title: Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia?
abstract: A previous report suggested that 88% of individuals in the general population with total cholesterol (TC) > 9.3 mmol/L have familial hypercholesterolaemia (FH). We tested this hypothesis in a cohort of 4896 UK civil servants, mean (SD) age 44 (±6) years, using next generation sequencing to achieve a comprehensive genetic diagnosis. 25 (0.5%) participants (mean age 49.2 years) had baseline TC > 9.3 mmol/L, and overall we found an FH-causing mutation in the LDLR gene in seven (28%) subjects. The detection rate increased to 39% by excluding eight participants with triglyceride levels over 2.3 mmol/L, and reached 75% in those with TC > 10.4 mmol/L. By extrapolation, the detection rate would be ∼25% by including all participants with TC > 8.6 mmol/L (2.5 standard deviations from the mean). Based on the 1/500 FH frequency, 30% of all FH-cases in this cohort would be missed using the 9.3 mmol/L cut-off. Given that an overall detection rate of 25% is considered economically acceptable, these data suggest that a diagnostic TC cut-off of 8.6 mmol/L, rather than 9.3 mmol/L would be clinically useful for FH in the general population.
authors: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, The Rayne Building, University College London, London, WC1E 6JF, UK.
authors: M
authors: M
authors: Futema
authors: University of Essex, Wivenhoe Park, Colchester, Essex, CO4 3SQ, UK.
authors: M
authors: M
authors: Kumari
authors: NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK.
authors: C
authors: C
authors: Boustred
authors: Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, UK.
authors: M
authors: M
authors: Kivimaki
authors: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, The Rayne Building, University College London, London, WC1E 6JF, UK. Electronic address: steve.humphries@ucl.ac.uk.
authors: S E
authors: SE
authors: Humphries
mesh_terms: D000328:Adult; D002309:Cardiology / Q000592:standards; D002784:Cholesterol / Q000097:blood*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000175:diagnosis*; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics; D014280:Triglycerides / Q000097:blood
chemical_list: D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol
keywords: APOB; Cholesterol; Diagnosis; Familial hypercholesterolaemia; LDLR