Language:

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

Clinical chemistry (Baltimore, Md.), 2015-01, Vol.61 (1), p.231-238 [Peer Reviewed Journal]

2014 American Association for Clinical Chemistry. ;COPYRIGHT 2015 American Association for Clinical Chemistry, Inc. ;Copyright American Association for Clinical Chemistry Jan 2015 ;ISSN: 0009-9147 ;EISSN: 1530-8561 ;DOI: 10.1373/clinchem.2014.231365 ;PMID: 25414277

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
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
Author: Futema, Marta ; Shah, Sonia ; Cooper, Jackie A ; Li, KaWah ; Whittall, Ros A ; Sharifi, Mahtab ; Goldberg, Olivia ; Drogari, Euridiki ; Mollaki, Vasiliki ; Wiegman, Albert ; Defesche, Joep ; D'Agostino, Maria N ; D'Angelo, Antonietta ; Rubba, Paolo ; Fortunato, Giuliana ; Waluś-Miarka, Małgorzata ; Hegele, Robert A ; Aderayo Bamimore, Mary ; Durst, Ronen ; Leitersdorf, Eran ; Mulder, Monique T ; Roeters van Lennep, Jeanine E ; Sijbrands, Eric J G ; Whittaker, John C ; Talmud, Philippa J ; Humphries, Steve E
Subjects: Adolescent ; Adult ; Alleles ; Apolipoproteins B - genetics ; Canada ; Case-Control Studies ; Child ; Cholesterol ; Cholesterol, LDL ; Cholesterol, LDL - blood ; Cholesterol, LDL - genetics ; Cohort Studies ; Colleges & universities ; Diagnosis ; Europe ; Female ; Genetic aspects ; Genetic variation ; Health aspects ; Humans ; Hypercholesterolemia ; Hyperlipoproteinemia Type II - blood ; Hyperlipoproteinemia Type II - genetics ; Israel ; Male ; Medical research ; Middle Aged ; Multifactorial Inheritance - genetics ; Mutation ; Observations ; Polymorphism, Single Nucleotide ; Proprotein Convertase 9 ; Proprotein Convertases - genetics ; Receptors, LDL - genetics ; Risk Factors ; ROC Curve ; Serine Endopeptidases - genetics ; Young Adult
Is Part Of: Clinical chemistry (Baltimore, Md.), 2015-01, Vol.61 (1), p.231-238
Description: 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. 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). 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. 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.
Publisher: England: American Association for Clinical Chemistry, Inc
Language: English
Identifier: ISSN: 0009-9147
EISSN: 1530-8561
DOI: 10.1373/clinchem.2014.231365
PMID: 25414277
Source: AUTh Library subscriptions: ProQuest Central
MEDLINE

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

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

2014 American Association for Clinical Chemistry. ;COPYRIGHT 2015 American Association for Clinical Chemistry, Inc. ;Copyright American Association for Clinical Chemistry Jan 2015 ;ISSN: 0009-9147 ;EISSN: 1530-8561 ;DOI: 10.1373/clinchem.2014.231365 ;PMID: 25414277

Searching Remote Databases, Please Wait