16 research outputs found
Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward
Familial hypercholesterolemia (FH) is a leading cause of premature
atherosclerosis. Genetic defects in the LDLR, APOB and PCSK9 genes cause
FH, and confirmation of a gene defect is essential for an indisputable
diagnosis of the disease. FH is underdiagnosed and we aimed to revise
the genetic defects that have been characterized in FH patients of Greek
origin and define an effective, future strategy for genetic studies. A
literature search was performed in MEDLINE and EMBASE on genetic studies
with FH patients of Greek origin. To date, no APOB and PCSK9 mutations
have been found in the Greek population. It must be noted however, that
only a small number of patients has been screened for PCSK9 mutations.
In total, 41 LDLR defects have been characterized, with 6 common
mutations c.1646G>A (p.Gly546Asp), c.858C>A (p.Ser286Arg), c.81C>G
(p.Cys27Trp), c.1285G>A (p.Va1429Met), c.517T>C (p.Cys173Arg), and
c.1775G>A (p.Gly592G1u) that account for >80% of all mutations. Due to
geographic isolation, founder mutations exist in a subpopulation in
North West Greece and the Greek Cypriot population but not in the
general population. Genetic testing should focus primarily on LDLR, and
subsequently on PCSK9 and APOB. The Greek population is genetically
homogeneous, which allows for a quick molecular diagnosis of the
disease. Cascade screening is feasible and will certainly facilitate the
identification of additional patients. (C) 2016 National Lipid
Association. All rights reserved
Familial Hypercholesterolemia in Greek children and their families: Genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum
Objective: Familial Hypercholesterolemia (FH) is a common lipid
metabolism disease, resulting in premature atherosclerosis, even from
childhood. We aimed to define the genetic basis of FH in children and
their families, to refine the spectrum of Low-Density Lipoprotein
Receptor gene (LDLR) mutations and identify genotype-to-phenotype
correlations in patients of Greek origin. Methods: LDLR was analyzed in
561 patients from 262 families, by whole-gene sequencing. Results:
Children with identified LDLR mutations showed higher lipid levels
compared to non-carriers. Molecular analysis identified a mutation in
53.4% of index cases. Twenty six LDLR mutations were identified,
including 19 point mutations, 2 nonsense mutations, 3 splice site
mutations and 2 small insertions. Amongst patients with common
mutations, carriers of c.1646G > A and c.1285G > A showed higher lipid
levels, whereas carriers of c.858C > A and c.81C > G showed a milder
phenotype. Conclusions: The spectrum of LDLR mutations in Greece is
refined and expanded, with more patients analyzed by whole-gene
sequencing. Although a quick screening method is feasible for the Greek
population, whole-gene sequencing is essential to identify rare
variants. Children with border line lipid levels and a family history of
hypercholesterolemia should be considered for molecular diagnosis, since
carriers of certain mutations show milder phenotypes and may be missed
during clinical diagnosis. (C) 2014 Elsevier Ireland Ltd. All rights
reserved
Novel LDLR Variants in Patients with Familial Hypercholesterolemia: In Silico Analysis as a Tool to Predict Pathogenic Variants in Children and Their Families
{Familial hypercholesterolemia (FH) is an autosomal dominant disease with
a frequency of 1: 500 in its heterozygous form. To date, mutations in
the low-density lipoprotein receptor gene (LDLR) are the only identified
causes of FH in the Greek population, causing high levels of low-density
lipoprotein (LDL) and total cholesterol and premature atherosclerosis.
The Greek FH population is genetically homogeneous, but most previous
studies screened for the most common mutations only. The study aimed to
characterize and assess novel LDLR variants. LDLR was examined by
whole-gene DNA sequencing in 561 FH patients from 262 families of Greek
origin. Novel LDLR variants were analyzed in silico using various
software predicting pathogenicity and changes in protein stability.
Twelve novel LDLR variants were identified, six of which are putative
disease-causing variants: c.977C>G in exon 7, c.1124A>C in exon 8,
c.1381G>T in exon 10, c.628\_643dup\{636del\}, c.661-673dup in exon 4,
and 13 c.1987+1\_+33del in intron 13. All six putative variants were
confirmed in the hypercholesterolemic members of the family. The results
show that in silico analysis is a valuable tool to predict potential
pathogenicity of novel variants, especially for populations that have
not been extensively studied. The identification of novel pathogenic
variants will facilitate the molecular diagnosis of FH from early
childhood.
POR*28 SNP is associated with lipid response to atorvastatin in children and adolescents with familial hypercholesterolemia
BACKGROUND: In children and adolescents with familial hypercholesterolemia (FH) pharmacotherapy with statins is the cornerstone in the current regimen to reduce low-density lipoprotein cholesterol (LDLc) and premature coronary heart disease risk. There is, however, a great interindividual variation in response to therapy, partially attributed to genetic factors. The polymorphic enzyme POR transfers electrons from NADPH to CYP450 enzymes including CYP3A, which metabolize atorvastatin. POR*28 polymorphism is associated with increased CYP3A enzyme activity. We analyzed the association of POR*28 allele with response to atorvastatin.
MATERIALS & METHODS: One hundred and five FH children and adolescents treated with atorvastatin at doses 10-40 mg were included in the study. Total cholesterol (TChol) and LDLc were measured at baseline and after 6 months of treatment. POR*28 allele was analyzed with TaqMan assay. CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G genotypes were also determined with TaqMan or PCR-RFLP methods.
RESULTS: POR*28 carriers had significantly lower percent mean reduction of TChol (33.1% in *1/*1, 29.8% in *1/*28 and 25.9% in *28/*28 individuals, p = 0.045) and of LDLc (43.9% in *1/*1, 40.9% in *1/*28 and 30.8% in *28/*28 individuals, p = 0.013). In multivariable linear regression adjusted for confounding factors, POR*28 genotypes, additionally to baseline cholesterol level, accounted for an estimated 8.3% and 7.3% of overall variability in % TChol and LDLc reduction (β: 4.05; 95% CI: 1.73-6.37; p = 0.001 and β: 5.08; 95% CI: 1.62-8.54; p = 0.004, respectively). CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G polymorphisms were not associated with lipid reductions and did not modify the effect of POR*28 on atorvastatin response.
CONCLUSION: In children with FH, carriage of POR*28 allele is associated with reduced effect of atorvastatin on TChol and LDLc and therefore identifies FH children that may require higher atorvastatin doses to achieve full therapeutic benefits. Additional studies in different populations are needed to replicate this association
Refinement of Variant Selection for the LDL Cholesterol Genetic Risk Score in the Diagnosis of the Polygenic Form of Clinical Familial Hypercholesterolemia and Replication in Samples from 6 Countries
BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal-dominant
disorder caused by mutations in 1 of 3 genes. In the 60% of patients
who are mutation negative, we have recently shown that the clinical
phenotype can be associated with an accumulation of common small-effect
LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide
polymorphism (12-SNP) score. The aims of the study were to improve the
selection of SNPs and replicate the results in additional samples.
METHODS: We used ROC curves to determine the optimum number of LDL-C
SNPs. For replication analysis, we genotyped patients with a clinical
diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We
compared the weighted SNP score among patients with no confirmed
mutation (FH/M-), those with amutation(FH/M+), and controls from a UK
population sample (WHII).
RESULTS: Increasing the number of SNPs to 33 did not improve the ability
of the score to discriminate between FH/M- and controls, whereas
sequential removal of SNPs with smaller effects/lower frequency showed
that a weighted score of 6 SNPs performed as well as the 12-SNP score.
Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms
in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB
(apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G
(WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE
(apolipoprotein E) loci, in the independent FH/M- cohorts showed a
consistently higher score in comparison to the WHII population (P < 2.2
x 10(-16)). Modeling in individuals with a 6-SNP score in the top
three-fourths of the score distribution indicated a >95% likelihood of
a polygenic explanation of their increased LDL-C.
CONCLUSIONS: A 6-SNP LDL-C score consistently distinguishes FH/M-
patients from healthy individuals. The hypercholesterolemia in 88% of
mutation-negative patients is likely to have a polygenic basis. (C) 2014
American Association for Clinical Chemistr