH) in wales

s / Atherosclerosis 223 (2012) 527–535 530 Methods: ApoE and glycated apoE distributions in different lipoproteins in 32 (18 men and 14 women) healthy volunteers were determined. Results: Total apoE concentration (mean SEM) was 48.2 2.4 mg/l. Of this 13.3 2.5 mg/l (27.6%) was in VLDL, 10.6 2.2 mg/l (22.0%) in LDL, 14.4 1.2 mg/l (29.9%) in HDL and 9.9 2.0 mg/l (20.5%) in the density range >1.21 g/ml. ApoE concentration in VLDL was strongly correlated with VLDL-apoB and VLDL-TG. There was no significant difference in total apoE between men and women. However, in men VLDL-apoE was significantly higher (15.6 1.4 mg/l vs. 10.3 1.4 mg/l, p 1.21 g/ml were glycated. Conclusions: The apoE concentration and lipoproteins distribution are influenced by age and gender. VLDL and LDL apoE are more susceptible to glycation in vivo.

Discriminative Ability of LDL-Cholesterol to Identify Patients With Familial Hypercholesterolemia

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.

Individuals’ experiences of, and responses to, a negative genetic test result for familial hypercholesterolaemia

This study aimed to explore the responses of individuals who have undergone genetic testing for familial hypercholesterolaemia (FH) where no genetic mutation has been identified. Semi-structured interviews were conducted with 11 patients and interpretative phenomenological analysis (IPA) was employed. This article describes three inter-related themes: 'feeling in limbo', 'exploring causes of raised cholesterol' and 'contradictions in talk about diet'. Although participants generally adhered to medication and engaged in healthy lifestyles, the findings have clinical implications for how genetic test results are communicated.

Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study

A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of 'DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country.

How do index patients participating in genetic screening programmes for familial hypercholesterolemia (FH) interpret their DNA results? A UK-based qualitative interview study

ObjectiveTo explore patients’ interpretations of their DNA results for familial hypercholesterolemia (FH). MethodsIn-depth interviews were conducted with patients from two lipid clinics in Scotland, who were offered genetic testing as part of a nationwide cascade screening service. ResultsPatients were receptive to taking part in genetic screening and most expected a positive result. Receiving a molecular diagnosis of FH could provide reassurance to patients that diet and lifestyle factors were not the primary causes of their condition. Patients who received inconclusive results tended to interpret this as meaning that their high cholesterol was not genetic, which could induce feelings of uncertainty and self-blame. With the exception of newly diagnosed patients, for whom a positive result could provide a useful rationale for initiating statins, most perceived DNA screening to be of little relevance to their own medication use or their own approaches to lifestyle management. ConclusionsIndex patients are likely to view DNA screening for FH as non-threatening. Receiving a positive DNA result can be reassuring for patients. Patients may not, however, interpret inconclusive DNA results correctly. Practice implicationsHealth professionals need to ensure FH index patients are prepared to receive, and fully understand, inconclusive DNA results.

Sociological study of familial hypercholesterolaemia cascade testing

Cascade testing for Familial Hypercholesterolaemia (FH) was recommended in the 2008 NICE guidelines. The FH testing programme in Wales was launched last year and we are conducting a sociological study with FH patients and GPs. We are interviewing 30 patients across Wales to explore their experience of living with FH, their experience of diagnosis, their understanding of the genetic or familial nature of FH and their views on cascade testing through family tracing. We are also interviewing 30 GPs across Wales to ascertain their knowledge of FH itself, its genetic or familial nature, and their awareness of cascade testing. We are also exploring attitudes among both groups to the change in treatment age to 10 years.

Patients' experiences and views of cascade screening for familial hypercholesterolemia (FH): a qualitative study

Familial DNA cascade screening for familial hypercholesterolemia (FH) has recently been introduced in Scotland. This study investigated index patients' experiences of DNA testing and mediating cascade screening. Thirty-eight patients with a clinical diagnosis of definite or possible FH who had undergone DNA testing in the lipid clinic took part in semi-structured qualitative interviews. All patients were positive about DNA screening being undertaken by familiar and trusted clinicians within the lipid clinic. Most patients had already cascaded close relatives for serum cholesterol testing following their attendance at the lipid clinic. Identified mutation carriers who had attended the genetics clinic (n = 15) for a cascading appointment described finding this consultation helpful because it identified other at-risk family members and provided them with tailored information for their relatives. Participants who expressed a preference said they favoured indirect (patient-mediated) methods of cascading as they considered indirect approaches to be less threatening to family members than direct clinical contact. We conclude that DNA screening and indirect familial cascading is perceived as highly acceptable to index patients with FH. However, while indirect cascading methods may be more acceptable to patients, they do not yield the same numbers as more direct methods. There is, therefore, a need for further systematic research to investigate patients', family members' and staff views of the acceptability of direct versus indirect methods of cascade screening.

Temporal Change in Pre-hospital Statin Use and Total Cholesterol Levels in Patients Presenting with Acute Coronary Syndromes

Background: We assessed if patients presenting with acute coronary syndromes (ACS) were better treated with statins prior to hospitalisation and the effect on total cholesterol (TC) with time. Method: Australian patients with discharge diagnosis of ACS enrolled in the Global Registry of Acute Coronary Events (GRACE, 1999–2007, n= 4069) and The Cooperative National Registry of Acute Coronary Care Guideline Adherence and Clinical Events (CONCORDANCE, 2009–2010, n= 777) were included. Yearly change in initial admission TC and statin use prior to hospitalisation were assessed and adjusted for temporal change in demographic characteristics, background cardiac history 140 The FHWA Program: Nurse-led Cascade Screening for Familial Hypercholesterolaemia (FH)

Cardiovascular risk factors and non-invasive assessment of subclinical atherosclerosis in youth

Our understanding of the natural history of atherosclerosis in childhood and its response to cardiovascular (CV) risk factor reduction have been hampered by the lack of a reliable, non-invasive measure of atherosclerosis. Carotid intima media thickness (IMT), a surrogate marker of atherosclerosis in adults, is increased in youth heterozygous for familial hypercholesterolemia (FH) and declines with lipid lowering pharmacotherapy. The age at which vascular changes can be reliably identified using IMT and the influence of CV risk factors beyond FH on IMT remains unclear. ObjectiveTo examine the influence of demographic, family history, anthropometric characteristics and traditional CV risk factors on IMT in children 5–16 years of age (mean age 11 year). MethodsIn a cross-sectional study, we assessed IMT in 148 children (51 with elevated low density lipoprotein (LDL)-cholesterol, 44 with overweight and 53 controls). Measures included: family history of premature coronary heart disease (CHD), physical activity, pubertal stage, smoking history, fasting glucose, insulin, lipid profile, apolipoproteins A1 and B, anthropometry, blood pressure and IMT. ResultsThe groups were similar for age and family history of premature CHD. Compared to controls, average maximum IMT (0.403±0.04 vs 0.387±0.029) and average mean IMT were elevated in the hyperlipidemia group (p<0.05), but not in the overweight group (max IMT 0.393±0.034; p vs control=0.17). Using multiple regression modelling, age, family history of premature CHD and apoliprotein A1 and B predicted 17% of the variability in IMT. No measure of adiposity predicted IMT. ConclusionAge is an important predictor of IMT in youth. Among traditional CV risk factors, dyslipidemia and family history of premature CHD are independent predictors of IMT.

Cascade screening for familial hypercholesterolaemia and its effectiveness in the prevention of vascular disease

We describe cascade screening for familial hypercholesterolaemia (FH) and review the evidence for its effectiveness. We consider how it will be implemented into primary and secondary care, its potential advantages and disadvantages, and how it will help to prevent myocardial infarctions in patients with FH. Evidence from European countries and the recent pilot study in the UK show cascade screening for FH to be highly effective by facilitating early identification of many new patients. Treatment to lower cholesterol, if started early, is likely to lead to reductions in cardiovascular events. There are shortcomings in the current care of patients with FH and these should be addressed with the implementation of the new guidelines. To reduce the premature cardiovascular events seen in FH new healthcare infrastructures need to be in place and more education provided for both patients and professionals. Br J Diabetes Vasc Dis 2009;9:171—174

Communicating Familial Hypercholesterolemia Genetic Information Within Families

To explore the views of the Western Australian community on cascade screening for familial hypercholesterolemia (FH), focusing on the desire of relatives to be informed about a familial risk, the acceptability of being informed by family or by health professionals, and preferences around how this information is shared. A cross-sectional computer assisted telephone interviewing (CATI) survey was employed, and 430 respondents were recruited randomly from the electronic version of the Western Australian telephone directory. Interviews were conducted in June 2008 and had a response rate of 75%. Most respondents (93%) indicated a desire to be informed about their familial risk of FH. Of these, 91% desired to be informed by their relative, 77% by the health clinic involved in the FH screening program, and 95% indicated a desire to be offered screening for the condition. Women aged 18-54 years were more likely to report a preference for being informed by their relative. The odds of reporting a high likelihood of attending the program health clinic for testing were significantly lower among men aged 18-54 years. If contacted by the program health clinic, 1 in 3 respondents found it unacceptable to not be told their relative's name. This study provides evidence of community support for FH cascade screening programs that adopt a policy of "direct contact," where program staff contact the relatives of the index cases and inform them of their familial risk. Maximizing community support for the screening program may require that index cases give consent to include their personal details when the initial contact is made with their relatives. It may also require special consideration of how younger members of the community are contacted and encouraged to participate in the screening programs.

5-Lipoxygenase activating protein (ALOX5AP) gene variants associate with the presence of xanthomas in familial hypercholesterolemia

BackgroundTendon xanthomas are characteristic for familial hypercholesterolemia (FH), and are associated with a higher risk of coronary heart disease (CHD). They often present with local inflammation. Inflammation may therefore be involved in their pathogenesis, as it is in the pathogenesis of CHD. A key role in the inflammatory pathway is played by the 5-lipoxygenase activating protein (ALOX5AP), which is known to influence the risk of CHD in FH. To test our hypothesis that ALOX5AP contributes to the development of xanthomas, we studied whether variants in the ALOX5AP gene influence the risk of xanthomas. MethodsWe examined 945 patients with genetically confirmed heterozygous FH to determine whether they had tendon xanthomas. We genotyped seven polymorphisms in the ALOX5AP gene and constructed haplotypes of these polymorphisms. ResultsThe A allele of the rs9551963 polymorphism was associated with an increased risk of xanthomas (OR 1.52, 95% CI 1.11–2.07, p=0.01), while the A allele of rs17222842 was protective (OR 0.62, 95% CI 0.43–0.90, p=0.01). These two polymorphisms fully explained the risk estimates of all haplotypes. Individual haplotypes, however, were not significantly associated with xanthomas. ConclusionVariants in the ALOX5AP gene are associated with the presence of xanthomas in FH patients. This result supports our hypothesis that inflammation is a pathogenetic factor of xanthomas.

Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing

The plasma total and low-density lipoprotein-cholesterol (LDL-C) levels that are used as diagnostic criteria for familial hypercholesterolaemia (FH) probands in the general population are too stringent for use in relatives, given the higher prior probability of a first-degree relative being FH (50% vs. 1/500). Our objective was therefore to develop more appropriate LDL-C cutoffs to identify "affected" first-degree relatives found by cascade testing, to test their accuracy and utility in case identification, and to compare them with the published "Make early diagnosis to prevent disease" (MEDPED) cutoffs from the US. Using a large, anonymised sample of genetically tested first-degree relatives of Netherlands FH probands (mutation carriers/non-carriers, n=825/2,469), age- and gender-specific LDL-C diagnostic cutoffs for first-degree relatives were constructed. These were used to test similar data from Denmark (n=160/161) and Norway (n=374/742). Gender-specific LDL-C diagnostic cutoffs were established for six different age groups, which achieved an overall accuracy (measured as Youden's index) of 0.53 in the Netherlands data, and performed significantly better amongst younger (<25 years) compared to older first-degree relatives (0.68 vs. 0.42 Youden's index, p<0.001). Compared with the Netherlands data, age- and gender-adjusted mean LDL-C levels were significantly higher (approximately 0.5 mmol/L) in the Denmark and Norway subjects for both mutation carriers and non-carriers. After adjusting for this difference, the LDL-C cut-offs showed a similar accuracy in identifying mutation carriers from Denmark (81%, range 78%-86%) and Norway (84%, range 82%-86%). Although the MEDPED cutoffs performed significantly worse than these for the Netherlands data (p<0.001), they performed equally well in overall accuracy for the Norwegian and Danish data, although the LDL-C cutoffs had a significantly higher sensitivity but lower specificity for all three countries. The cutoffs developed here are designed to give the greatest overall accuracy when testing relatives of FH patients in the absence of a genetic diagnosis. They have a more balanced specificity and sensitivity than the MEDPED cutoffs that are designed to achieve higher specificity, which is more appropriate for cascade testing purposes. The data suggest that country-specific LDL-C cutoffs may lead to greater accuracy for identifying FH patients, but should be used with caution and only when a genetic diagnosis (DNA) is not available.

A survey of needs from a patient forum for familial hypercholesterolaemia (FH)

A survey of needs from a patient forum for familial hypercholesterolaemia (FH)

Semiquantitative multiplex PCR: a useful tool for large rearrangement screening and characterization

Methods presently employed for detection of large rearrangements have several drawbacks, such as the amount of sample and time required, technical difficulty, or the probability of false-negative carriers. Using the low-density-lipoprotein receptor (LDLR) gene, whose mutations are responsible for familial hypercholesterolemia (FH), we have developed a procedure to detect large rearrangements in this gene based on semiquantitative PCR, with important improvements as compared to previous methods. Our method covers the complete LDLR gene and introduces an internal control in the reaction. The procedure discriminates the four different large rearrangements (two deletions and two insertions) that we have used as positive mutation controls (Valencia-1 to -5). All altered exons from each rearrangement are identified. Furthermore, when families from probands carrying these large rearrangements (34 members) were analyzed, our results agreed with those obtained previously with Southern blot. We have also analyzed a sample of 110 unrelated FH probands and the method has correctly identified the two different large rearrangements present and insertions or deletions as small as 1 bp. In conclusion, the method we present allows the identification of large rearrangements affecting exons of the gene, including small insertions or deletions or complete gene deletion. In addition, it constitutes a first characterization step of rearrangements, and is easy to carry out fast, and can be applied to the analysis of any gene.

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing

As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15+/-1.62 vs LDLR=9.13+/-1.16 vs APOB=10.26+/-2.07 mmol/l p<0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71+/-2.39 mmol/l vs 9.88+/-2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p<0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening.

Update of the molecular basis of familial hypercholesterolemia in The Netherlands

Autosomal-dominant hypercholesterolemia (ADH) has been identified as a major risk factor for coronary vascular disease (CVD) and is associated with mutations in the low-density lipoprotein receptor (LDLR) and the apolipoprotein B (APOB) gene. Since 1991 DNA samples from clinically diagnosed ADH patients have been routinely analyzed for the presence of LDLR and APOB gene mutations. As of 2001, 1,641 index patients (164 index patients per year) had been identified, while from 2001 onward a more sensitive, high-throughput system was used, resulting in the identification of 1,177 new index patients (average=294 index patients per year). Of these 1,177 index cases, 131 different causative genetic variants in the LDLR gene and six different causative mutations in the APOB gene were new for the Dutch population. Of these 131 mutations, 83 LDLR and four APOB gene mutations had not been reported before. The inclusion of all 2,818 index cases into the national screening program for familial hypercholesterolemia (FH) resulted in the identification of 7,079 relatives who carried a mutation that causes ADH. Screening of the LDLR and APOB genes in clinically diagnosed FH patients resulted in approximately 77% of the patients being identified as carriers of a causative mutation. The population of patients with ADH was divided into three genetically distinct groups: carriers of an LDLR mutation (FH), carriers of an APOB mutation (FDB), and non-LDLR/non-APOB patients (FH3). No differences were found with regard to untreated cholesterol levels, response to therapy, and onset of CVD. However, all groups were at an increased risk for CVD. Therefore, to ultimately identify all individuals with ADH, the identification of new genes and mutations in the genes that cause ADH is of crucial importance for the ongoing national program to identify patients with ADH by genetic cascade screening.