Background: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the60%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 aUK 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.

dx.doi.org/10.1373/clinchem.2014.231365, hdl.handle.net/1765/82668
Clinical Chemistry
Department of Cardiology

Futema, M, Shah, S, Cooper, J.A, Li, K, Whittall, R.A, Sharifi, M, … Humphries, S.E. (2015). 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), 231–238. doi:10.1373/clinchem.2014.231365