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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.
- Source :
-
Clinical chemistry [Clin Chem] 2015 Jan; Vol. 61 (1), pp. 231-8. Date of Electronic Publication: 2014 Nov 20. - Publication Year :
- 2015
-
Abstract
- 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.<br />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 a mutation (FH/M+), and controls from a UK population sample (WHII).<br />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 × 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.<br />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.<br /> (© 2014 American Association for Clinical Chemistry.)
- Subjects :
- Adolescent
Adult
Alleles
Apolipoproteins B genetics
Canada
Case-Control Studies
Child
Cholesterol, LDL genetics
Cohort Studies
Europe
Female
Humans
Hyperlipoproteinemia Type II blood
Israel
Male
Middle Aged
Mutation
Proprotein Convertase 9
Proprotein Convertases genetics
ROC Curve
Receptors, LDL genetics
Risk Factors
Serine Endopeptidases genetics
Young Adult
Cholesterol, LDL blood
Hyperlipoproteinemia Type II genetics
Multifactorial Inheritance genetics
Polymorphism, Single Nucleotide
Subjects
Details
- Language :
- English
- ISSN :
- 1530-8561
- Volume :
- 61
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25414277
- Full Text :
- https://doi.org/10.1373/clinchem.2014.231365