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
