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. (6th January 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Clinical chemistry. Volume 61:Number 1(2015)
• Page Start: 231
• Page End: 238
• Publication Date: 2020-01-06
• Subjects: Clinical chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Biochimie -- Périodiques; Diagnostics biologiques -- Périodiques; Biochemistry; Clinical chemistry; Pharmaceutical chemistry; Biochemistry; Laboratory Techniques and Procedures; Klinische chemie; Periodicals; 616.075605
• DOI: 10.1373/clinchem.2014.231365
• Languages: English
• ISSNs: 0009-9147

Abstract

Abstract: 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.