Marta Futema1, Sonia Shah2, Jackie A Cooper1, KaWah Li1, Ros A Whittall1, Mahtab Sharifi1, Olivia Goldberg1, Euridiki Drogari3, Vasiliki Mollaki3, Albert Wiegman4, Joep Defesche5, Maria N D'Agostino6, Antonietta D'Angelo6, Paolo Rubba7, Giuliana Fortunato6, Małgorzata Waluś-Miarka8, Robert A Hegele9, Mary Aderayo Bamimore9, Ronen Durst10, Eran Leitersdorf10, Monique T Mulder11, Jeanine E Roeters van Lennep11, Eric J G Sijbrands11, John C Whittaker12, Philippa J Talmud1, Steve E Humphries13. 1. Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and. 2. UCL Genetics Institute, Department of Genetics, Environment and Evolution, London, University College London, UK; Current affiliation: Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St. Lucia, Brisbane, Australia; 3. 1st Department of Pediatrics, Unit of Metabolic Diseases, Choremio Research Laboratory, University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece; 4. Department of Pediatrics and. 5. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; 6. CEINGE S.C.a r.l. Advanced Biotechnology, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; 7. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; 8. Department of Metabolic Diseases and Department of Medical Didactics, Jagiellonian University Medical College, Krakow, Poland; 9. Robarts Research Institute, London, Ontario, Canada; 10. Center for Research, Prevention and Treatment of Atherosclerosis, Department of Medicine, Cardiology Division, Hadassah Hebrew University Medical Centre, Jerusalem, Israel; 11. Departments of Cardiology and Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; 12. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK; GlaxoSmithKline Quantitative Sciences, Medicines Research Centre, Stevenage, Hertfordshire, UK. 13. Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and steve.humphries@ucl.ac.uk.
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.
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.
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