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 - Tập 61 Số 1 - Trang 231-238 - 2015
Marta Futema1, Sonia Shah2,3, Jackie Cooper1, KaWah Li1, Ros Whittall1, Mahtab Sharifi1, Olivia Goldberg1, Euridiki Drogari4, Vasiliki Mollaki4, Albert Wiegman5, Joep C. Defesche6, Maria D’Agostino7,8, Antonietta D’Angelo7,8, Paolo Rubba9, Giuliana Fortunato7,8, Małgorzata Waluś‐Miarka10, Robert A. Hegele11, Mary A. Bamimore11, Ronen Durst12, Eran Leitersdorf12, Monique Mulder13, Jeanine E. Roeters van Lennep13, Eric J.G. Sijbrands13, John C. Whittaker14,15, Philippa J. Talmud1, Steve E. Humphries1
1Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and
2Current affiliation: Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St. Lucia, Brisbane, Australia
3UCL Genetics Institute, Department of Genetics, Environment and Evolution, London, University College London, UK
41st Department of Pediatrics, Unit of Metabolic Diseases, Choremio Research Laboratory, University of Athens Medical School, “Aghia Sophia” Children's Hospital, Athens, Greece
5‡Department of Pediatrics and
6Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
7CEINGE S.C.a r.l. Advanced Biotechnology, Naples, Italy
8Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
9Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy
10Department of Metabolic Diseases and Department of Medical Didactics, Jagiellonian University Medical College, Krakow, Poland
11Robarts Research Institute, London, Ontario, Canada
12Center for Research, Prevention and Treatment of Atherosclerosis, Department of Medicine, Cardiology Division, Hadassah Hebrew University Medical Centre, Jerusalem, Israel
13Departments of Cardiology and Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
14Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
15GlaxoSmithKline Quantitative Sciences, Medicines Research Centre, Stevenage, Hertfordshire, UK

Tóm tắt

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.

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Clinical Chemistry

Tập 61 Số 1

231-238

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