Diagnosing familial hypercholesterolaemia: the relevance of genetic testing

Cohen, Emily

doi:10.1093/eurheartj/ehl113

Cited by 93 publications

(41 citation statements)

References 31 publications

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“…However, it has been suggested that the diagnosis of FH should be based on the identification of the genetic defect because statin therapy needs to be initiated in young carriers of a LDLR mutation even if their plasma LDLc is normal. 27 However, no general agreement exists on this approach because the risk of CHD is about the same in phenotypically defined FH patients with or without mutation in the LDLR gene. 28 The clinical benefit of the genetic diagnosis over the careful monitoring of LDLc levels, which is required anyway, is therefore questionable.…”

Section: Ldl Receptor Genementioning

confidence: 99%

Genetics of Cardiovascular Diseases

Cambien

Tiret

2007

Circulation

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When the search for genes that predispose to cardiovascular diseases (CVD) started Ͼ20 years ago, it was anticipated that genetic polymorphisms might be analogous to the already known CVD risk factors and could be incorporated in a risk model such as the Framingham score 1 to assess the risk of an individual and adopt preventive or therapeutic measures accordingly. However, despite years of intensive research, not a single genetic risk factor is used for risk assessment. The new strategy of genome-wide association (GWA) studies (for example, see http://www.wtccc. org.uk/) coupled with the availability of very large cohorts of patients 2 is starting to reveal novel genetic factors that contribute to disease risk. Whether these variants will be clinically more useful than those that were derived from the study of candidate genes still needs to be demonstrated. As time passes, the interest for genetic research on common CVD moves progressively from the direct expectation of risk stratification to the more fundamental understanding of disease origins and pathophysiology and their indirect diagnostic and therapeutic implications.The objective of the present review is not to provide an exhaustive account of the numerous studies conducted on the genetics of CVD (eg, Arnett et al 3 ), but to introduce a few basic notions required to understand the language of genetics and genomics (see Appendix) and illustrate with a limited number of examples the important insights provided by genetic research into the causes and mechanisms of CVD. We will also discuss the new GWA strategy and why this approach is likely to have a considerable impact on biomedicine and human disease understanding. Finally, we will try to explain the unsuccessful search for genetic markers of risk and why phenotypic biomarkers are likely to be clinically more useful.

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Section: Ldl Receptor Genementioning

confidence: 99%

Genetics of Cardiovascular Diseases

Cambien

Tiret

2007

Circulation

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“…Comparison of individuals with and without LDLR mutation in this cohort showed significant differences as published earlier by Van Aalst-Cohen et al: patients with FH without an LDLR mutation had higher triglyceride levels (1.71 versus 1.39 mmol/L), body mass index (25.6 versus 24.7 kg/m 2 ), and systolic blood pressure (137 versus 133 mm Hg) and were more likely to have ever smoked (79.5% versus 68.7%), whereas patients with FH with an LDLR mutation had higher low-density lipoprotein cholesterol levels (8.18 versus 6.61 mmol/L). 25 Successfully genotyping for APOE was assessed in 2061 patients of whom 1150 had an LDLR mutation. The polymorphisms at positions 112 and 158 were in Hardy-Weinberg equilibrium both in the whole population and in the group with an LDLR mutation.…”

Section: Resultsmentioning

confidence: 99%

Apolipoprotein Isoform E4 Does Not Increase Coronary Heart Disease Risk in Carriers of Low-Density Lipoprotein Receptor Mutations

Versmissen

Oosterveer

Hoekstra

et al. 2011

Circ Cardiovasc Genet

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Background-In humans, the E4 allele of the apolipoprotein E gene is associated with increased coronary heart disease risk. Surprisingly, in rodents, apolipoprotein E4 only accelerates the atherosclerotic process when transgenic for the human low-density lipoprotein receptor (LDLR) protein. We therefore investigated whether the LDLR locus interacted with the apolipoprotein E gene genotype on coronary heart disease risk in patients clinically diagnosed with familial hypercholesterolemia with and without LDLR mutation. We investigated whether the presence of an LDLR mutation diminishing LDLR function was protective in E4/E4 carriers. Methods and Results-In a cohort of 2400 patients clinically diagnosed with familial hypercholesterolemia, we found an LDLR gene mutation in 1383 patients, whereas in 1013 patients, such mutation was not present. In 92 patients homozygous for the apolipoprotein E4, the presence of an LDLR mutation conferred lower coronary heart disease risk (hazard ratio, 0.16; 95% CI, 0.05-0.58; Pϭ0.005). Mirroring these results, the apolipoprotein E4/E4 genotype was also associated with lower coronary heart disease risk in patients with familial hypercholesterolemia with an LDLR mutation (hazard ratio, 0.26; hazard ratio, 0.08 -0.80; Pϭ0.02). Conclusions-LDLR function is key to the detrimental effects of apolipoprotein E4 in humans. Kinetic studies in humans are now required to study the consequences of our observation for prevention of both coronary heart disease and Alzheimer disease. (Circ Cardiovasc Genet. 2011;4:655-660.)Key Words: apolipoprotein E Ⅲ coronary heart disease Ⅲ familial hypercholesterolemia C omplications of atherosclerotic vascular disease are the most common causes of death and morbidity in the Western world with coronary heart disease (CHD) as its most prominent manifestation. 1 Hereditary predisposition plays an important role in the pathobiology of atherosclerosis. One of the genes best known for its association with CHD risk is the 1 coding for the low-density lipoprotein receptor (LDLR) protein. Mutations in this gene cause an autosomal-dominant disorder called familial hypercholesterolemia (FH), which is characterized by severe hypercholesterolemia and premature CHD. 2 Another important gene known to influence CHD risk is apolipoprotein E (APOE). 3 Mice completely lacking the ApoE protein are severely hypercholesterolemic and develop extensive atherosclerotic lesions, a process that is accelerated when they are fed a high-fat diet. 4,5 Homozygous deficiency of the APOE gene in humans is extremely rare and is also characterized by atherogenic lipid abnormalities and premature CHD. 6,7 Clinical Perspective on p 660In humans, 3 main haplotypes of the APOE gene have been identified: APOE2, APOE3, and APOE4. The encoded ApoE2, ApoE3, and ApoE4 proteins differ in their amino acid sequences at positions 112 and 158. Although these differences are not located in the LDLR binding domain, affinity to the LDLR differs between genotypes: ApoE2 has the lowest affinity for the LDLR, where...

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“…All described variants will be submitted to the following public variant database Leiden Open Variation Database (LOVD) 3 (http://databases.lovd.nl/ shared/genes/).…”

Section: Discussionmentioning

confidence: 99%

“…1 By virtue of the elevated LDL-C levels, FH results in lipid accumulation in the arterial wall and as a consequence accelerated atherosclerosis. 2,3 If left untreated, 50% of male and 30% of female heterozygous FH patients will develop CAD before 60 years of age. 4 The age of onset and severity of CAD varies considerably between FH patients, even among individuals who share an identical gene defect.…”

Section: Introductionmentioning

confidence: 99%

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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Diagnosing familial hypercholesterolaemia: the relevance of genetic testing

Cited by 93 publications

References 31 publications

Genetics of Cardiovascular Diseases

Genetics of Cardiovascular Diseases

Apolipoprotein Isoform E4 Does Not Increase Coronary Heart Disease Risk in Carriers of Low-Density Lipoprotein Receptor Mutations

Common genetic variants do not associate with CAD in familial hypercholesterolemia

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