Hypercholesterolemia: Humphries SE

Minhas R, Humphries SE, Qureshi N, Neil HA, Anonymous00039. · RAND Health, RAND Corporation, Santa Monica, Los Angeles, CA 90407, USA. · Heart. · Pubmed #19168470 No free full text.

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Wierzbicki AS, Humphries SE, Minhas R, Anonymous00232. · St Thomas' Hospital, London SE1 7EH. · BMJ. · Pubmed #18753174 No free full text.

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Neil A, Humphries SE. · No affiliation provided · BMJ. · Pubmed #19158168 No free full text.

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Humphries SE, Hadfield G. · No affiliation provided · Heart. · Pubmed #18480347 No free full text.

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Humphries SE, Norbury G, Leigh S, Hadfield SG, Nair D. · Division of Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Royal Free and UCL Medical School, London, UK. · Curr Opin Lipidol. · Pubmed #18607183 No free full text.

Abstract: PURPOSE OF REVIEW: Familial hypercholesterolaemia is a common genetic disorder of lipid metabolism in which patients have a significantly elevated risk of early coronary heart disease, which can be substantially lowered by treatment with the statin class of drugs. In many countries in Europe, tracing of relatives using DNA information, once the family mutation has been identified, is being actively carried out. The present review examines the specificity and clinical utility of DNA testing in patients with familial hypercholesterolaemia. RECENT FINDINGS: Technological progress has improved the detection rate in patients with the strongest clinical suspicion of familial hypercholesterolaemia to more than 70-80%. Patients carrying a mutation have, on average, higher low-density lipoprotein cholesterol levels and greater risk of early coronary heart disease, and studies have reported the utility of DNA information in the identification of affected relatives. More than 1000 different molecular causes of familial hypercholesterolaemia are documented in the University College London database, and although more than 90% of these clearly cause familial hypercholesterolaemia, the remainder require careful interpretation. SUMMARY: DNA testing, as an adjunct to the measurement of plasma low-density lipoprotein cholesterol levels, has clinical utility in providing an unequivocal diagnosis in patients and in identifying affected relatives at an early age so that they can be offered lifestyle advice and appropriate lipid-lowering therapies. Researchers and DNA diagnostic laboratories need to interpret novel sequence changes with caution in order to avoid a false positive diagnosis.

Hadfield SG, Humphries SE. · London IDEAS Genetics Knowledge Park, London, UK. · Curr Opin Lipidol. · Pubmed #15990592 No free full text.

Abstract: PURPOSE OF REVIEW: Cascade testing is an important method for identifying individuals at risk of a genetic condition. Recent advances in its application to familial hypercholesterolaemia are reviewed to identify potential problems impeding its application and the extent to which current data address these concerns. RECENT FINDINGS: Different paradigms for cascade testing are being applied in national programmes. Current data demonstrates cost-effectiveness, and an increased uptake of preventive measures. The relationship between molecular and clinical diagnostic methods is discussed. Psychological impacts of a diagnosis of familial hypercholesterolaemia are in line with the risks associated with the disorder. The efficacy of statins in improving vascular function of children with familial hypercholesterolaemia has been demonstrated, but extensive safety data are lacking. Ethical arguments support that it is equally acceptable for relatives of familial hypercholesterolaemia patients to be contacted by healthcare workers as by family members, but the former is likely to be more efficient. Concerns about increased life insurance premiums are valid but insurance companies are assessing risk realistically, so this should not be a barrier to cascade testing. SUMMARY: Current data support the implementation of cascade testing for familial hypercholesterolaemia as being feasible and cost-effective, but national implementation is limited to a small number of countries. Funding and the infrastructure to support it may be the major stumbling blocks in implementing this technique in many countries. Concerns about the ethics of carrying out cascade testing, and the potential psychological damage of DNA testing, appear to have been largely addressed for familial hypercholesterolaemia.

Newson AJ, Humphries SE. · Medical Ethics Unit, Imperial College London, London, UK. · Eur J Hum Genet. · Pubmed #15657617 links to  free full text

Abstract: Cascade testing or screening provides an important mechanism for identifying people at risk of a genetic condition. For some autosomal dominant conditions, such as familial hpercholesterolaemia (FH), identifying relatives allows for significant health-affecting interventions to be administered, which can extend a person's life expectancy significantly. However, cascade screening is not without ethical implications. In this paper, we examine one ethically contentious aspect of cascade screening programmes, namely the alternative methods by which relatives of a proband can be contacted. Should the proband be invited to contact his or her family members, or should the screening programme contact family members directly? We argue that direct contact is an ethically justifiable method of contact tracing in cascade screening for FH. Not only has this method already been utilised without adverse effects, an examination of the ethical arguments against it shows these are unsubstantiated. We describe several criteria that, if met, will allow an appropriate balance to be struck between maximising the efficiency of family tracing and respecting the interests of probands and their relatives.

Hutter CM, Austin MA, Humphries SE. · Institute for Public Health Genetics and Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, 1959 NE Pacific Avenue, Seattle, WA 98195, USA. · Am J Epidemiol. · Pubmed #15321839 links to  free full text

Abstract: Heterozygous familial hypercholesterolemia (FH) is an autosomal dominant disorder known to be associated with elevated cholesterol levels and increased risk of premature coronary heart disease. Since increased cholesterol levels lead to atherosclerosis, FH has also been proposed as a risk factor for peripheral vascular and ischemic cerebrovascular disease. Currently, the association between clinical FH and risk of stroke is unclear: Two studies conducted in the 1980s indicated an increased risk of stroke in FH subjects; however, two others found no higher risk, and all had methodological limitations. A recent prospective study of familial hypercholesterolemia by the United Kingdom-based Simon Broome Register Group did not find an excess risk of stroke mortality for subjects with clinical FH. By contrast, the prevalence of peripheral arterial disease is increased from five- to 10-fold in FH subjects compared with non-FH controls. In addition, the intima-media thickness of the carotid and/or femoral artery is increased in FH subjects. Better understanding of the association between FH and the incidence of ischemic stroke events could have a public health impact by improving the diagnosis, prognosis, and treatment of individuals with FH and their relatives and by elucidating the relation between cholesterol levels and ischemic cerebrovascular disease.

Austin MA, Hutter CM, Zimmern RL, Humphries SE. · Institute for Public Health Genetics and Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, 1959 NE Pacific Avenue, Seattle, WA 98195, USA. · Am J Epidemiol. · Pubmed #15321838 links to  free full text

Abstract: Familial hypercholesterolemia (FH) is an autosomal disorder characterized by increased levels of total cholesterol and low density lipoprotein cholesterol. The FH clinical phenotype has been shown to be associated with increased coronary heart disease and premature death. Mutations in the low density lipoprotein receptor gene (LDLR) can result in the FH phenotype, and there is evidence that receptor-negative mutations result in a more severe phenotype than do receptor-defective mutations. Mutations in the apolipoprotein B-100 gene (APOB) can result in a phenotype that is clinically indistinguishable from familial hypercholesterolemia, and mutations in this gene have also been shown to be associated with coronary heart disease. Preliminary research indicates that the FH phenotype is influenced by other genetic and environmental factors; however, it is not clear if these are synergistic interactions or simply additive effects.

Austin MA, Hutter CM, Zimmern RL, Humphries SE. · Institute for Public Health Genetics and Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, 1959 NE Pacific Avenue, Seattle, WA 98195, USA. · Am J Epidemiol. · Pubmed #15321837 links to  free full text

Abstract: The clinical phenotype of heterozygous familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease. It is inherited as an autosomal dominant disorder with homozygotes having a more severe phenotype than do heterozygotes. FH can result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), and the recently identified proprotein convertase subtilisin/kexin type 9 gene (PCSK9). To date, over 700 variants have been identified in the LDLR gene. With the exception of a small number of founder populations where one or two mutations predominate, most geographically based surveys of FH subjects show a large number of mutations segregating in a given population. Studies of the prevalence of FH would be improved by the use of a consistent and uniformly applied clinical definition. Because FH responds well to drug treatment, early diagnosis to reduce atherosclerosis risk is beneficial. Cascade testing of FH family members is cost effective and merits further research. For screening to be successful, public health and general practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment.

Marks D, Thorogood M, Neil HA, Humphries SE. · London School of Hygiene and Tropical Medicine, Keppel Street, UK. · Atherosclerosis. · Pubmed #12732381 No free full text.

Abstract: BACKGROUND: Familial hypercholesterolaemia (FH) affects approximately 1 in 500 people (10 million world-wide) and the elevated serum cholesterol concentrations lead to a more than 50% risk of fatal or non-fatal coronary heart disease by age 50 years in men and at least 30% in women aged 60 years. Based on a systematic literature search, we review the natural history of FH, describe the diagnostic criteria, and consider the effectiveness of treatment. METHODS: A comprehensive review was conducted of the literature on the diagnosis of FH, the morbidity and mortality related to treated and untreated FH, and the evidence on the effectiveness of treatment of FH in adults and children. Treatment options have changed since statin treatment became available, and we have not considered pre-statin therapy studies of treatment effectiveness. FINDINGS AND DISCUSSION: A clinical diagnosis of FH is widely used, but a definitive diagnosis can be made by genetic screening, although mutations are currently only detected in 30-50% of patients with a clinical diagnosis. Under-diagnosis of FH has been reported world-wide ranging from less than 1% to 44%. The relative risk of death of FH patients not treated with statins is between three and fourfold but treatment is effective, and delays or prevents the onset of coronary heart disease. Early detection and treatment is important. Aggressive LDL therapy is more effective in the regression of the carotid intima media thickness than conventional LDL therapy. Diagnosis at birth is problematic, and should be delayed until at least 2 years of age. Statins are not generally recommended for the treatment of children up to adolescence. Resins may be used but poor adherence is a problem. Technical advances in mutation detection, and the identification of other genes that cause FH, are likely to have important implications for the cost effectiveness of genetic diagnosis of FH.

Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA. · The London School of Hygiene and Tropical Medicine, Department of Public Health and Policy, Health Promotion Research Unit, London, UK. · Health Technol Assess. · Pubmed #11109029 links to  free full text

Abstract: BACKGROUND: In the majority of people with familial hypercholesterolaemia (FH) the disorder is caused by a mutation of the low-density lipoprotein receptor gene that impairs its proper function, resulting in very high levels of plasma cholesterol. Such levels result in early and severe atherosclerosis, and hence substantial excess mortality from coronary heart disease. Most people with FH are undiagnosed or only diagnosed after their first coronary event, but early detection and treatment with hydroxymethylglutaryl-coenzyme (HMG CoA) reductase inhibitors (statins) can reduce morbidity and mortality. The prevalence of FH in the UK population is estimated to be 1 in 500, which means that approximately 110,000 people are affected. OBJECTIVES: To evaluate whether screening for FH is appropriate. To determine which system of screening is most acceptable and cost-effective. To assess the deleterious psychosocial effects of genetic and clinical screening for an asymptomatic treatable inherited condition. To assess whether the risks of screening outweigh potential benefits. METHODS: DATA SOURCES: Relevant papers were identified through a search of the electronic databases. Additional papers referenced in the search material were identified and collected. Known researchers in the field were contacted and asked to supply information on unpublished or ongoing studies. INCLUSION/EXCLUSION CRITERIA: SCREENING AND TREATMENT: The review included studies of the mortality and morbidity associated with FH, the effectiveness and cost of treatment (ignoring pre-statin therapies in adults), and of the effectiveness or cost of possible screening strategies for FH. PSYCHOSOCIAL EFFECTS OF SCREENING: The search for papers on the psychological and social effects of screening for a treatable inherited condition was limited to the last 5 years because recent developments in genetic testing have changed the nature and implications of such screening tests. Papers focusing on genetic testing for FH and breast cancer were included. Papers relating to the risk of coronary heart disease with similarly modifiable outcome (non-FH) were also included. DATA EXTRACTION AND ASSESSMENT OF VALIDITY: A data assessment tool was designed to assess the quality and validity of the papers which reported primary data for the social and psychological effects of screening. Available guidelines for systematically reviewing papers concentrated on quantitative methods, and were of limited relevance. An algorithm was developed which could be used for both the qualitative and quantitative literature. MODELLING METHODS: A model was constructed to investigate the relative cost and effectiveness of various forms of population screening (universal or opportunistic) and case-finding screening (screening relatives of known FH cases). All strategies involved a two-stage process: first, identifying those people with cholesterol levels sufficiently elevated to be compatible with a diagnosis of FH, and then either making the diagnosis based on clinical signs and a family history of coronary disease or carrying out genetic tests. Cost-effectiveness has been measured in terms of incremental cost per year of life gained. RESULTS: MODELLING COST-EFFECTIVENESS: FH is a life-threatening condition with a long presymptomatic state. Diagnostic tests are reasonably reliable and acceptable, and treatment with statins substantially improves prognosis. Therefore, it is appropriate to consider systematic screening for this condition. Case finding amongst relatives of FH cases was the most cost-effective strategy, and universal systematic screening the least cost-effective. However, when targeted at young people (16 year olds) universal screening was also cost-effective. Screening patients admitted to hospital with premature myocardial infarction was also relatively cost-effective. Screening is least cost-effective in men aged over 35 years, because the gains in life expectancy are small. (ABSTRACT TRUNCA

Marteau T, Senior V, Humphries SE, Bobrow M, Cranston T, Crook MA, Day L, Fernandez M, Horne R, Iversen A, Jackson Z, Lynas J, Middleton-Price H, Savine R, Sikorski J, Watson M, Weinman J, Wierzbicki AS, Wray R, Anonymous00031. · Psychology & Genetics Research Group, King's College London, London, United Kingdom. · Am J Med Genet A. · Pubmed #15216550 No free full text.

Abstract: This trial tests the hypothesis that confirming a clinical diagnosis of familial hypercholesterolemia (FH) by finding a genetic mutation reduces patients' perceptions of control over the disease and adherence to risk-reducing behaviors. Three hundred forty-one families, comprising 341 hypercholesterolemia probands and 128 adult relatives, were randomized to one of two groups: (a) routine clinical diagnosis; (b) routine clinical diagnosis plus genetic testing (mutation searching in probands and direct gene testing in relatives). The main outcome measures were perceptions of control over hypercholesterolemia, adherence to cholesterol-lowering medication, diet, physical activity, and smoking. There was no support for the main hypothesis: finding a mutation had no impact on perceived control or adherence to risk-reducing behavior (all P-values > 0.10). While all groups believed that lowering cholesterol was an effective way of reducing the risk of a heart attack, participants in whom a mutation was found believed less strongly in the efficacy of diet in reducing their cholesterol level (P = 0.02 at 6 months) and showed a trend in believing more strongly in the efficacy of cholesterol-lowering medication (P = 0.06 at 6 months). In conclusion, finding a mutation to confirm a clinical diagnosis of FH in a previously aware population does not reduce perceptions of control or adherence to risk-reducing behaviors. The pattern of findings leads to the new hypothesis that genetic testing does not affect the extent to which people feel they have control over a condition, but does affect their perceptions of how control is most effectively achieved. Further work is needed to determine whether similar results will be obtained in populations with little previous awareness of their risks.

Zito F, Lowe GD, Rumley A, McMahon AD, Humphries SE, Anonymous00326. · Centre for Cardiovascular Genetics, Royal Free and University College London Medical School, London WC1E 6JJ, UK. · Atherosclerosis. · Pubmed #12208481 No free full text.

Abstract: AIM: To evaluate the contribution of the 46C>T polymorphism of the Factor XII (FXII) gene to risk for coronary heart disease (CHD) in the West of Scotland Coronary Prevention Study (WOSCOPS) of men with high cholesterol. BACKGROUND: WOSCOPS is a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. FXII is a protein of the contact system that plays a key role in both coagulation and fibrinolysis. Elevated activated FXII (FXIIa) levels have been previously associated with CHD. Plasma FXIIa levels are strongly determined by a 46C>T polymorphism in the FXII gene. RESULTS: 441 CHD cases and 990 controls were genotyped. The frequency of TT homozygotes was 8.3% in controls and 11.8% in cases (P=0.04). When compared with the CC+CT group (after adjustment for age, blood pressure, BMI, fibrinogen and lipid levels) the TT genotype was an independent risk factor for CHD (OR 1.48 95% CI 1.01-2.17), an effect that was only significant in the pravastatin group (OR 1.95 95% CI 1.09-3.47) and not in the placebo group (OR 1.20, 95%CI 0.72-2.02). Compared with risk in the placebo group as a whole (reference group), and after adjustment for other risk factors, men with the CC or CT genotype, but not the TT genotype showed a significant benefit from pravastatin treatment (OR, respectively, 0.61 (0.46-0.81) and 0.56 (0.40-0.79) compared with 1.10 (0.64-1.96). In a subgroup of these men, subjects with the TT genotype had, as expected, baseline levels of FXIIa that were 50% lower than those with the CC genotype, with CT subjects having intermediate levels (P<0.001 by Kruskal-Wallis test). CONCLUSIONS: The TT genotype of the FXII 46C>T polymorphism is associated with a high risk of CHD in men with high cholesterol. We hypothesise that reduced fibrinolysis in these men, as a consequence of lower plasma FXIIa, may be the mechanism leading to higher risk, and that pravastatin treatment may enhance this effect.

Basso F, Lowe GD, Rumley A, McMahon AD, Humphries SE. · Centre for Cardiovascular Genetics, BHF Laboratories, Royal Free and University College London Medical School, London, UK. · Arterioscler Thromb Vasc Biol. · Pubmed #11950697 links to  free full text

Abstract: Interleukin (IL)-6 plays an important role in the pathogenesis of coronary heart disease (CHD). Two functional polymorphisms in the IL-6 promoter have been identified (-174G>C and -572G>C), with both the rare alleles being associated with higher plasma levels of IL-6 after bypass surgery and one of them (-174G>C) associated with CHD risk. We have studied the contribution of these polymorphisms to CHD risk in the West of Scotland Coronary Prevention Study (WOSCOPS), a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. Four hundred ninety-eight cases (consisting of individuals experiencing a cardiovascular event during 4.8 years of follow-up) and 1109 controls (individuals matched for age and smoking habits) were genotyped. In the placebo group, there was no significant evidence of higher risk associated with the -174CC genotype compared with the GG+GC group. However, in the pravastatin-treated group, CC homozygotes had a significantly lower risk of CHD compared with the GG+GC placebo group (odds ratio 0.46, 95% CI 0.27 to 0.79), and this remained statistically significant after adjustment for classic risk factors. Compared with the GG+GC group, men with the CC genotype had modestly, but not significantly, higher baseline levels of IL-6, C-reactive protein, or fibrinogen but showed a significantly greater fall in LDL cholesterol with statin treatment (P=0.036). The -572G>C polymorphism was not significantly associated with any plasma trait or CHD risk. Thus, in subjects under pravastatin treatment, the -174CC genotype was associated with a lower risk of CHD. These results demonstrate the importance of the inflammatory system in determining the risk of CHD and support the nonlipid effect of statins on risk.

Wallace AJ, Mann JI, Sutherland WH, Williams S, Chisholm A, Skeaff CM, Gudnason V, Talmud PJ, Humphries SE. · Department of Human Nutrition, PO Box 56, Room 7n8, Science II Building, Union Street, University of Otago, Dunedin, New Zealand. · Atherosclerosis. · Pubmed #10998460 No free full text.

Abstract: There are no definitive explanations as to why individuals with hypercholesterolemia, a major cardiovascular risk factor, respond differently to dietary change. Fifty five free-living individuals completed a double crossover trial with two dietary regimens, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat), each phase continuing for 4 weeks. Extensive genotyping and several measures of dietary compliance have provided further insights regarding the determinants of extent of cholesterol response to changes in the nature of dietary fat. Individuals with the CETP B1B1 genotype and the LPL X447+ allele showed an average 0. 44 (95% CI: 0.22, 0.66) and 0.45 (95% CI: 0.18, 0.72) mmol/l greater change in total cholesterol, respectively, than those with one or more CETP B2 allele or homozygous for the LPL S447 allele when comparing diets high and low in saturated fat. Indices of dietary compliance including changes in reported saturated and polyunsaturated fat intake and change in triglyceride linoleate were not significantly different between the CETP genotypes. Change in reported saturated (r=0.36, P=0.04) and polyunsaturated (r=0.22, P=0. 05) fat intake and change in triglyceride linoleate (reflecting polyunsaturated fat intake) (r=0.21, P=0.07), also predicted total cholesterol response to dietary fat changes. In multivariate analyses, variation in the cholesterol ester transfer protein and lipoprotein lipase genes predicted response independent of measures of dietary compliance, suggesting that these two genes are important determinants of variation in cholesterol response to dietary change in free-living individuals.

Wallace AJ, Humphries SE, Fisher RM, Mann JI, Chisholm A, Sutherland WH. · Department of Human Nutrition, Dunedin School of Medicine, University of Otago Medical School, Great King St, PO Box 913, Dunedin, New Zealand. · Atherosclerosis. · Pubmed #10729389 No free full text.

Abstract: A preponderance of dense low density lipoprotein (LDL) particles is associated with an increased risk of coronary heart disease. It has been shown that dense LDL levels can be modified by diet. We investigated the contribution of polymorphisms in the genes for apolipoprotein (apo) B, apo AIV, lipoprotein lipase (LPL) and cholesterol ester transfer protein (CETP) to variation in the changes in plasma concentrations of dense LDL between a high saturated and a high polyunsaturated fatty acid diet. A total of 46 freeliving individuals (19 men and 27 women) completed a crossover trial with two dietary interventions of 4 weeks each, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat). Overall, the change in dense LDL between the saturated and polyunsaturated fat period was 0.17+/-0.33 mmol/L and this change was similar in men and women. Of the polymorphisms studied only variation in the apo AIV gene causing the substitution of histidine for glutamine at position 360 (Q360H) was associated with significant differences in the change in dense LDL concentration. Apo AIV Q/H individuals (n=6) showed a three-fold greater change in dense LDL cholesterol unadjusted for Lp(a) levels than Q/Q individuals (0.46+/-0.27 versus 0.12+/-0.31 mmol/L, p=0.02). The greater decrease in dense LDL cholesterol with an increase in polyunsaturated fat seen in those with the apo AIV H360 variant, who represent roughly 10% of the general population, suggests that they may benefit most from a PUFA rich lipid lowering diet.

Hadfield SG, Horara S, Starr BJ, Yazdgerdi S, Marks D, Bhatnagar D, Cramb R, Egan S, Everdell R, Ferns G, Jones A, Marenah CB, Marples J, Prinsloo P, Sneyd A, Stewart MF, Sandle L, Wang T, Watson MS, Humphries SE, Anonymous00028. · Institute of Child Health, London IDEAS Genetics Knowledge Park, UCL, 30 Guilford Street, London WC1N 1EH. · Ann Clin Biochem. · Pubmed #19028807 No free full text.

Abstract: BACKGROUND: Family tracing is a method recognized to find new patients with familial hypercholesterolaemia (FH). We have implemented family tracing led by FH Nurses and have determined acceptability to patients, feasibility and costs. METHODS: Nurses were located at five National Health Service (NHS) Trusts; they identified FH patients and offered them family tracing. Responses and test results were recorded on a database and summarized on a family pedigree. RESULTS: The majority ( approximately 70%) of index cases participated; the proportion was lower when patients had been discharged from the clinics and in metropolitan areas. On average, 34% (range 13-50%) of relatives lived outside the catchment area of the clinics and could not attend the nurse-led FH clinics. Of the previously untested relatives, 76% who lived in the catchment area of the clinic came forward to be tested. One-third of the relatives who came forward for testing were children <or=16 y of age. The proportion of relatives diagnosed as likely to have FH was lower than would be predicted (30% vs. 50%). This was mainly due to the uncertainty of a diagnosis based on lipid measurements. The average cost to identify and test one relative was approximately pound 500 but was higher in the metropolitan areas. CONCLUSION: Cascade testing for FH in the UK is feasible, acceptable and likely to be cost-effective if it is a routine aspect of clinical care. However, national implementation would require an integrated infrastructure, so that all individuals have access to testing, and specialist services for the management of young people.

Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries SE. · NIHR School of Primary Care Research, Division Public Health and Primary Health Care, University of Oxford, Old Road Headington, Oxford, UK. · Eur Heart J. · Pubmed #18840879 links to  free full text

Abstract: AIMS: To examine the changes in coronary, all-cause, and cancer mortality in patients with heterozygous familial hypercholesterolaemia (FH) before and after lipid-lowering therapy with statins. METHODS AND RESULTS: A total of 3382 patients (1650 men) aged <80 years were recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2006 for 46 580 person-years. There were 370 deaths, including 190 from coronary heart disease (CHD) and 90 from cancer. The standardized mortality ratio (compared with the population in England and Wales) was calculated before and from 1 January 1992. In patients aged 20-79 years, CHD mortality fell significantly by 37% (95% CI = 7-56) from 3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established disease. Coronary mortality was reduced more in women than in men. In patients without known CHD at registration, all-cause mortality from 1992 was 33% (21-43), lower than in the general population, mainly due to a 37% (21-50) lower risk of fatal cancer. CONCLUSION: The results emphasize the importance of early identification of FH and treatment with statins.

Wright WT, Heggarty SV, Young IS, Nicholls DP, Whittall R, Humphries SE, Graham CA. · Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK. · Clin Genet. · Pubmed #18700895 No free full text.

Abstract: Familial hypercholesterolaemia (FH) is a common single gene disorder, pre-disposing to cardiovascular disease, which is most commonly caused by mutations in the LDL-receptor (LDLR) gene. About 5% of patients carry the p.R3527Q (previously R3500Q) mutation in the apolipoprotein B (APOB) gene and 2% carry the p.D374Y mutation in the PCSK9 gene, but the lack of high-throughput methods make routine genetic diagnosis difficult. In this study, we developed an iPLEX MassARRAY Spectrometry mutation test to identify 56 mutations (54 in the LDLR gene, 1 in the APOB gene and 1 in the PCSK9 gene). The iPLEX test was verified by analysing 150 DNA samples from FH patients with a previously characterized mutation and 96 no-mutation control samples. Mutations were identified in all 150 FH mutation-positive samples using the iPLEX assay, with 96% directly called by the software. The false-positive rate in no-mutation control samples was 0.015%. The overall specific mutation assay failure rate was 2.1%. In the UK, this gives an average detection rate of 75%.The FH iPLEX test is not only designed for large-scale targeted population screening for FH mutations, such as lipid clinic patients, but can also be used for population screening. The assay can easily be developed further to include additional FH-causing mutations, thus increasing the sensitivity of the diagnostic assay.

Starr B, Hadfield SG, Hutten BA, Lansberg PJ, Leren TP, Damgaard D, Neil HA, Humphries SE. · London IDEAS Genetics Knowledge Park, London, UK. · Clin Chem Lab Med. · Pubmed #18601600 No free full text.

Abstract: BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Hadfield SG, Horara S, Starr BJ, Yazdgerdi S, Bhatnagar D, Cramb R, Egan S, Everdell R, Ferns G, Jones A, Marenah CB, Marples J, Prinsloo P, Sneyd A, Stewart MF, Sandle L, Wang T, Watson MS, Humphries SE. · London IDEAS Genetics Knowledge Park, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. · Ann Clin Biochem. · Pubmed #18325186 No free full text.

Abstract: BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder which is relatively common, leads to high levels of LDL-cholesterol and if untreated to early coronary heart disease. An audit of current practice at National Health Service Trusts in England was undertaken to determine whether FH patients meet the diagnostic criteria for FH; are being offered appropriate advice and treatment; and to what extent their families are contacted and offered testing for the disorder. METHODS: Medical records of known FH patients (over 18 years of age and diagnosed before 31 December 2003) were accessed to obtain information on diagnosis, treatment and family tracing. RESULTS: The records of 733 FH patients were examined, 79% met the UK 'Simon Broome' register criteria for the diagnosis of definite or possible FH. Analyses showed that patients were usually offered appropriate advice and treatment, with 89% being on a statin. However, the audit indicated a high variability in family tracing between the sites, with significant differences in the frequency of inclusion of a family pedigree in the notes (range 1-71%, mean 35%); the general practitioner (GP) being advised that first-degree relatives should be tested (range 4-52%, mean 27%); and the proportion of relatives contacted and tested (range 6-50%, mean 32%). CONCLUSION: FH patients are well cared for in lipid clinics in England, are being given appropriate lifestyle advice and medication, but an increase in recording of LDL-cholesterol levels may lead to improvements in their management. Practice in family tracing appears to vary widely between clinics.

Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE. · Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, The Rayne Building, Royal Free and University College London Medical School, London WC1E 6JJ, UK. · Ann Hum Genet. · Pubmed #18325082 No free full text.

Abstract: Familial hypercholesterolemia (FH) (OMIM 143890) is most commonly caused by variations in the LDLR gene which encodes the receptor for Low Density Lipoprotein (LDL) cholesterol particles. We have updated the University College London (UCL) LDLR FH database (http://www.ucl.ac.uk/ldlr) by adding variants reported in the literature since 2001, converting existing entries to standard nomenclature, and transferring the database to the Leiden Open Source Variation Database (LOVD) platform. As of July 2007 the database listed 1066 unique LDLR gene events. Sixty five percent (n = 689) of the variants are DNA substitutions, 24% (n = 260) small DNA rearrangements (<100bp) and 11% (n = 117) large DNA rearrangements (>100bp), proportions which are similar to those reported in the 2001 database (n = 683, 62%, 24% and 14% respectively). The DNA substitutions and small rearrangements occur along the length of the gene, with 24 in the promoter region, 86 in intronic sequences and 839 in the exons (93 nonsense variants, 499 missense variants and 247 small rearrangements). These occur in all exons, with the highest proportion (20%) in exon 4 (186/949); this exon is the largest and codes for the critical ligand binding region, where any missense variant is likely to be pathogenic. Using the PolyPhen and SIFT prediction computer programmes 87% of the missense variants are predicted to have a deleterious effect on LDLR activity, and it is probable that at least 48% of the remainder are also pathogenic, but their role in FH causation requires confirmation by in vitro or family studies.

Smith AJ, Ahmed F, Nair D, Whittall R, Wang D, Taylor A, Norbury G, Humphries SE. · Department of Medicine, Centre for Cardiovascular Genetics, University College London, London, UK. · Eur J Hum Genet. · Pubmed #17625505 links to  free full text

Abstract: A novel sequence change in repeat 3 of the promoter of the low-density lipoprotein receptor (LDLR) gene, -139C>G, has been identified in a patient with familial hypercholesterolemia (FH). LDLR -139G has been passed to one offspring who also shows an FH phenotype. Transient transfection studies using luciferase gene reporter assays revealed a considerable reduction (74+/-1.4% SEM) in reporter gene expression from the -139G variant sequence compared to the wild-type sequence, strongly suggesting that this change is the basis for FH in these patients. Analysis using electrophoretic mobility shift assay demonstrated the loss of Sp1 binding to the variant sequence in vitro, explaining the reduction of transcription.

Scartezini M, Hubbart C, Whittall RA, Cooper JA, Neil AH, Humphries SE. · Department of Medical Pathology, Federal University of Paraná, Rua Lothário Meissner 3400, Curitiba-Paraná 80210-170, Brazil. · Clin Sci (Lond). · Pubmed #17550346 No free full text.

Abstract: In the present study, we have determined the relative frequency of the R46L, I474V and E670G variants in the PCSK9 (protein convertase subtilisin/kexin type 9) gene and its association with plasma lipid levels and CHD (coronary heart disease) in healthy U.K. men and patients with clinically defined definite FH (familial hypercholesterolaemia). Genotypes were determined using PCR and restriction enzyme digestion in 2444 healthy middle-aged (50-61 years) men from the prospective NPHSII (Second Northwick Park Heart Study), with 275 CHD events (15 years of follow-up), and in 597 U.K. FH patients from the Simon Broome Register. In the NPHSII healthy men, the R46L genotype distribution was in Hardy-Weinberg equilibrium and the frequency of 46L was 0.010 [95% CI (confidence interval), 0.007-0.013], with one man homozygous for the 46L allele. There was significant association of the 46L allele with lower mean (S.D.) total cholesterol [5.74 (1.01) mmol/l for RR compared with 5.26+/-1.03 mmol/l for RL; P=0.001], apolipoprotein B [0.87 (0.24) g/l for RR compared with 0.75 (0.26) g/l for RL; P<0.0001] and low-density lipoprotein cholesterol [4.01 (0.95) mmol/l for RR compared with 3.62 (0.97) mmol/l for RL; P=0.02]) levels, after adjustment for age, general medical practice, smoking, body mass index and systolic blood pressure. As expected, 46L carriers had a low risk of definite or possible CHD [hazard ratio, 0.46 (95% CI, 0.11-1.84)], but this was not statistically significant (P=0.27). Two other common PCSK9 variants I474V [V allele frequency, 0.179 (95% CI, 0.17-0.19)] and E670G [G allele frequency, 0.034 (CI, 0.03-0.04)] were not associated with any significant effects on lipid levels or CHD risk. In FH patients, the frequency of 46L was 0.003 (95% CI, 0.00-0.01), which was significantly lower (P=0.037) than the healthy subjects. In the four FH patients carrying 46L, mean untreated total cholesterol levels were not different (P=0.91) in carriers and non-carriers (median, 10.3 mmol/l compared with 10.2 mmol/l respectively, after adjustment for age, gender and mutation type). In conclusion, the PCSK9 46L allele is more frequent in healthy U.K. men than in FH patients and is strongly associated with a protective plasma lipid profile risk for CHD. Its low frequency (approx. 2% carriers) means that it does not make a major contribution to determining population CHD risk in the U.K.