title: Phenotype of heterozygotes for low-density lipoprotein receptor mutations identified in different background populations.
abstract: BACKGROUND
  The effect of mutations on phenotype is often overestimated because of ascertainment bias. We determined the effect of background population on cholesterol phenotype associated with specific mutations in the low-density lipoprotein (LDL) receptor and the relative importance of background population and type of mutation (LDL receptor [LDLR] or APOB R3500Q) for cholesterol phenotype.
  
  
  RESULTS
  We studied 9255 individuals from the general population, 948 patients with ischemic heart disease (IHD), and 63 patients with clinical familial hypercholesterolemia (FH) for 3 common LDL receptor mutations. Average increase in cholesterol in LDL receptor heterozygotes identified in the general population or among patients with IHD or FH compared with noncarriers was 2.9 mmol/L, 4.1 mmol/L, and 4.9 mmol/L, respectively (P=0.02). Background population and type of mutation determined cholesterol phenotype; average increase in LDL cholesterol from carriers in the general population to carriers with clinical FH was 1.6 mmol/L (P=0.03). The average increase for carriers of LDLR mutations compared with carriers of APOB R3500Q was 1.2 mmol/L (P=0.05).
  
  
  CONCLUSIONS
  The phenotype associated with a given mutation should not be determined in patients, but rather in unselected individuals in the general population.
authors.affiliation: Department of Clinical Biochemistry KB 3011, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. at-h@rh.dk
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjaerg-Hansen
authors.forename: Henrik Kjaerulf
authors.initials: HK
authors.lastname: Jensen
authors.forename: Marianne
authors.initials: M
authors.lastname: Benn
authors.forename: Rolf
authors.initials: R
authors.lastname: Steffensen
authors.forename: Gorm
authors.initials: G
authors.lastname: Jensen
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution / Q000235:genetics; D001055:Apolipoproteins B / Q000235:genetics; D001120:Arginine / Q000235:genetics; D015982:Bias; D002784:Cholesterol / Q000097:blood / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening / Q000379:methods*; D005828:Genetics, Population / Q000379:methods*; D005973:Glutamine / Q000235:genetics; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017202:Myocardial Ischemia / Q000235:genetics; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D001055:Apolipoproteins B; D011973:Receptors, LDL; D005973:Glutamine; D001120:Arginine; D002784:Cholesterol