title: 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.
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.
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and.
authors.forename: Marta
authors.initials: M
authors.lastname: Futema
authors.affiliation: 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;
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and.
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and.
authors.forename: KaWah
authors.initials: K
authors.lastname: Li
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and.
authors.forename: Ros A
authors.initials: RA
authors.lastname: Whittall
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Sharifi
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and.
authors.forename: Olivia
authors.initials: O
authors.lastname: Goldberg
authors.affiliation: 1st Department of Pediatrics, Unit of Metabolic Diseases, Choremio Research Laboratory, University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece;
authors.forename: Euridiki
authors.initials: E
authors.lastname: Drogari
authors.affiliation: 1st Department of Pediatrics, Unit of Metabolic Diseases, Choremio Research Laboratory, University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece;
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Mollaki
authors.affiliation: Department of Pediatrics and.
authors.forename: Albert
authors.initials: A
authors.lastname: Wiegman
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Joep
authors.initials: J
authors.lastname: Defesche
authors.affiliation: CEINGE S.C.a r.l. Advanced Biotechnology, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy;
authors.forename: Maria N
authors.initials: MN
authors.lastname: D'Agostino
authors.affiliation: CEINGE S.C.a r.l. Advanced Biotechnology, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy;
authors.forename: Antonietta
authors.initials: A
authors.lastname: D'Angelo
authors.affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Rubba
authors.affiliation: CEINGE S.C.a r.l. Advanced Biotechnology, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy;
authors.forename: Giuliana
authors.initials: G
authors.lastname: Fortunato
authors.affiliation: Department of Metabolic Diseases and Department of Medical Didactics, Jagiellonian University Medical College, Krakow, Poland;
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Waluś-Miarka
authors.affiliation: Robarts Research Institute, London, Ontario, Canada;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: Robarts Research Institute, London, Ontario, Canada;
authors.forename: Mary
authors.initials: M
authors.lastname: Aderayo Bamimore
authors.affiliation: Center for Research, Prevention and Treatment of Atherosclerosis, Department of Medicine, Cardiology Division, Hadassah Hebrew University Medical Centre, Jerusalem, Israel;
authors.forename: Ronen
authors.initials: R
authors.lastname: Durst
authors.affiliation: Center for Research, Prevention and Treatment of Atherosclerosis, Department of Medicine, Cardiology Division, Hadassah Hebrew University Medical Centre, Jerusalem, Israel;
authors.forename: Eran
authors.initials: E
authors.lastname: Leitersdorf
authors.affiliation: Departments of Cardiology and Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Monique T
authors.initials: MT
authors.lastname: Mulder
authors.affiliation: Departments of Cardiology and Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Jeanine E
authors.initials: JE
authors.lastname: Roeters van Lennep
authors.affiliation: Departments of Cardiology and Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK; GlaxoSmithKline Quantitative Sciences, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and.
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, and steve.humphries@ucl.ac.uk.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001055:Apolipoproteins B / Q000235:genetics; D002170:Canada; D016022:Case-Control Studies; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood* / Q000235:genetics; D015331:Cohort Studies; D005060:Europe; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D007557:Israel; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D012372:ROC Curve; D011973:Receptors, LDL / Q000235:genetics; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics; D055815:Young Adult
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases