title: Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.
abstract: BACKGROUND
  Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles.
  
  
  METHODS
  In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII.
  
  
  RESULTS
  We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0.90 [SD 0.23]) was strongly associated with LDL-C concentration (p=1.4 x 10(-77); R(2)=0.11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0 [SD 0.21]) than did WHII controls (p=4.5 x 10(-16)), as did the mutation-negative Belgian patients (0.99 [0.19]; p=5.2 x 10(-20)). The score was also higher in UK (0.95 [0.20]; p=1.6 x 10(-5)) and Belgian (0.92 [0.20]; p=0.04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles.
  
  
  CONCLUSIONS
  In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease.
  
  
  BACKGROUND
  British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.
authors: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors: Philippa J
authors: PJ
authors: Talmud
authors: Sonia
authors: S
authors: Shah
authors: Ros
authors: R
authors: Whittall
authors: Marta
authors: M
authors: Futema
authors: Philip
authors: P
authors: Howard
authors: Jackie A
authors: JA
authors: Cooper
authors: Seamus C
authors: SC
authors: Harrison
authors: Kawah
authors: K
authors: Li
authors: Fotios
authors: F
authors: Drenos
authors: Frederik
authors: F
authors: Karpe
authors: H Andrew W
authors: HA
authors: Neil
authors: Olivier S
authors: OS
authors: Descamps
authors: Claudia
authors: C
authors: Langenberg
authors: Nicholas
authors: N
authors: Lench
authors: Mika
authors: M
authors: Kivimaki
authors: John
authors: J
authors: Whittaker
authors: Aroon D
authors: AD
authors: Hingorani
authors: Meena
authors: M
authors: Kumari
authors: Steve E
authors: SE
authors: Humphries
mesh_terms: D000483:Alleles; D001530:Belgium; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D006113:United Kingdom
chemical_list: D008078:Cholesterol, LDL