Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217

Eur Heart J. 2016 May 1;37(17):1384-94. doi: 10.1093/eurheartj/ehw028. Epub 2016 Feb 22.


Aims: Ideally, familial hypercholesterolaemia (FH) is diagnosed by testing for mutations that decrease the catabolism of low-density lipoprotein (LDL) cholesterol; however, genetic testing is not universally available. The aim of the present study was to assess the frequency and predictors of FH causing mutations in 98 098 participants from the general population, the Copenhagen General Population Study.

Methods and results: We genotyped for LDLR[W23X;W66G;W556S] and APOB[R3500Q] accounting for 38.7% of pathogenic FH mutations in Copenhagen. Clinical FH assessment excluded mutation information. The prevalence of the four FH mutations was 0.18% (1:565), suggesting a total prevalence of FH mutations of 0.46% (1:217). Using the Dutch Lipid Clinic Network (DLCN) criteria, odds ratios for an FH mutation were 439 (95% CI: 170-1 138) for definite FH, 90 (53-152) for probable FH, and 18 (13-25) for possible FH vs. unlikely FH. Using the Simon Broome criteria, the odds ratio was 27 (20-36) for possible vs. unlikely FH, and using the Make Early Diagnosis to Prevent Early Death (MEDPED) criteria, 40 (28-58) for probable vs. unlikely FH. Odds ratios for an FH mutation were 17 (9-31) for LDL-cholesterol of 4-4.9 mmol/L, 69 (37-126) for LDL-cholesterol of 5-5.9 mmol/L, 132 (66-263) for LDL-cholesterol of 6-6.9 mmol/L, 264 (109-637) for LDL-cholesterol of 7-7.9 mmol/L, and 320 (129-798) for LDL-cholesterol above 7.9 mmol/L vs. LDL-cholesterol below 4 mmol/L. The most optimal threshold for LDL-cholesterol concentration to discriminate between mutation carriers and non-carriers was 4.4 mmol/L.

Conclusion: Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population and are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria or an LDL-cholesterol above 4.4 mmol/L.

Keywords: APOB mutation; Coronary artery disease; Familial hypercholesterolaemia; General population; Ischaemic heart disease; LDLR mutation; Low-density lipoprotein; Myocardial infarction.

MeSH terms

  • Cholesterol, LDL
  • Genetic Testing
  • Humans
  • Hyperlipoproteinemia Type II*
  • Mutation*
  • Prevalence
  • Receptors, LDL


  • Cholesterol, LDL
  • Receptors, LDL