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

作者：Marta Futema, Sonia Shah, Jackie Cooper, KaWah Li, Ros Whittall, Mahtab Sharifi, Olivia Goldberg, Euridiki Drogari, Vasiliki Mollaki, Albert Wiegman, Joep C. Defesche, Maria D’Agostino, Antonietta D’Angelo, Paolo Rubba, Giuliana Fortunato, Małgorzata Waluś‐Miarka, Robert A. Hegele, Mary A. Bamimore, Ronen Durst, Eran Leitersdorf, Monique Mulder, Jeanine E. Roeters van Lennep, Eric J.G. Sijbrands, John C. Whittaker, Philippa J. Talmud, Steve E. Humphries · 发表于：Clinical Chemistry · 年份：2014 · DOI：10.1373/clinchem.2014.231365 · 被引用次数：212 · 研究领域：Lipoproteins and Cardiovascular Health、Diabetes, Cardiovascular Risks, and Lipoproteins、Genetic Associations and Epidemiology

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 sc...