Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

Leigh, Sarah; Foster, A. H.; Whittall, R.; Hubbart, Christina; Humphries, Steve E.

doi:10.1111/j.1469-1809.2008.00436.x

Cited by 209 publications

(210 citation statements)

References 55 publications

(53 reference statements)

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“…These include, most commonly, mutations in the low density lipoprotein receptor gene (LDLR), less commonly in the apolipoprotein B (APOB) gene and rarely in the proprotein convertase subtilisin/kesin type 9 (PCSK9) gene [3]. At present, more than 1000 mutations have been described worldwide in the LDLR gene (http://www.ucl.ac.uk/fh) and the residual LDL receptor activity varies considerably between those [4]. Mutations in exons 26 and 29 of the APOB gene have been identified in FH patients, the most common of which is the nucleotide change c.10708G>A, predicted to lead to the amino acid substitution p.Arg3527Gln [5].…”

Section: Introductionmentioning

confidence: 99%

Update of the Portuguese Familial Hypercholesterolaemia Study

et al. 2010

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a b s t r a c tThe main aim of the Portuguese Familial Hypercholesterolaemia Study is to identify the genetic cause of hypercholesterolaemia in individuals with a clinical diagnosis of Familial Hypercholesterolaemia (FH). A total of 1340 blood samples were collected from 482 index patients and 858 relatives with the collaboration of clinicians from several hospitals all over the country. The genetic diagnosis of FH in this study is based on the analyses of three genes: LDLR, APOB and PCSK9. In the last 10 years, the Portuguese FH Study identified a genetic defect in a total of 171 index patients, corresponding to an overall of 48% of the total received cases with clinical diagnosis of FH. Although the Simon Broome FH register criteria have been adapted to our study, 59 patients that did not fulfil all criteria were included in the study and a mutation causing disease was identified in 8 of these patients. In the LDLR gene were found 80 different mutations in 165 unrelated index patients: 159 heterozygous, 3 compounds heterozygous and 3 true homozygous. The APOB p.Arg3527Gln and the PCSK9 p.Asp374His mutation were not found in any of our patients since our last report, but a novel mutation in the APOB gene, predicted to cause a single amino acid substitution p.Tyr3560Cys, was found in one patient. The cascade screening in relatives of these 171 index patients allowed the identification and genetic characterization of a total of 404 FH patients in Portugal.

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Section: Introductionmentioning

confidence: 99%

Update of the Portuguese Familial Hypercholesterolaemia Study

et al. 2010

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“…The prevalence of FH is B1:500. 11 This indicates that 12 out of 5945 subjects of the RS-I and 4 out of 2157 subjects of RS-II were expected to carry an LDLR mutation. However, a MDS plot based on the DNA similarity at the LDLR gene ±1 Mb between subjects from the ARGOS and all controls (RS-I and RS-II) did not show any pattern that distinguished carriers of LDLR mutations from non-carriers.…”

Section: Associated Polymorphisms Do Not Identify Patients With (Famimentioning

confidence: 99%

“…On the basis of our nationwide molecular screening program for familial hypercholesterolemia (FH, OMIM #143890), the rare causal mutation has been identified in a large population displaying extensive heterogeneity at the low-density lipoprotein receptor (LDLR) gene. 11 Hence, we had the opportunity to test whether well-known rare variants of the LDLR gene causing an autosomal dominant disorder create synthetic associations in real data of independent samples.…”

Section: Introductionmentioning

confidence: 99%

Low-density lipoprotein receptor mutations generate synthetic genome-wide associations

Oosterveer

Versmissen

Defesche³

et al. 2012

Eur J Hum Genet

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Genome-wide association (GWA) studies have discovered multiple common genetic risk variants related to common diseases. It has been proposed that a number of these signals of common polymorphisms are based on synthetic associations that are generated by rare causative variants. We investigated if mutations in the low-density lipoprotein receptor (LDLR) gene causing familial hypercholesterolemia (FH, OMIM #143890) produce such signals. We genotyped 480 254 polymorphisms in 464 FH patients and in 5945 subjects from the general population. A total of 28 polymorphisms located up to 2.4 Mb from the LDLR gene were genome-wide significantly associated with FH (Po10 À8 ). We replicated the 10 top signals in 2189 patients with a clinical diagnosis of FH and in 2157 subjects of a second sample of the general population (Po0.000087). Our findings confirm that rare variants are able to cause synthetic genome-wide significant associations, and that they exert this effect at relatively large distances from the causal mutation.

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“…[17][18][19] These data are invaluable for the purpose of universal screening and management of ADH. Unfortunately, only a handful of such studies have been conducted in Malaysian and related populations, and thus the repertoire of known ADH-associated or unassociated genetic variants are limited.…”

Section: Introductionmentioning

confidence: 99%

Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population

Alex¹,

Chahil²,

Lye³

et al. 2012

J Hum Genet

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Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n ¼ 141) and healthy control subjects (n ¼ 111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono-allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups.

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Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

Cited by 209 publications

References 55 publications

Update of the Portuguese Familial Hypercholesterolaemia Study

Update of the Portuguese Familial Hypercholesterolaemia Study

Low-density lipoprotein receptor mutations generate synthetic genome-wide associations

Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population

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