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.
Futema, Marta;
Shah, Sonia;
Cooper, Jackie A;
Li, KaWah;
Whittall, Ros A;
Sharifi, Mahtab;
Goldberg, Olivia;
Drogari, Euridiki;
Mollaki, Vasiliki;
Wiegman, Albert;
+16 more...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 JG;
Whittaker, John C;
Talmud, Philippa J;
Humphries, Steve E;
(2014)
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, 61 (1).
pp. 231-238.
ISSN 0009-9147
DOI: https://doi.org/10.1373/clinchem.2014.231365
Permanent Identifier
Use this Digital Object Identifier when citing or linking to this resource.
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 a mutation (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 × 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.