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Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing

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Abstract

As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15±1.62 vs LDLR=9.13±1.16 vs APOB=10.26±2.07 mmol/l p<0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71±2.39 mmol/l vs 9.88±2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p<0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening.

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References

  1. Goldstein JL, Hobbs HH, Brown MS (1995) Familial hypercholesterolaemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw Hill, New York, pp 1981–2030

    Google Scholar 

  2. Marks D, Thorogood M, Farrer M, Humphries SE (2004) Census of clinics providing specialist lipid services in the United Kingdom. J Public Health Med 26(4):353–354

    Article  CAS  Google Scholar 

  3. Simon Broome Steering Committee (1991) Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ 303:893–896

    Google Scholar 

  4. Betteridge DJ, Broome K, Durrington PN, Hawkins MM, Humphries SE, Mann JI, Miller JP, Neil HAW, Thompson GR, Thorogood M, Scientific Steering Committee on behalf of the Simon Broome Register Group (1999) Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Atherosclerosis 142:105–112

    Article  Google Scholar 

  5. Thompson GR, Maher VMG, Matthews S, Kitano Y, Neuwirth C, Short MB, Davies G, Rees A, Mir A, Prescott RJ, de Feyter P, Henderson A (1995) Familial hypercholesterolaemia regression study: a randomised trial of low density lipoprotein apheresis. Lancet 345:811–816

    Article  PubMed  CAS  Google Scholar 

  6. West RJ, Lloyd JK (1979) Hypercholesterolaemia in childhood. Adv Pediatr 26:1–34

    PubMed  CAS  Google Scholar 

  7. Umans-Eckenhausen Ma, Defesche JC, Sijbrands EJ, Scheerder RL, Kastelein JJ (2001) Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357:165–168

    Article  PubMed  Google Scholar 

  8. Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sorensen S, Bakken KS (2004) Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. Semin Vasc Med 4:75–85

    Article  PubMed  Google Scholar 

  9. Hobbs HH, Brown MS, Goldstein JL (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolaemia. Hum Mutat 1:445–466

    Article  PubMed  CAS  Google Scholar 

  10. Day INM, Whittall RA, O’Dell SD, Haddad L, Bolla MK, Gudnason V, Humphries SE (1997) Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolaemia. Hum Mutat 10:116–127

    Article  PubMed  CAS  Google Scholar 

  11. Heath KE, Gahan M, Whittall RA, Humphries SE (2001) Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis. Atherosclerosis 154:243–246

    Article  PubMed  CAS  Google Scholar 

  12. Myant NB (1993) Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia. Atherosclerosis 104:1–18

    Article  PubMed  CAS  Google Scholar 

  13. Varret M, Rabes JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, Devillers M, Krempf M, Coulon M, Thiart R, Kotze MJ, Schmidt H, Buzzi JC, Kostner GM, Bertolini S, Pocovi M, Rosa A, Farnier M, Martinez M, Junien C, Boileau C (1999) A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am J Hum Genet 64:1378–1387

    Article  PubMed  CAS  Google Scholar 

  14. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34(2):154–156

    Article  PubMed  CAS  Google Scholar 

  15. Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, Skolnick MH, Hopkins PN, Hunt SC, Shattuck DM (2004) A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet 114(4):349–353

    Article  PubMed  CAS  Google Scholar 

  16. Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH (2001) Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292(5520):1394–1398

    Article  PubMed  CAS  Google Scholar 

  17. Kwiterovich PO Jr, Fredrickson DS, Levy RI (1974) Familial hypercholesterolaemia (one form of type II hyperlipoproteinaemia). A study of its biochemical, genetic and clinical presentation in childhood. J Clin Invest 53:1237–1249

    PubMed  Google Scholar 

  18. Leonard JV, Whitelaw AG, Wolff OH, Lloyd JK, Slack J (1977) Diagnosing familial hypercholesterolaemia in childhood by measuring serum cholesterol. BMJ 1:1566–1568

    PubMed  CAS  Google Scholar 

  19. Koivisto PVI, Koivisto U-M, Miettinen TA, Kontula K (1992) Diagnosis of heterozygous familial hypercholesterolaemia. DNA analysis complements clinical examination and analysis of serum lipid levels. Arterioscler Thromb 12:584–592

    PubMed  CAS  Google Scholar 

  20. Ward AJ, O’Kane M, Nicholls DP, Young IS, Nevin N, Graham CA (1996) A novel single base deletion in the LDLR gene (211 del G). Effect on serum lipid profiles and the influence of other genetic polymorphisms in the ACE, APOE and APOB genes. Atherosclerosis 120:83–91

    Article  PubMed  CAS  Google Scholar 

  21. Heath KE, Humphries SE, Middleton-Price H, Boxer M (2001) A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH). Eur J Hum Gen 9:244–252

    Article  CAS  Google Scholar 

  22. Tonstad S (1996) Familial hypercholesterolaemia: a pilot study of parents and children’s concerns. Acta Pediatr 85:1307–1313

    Article  CAS  Google Scholar 

  23. Tonstadt S, Novik TS, Vandvik IH (1996) Psychosocial function during treatment for familial hypercholesterolaemia. Pediatrics 98:249–255

    Google Scholar 

  24. Marteau T, Senior V, Humphries SE, Bobrow M, Cranston T, Crook MA, Day L, Fernandez M, Horne R, Iversen A, Jackson Z, Lynas J, Middleton-Price H, Savine R, Sikorski J, Watson M, Weinman J, Wierzbicki AS, Wray R; Genetic Risk Assessment for FH Trial Study Group (2004) Psychological impact of genetic testing for familial hypercholesterolemia within a previously aware population: a randomized controlled trial. Am J Med Genet 128A(3):285–293

    Article  PubMed  Google Scholar 

  25. Nishtar S, Wierzbicki AS, Lumb PJ, Lambert-Hammill M, Turner CN, Crook MA, Mattu MA, Shahab S, Badar A, Ehsan A, Marber MS, Gill J (2004) Waist-hip ratio and low HDL predict the risk of coronary artery disease in Pakistanis. Curr Med Res Opin 20(1):55–62

    Article  PubMed  Google Scholar 

  26. Whittall R, Gudnason V, Weavind GP, Day LB, Humphries SE, Day INM (1995) Utilities for high throughput use of the single strand conformational polymorphism method: screening of 791 patients with familial hypercholesterolaemia for mutations in exon 3 of the low density lipoprotein receptor gene. J Med Genet 322:509–515

    Google Scholar 

  27. Mamotte CDS, van Bockxmeer FM (1993) A robust strategy for screening and confirmation of familial defective apolipoprotein B100. Clin Chem 39:118–121

    PubMed  CAS  Google Scholar 

  28. Cotton RGH, Scriver CR (1998) Proof of “disease causing” mutation. Hum Mutat 12:1–3

    Article  PubMed  CAS  Google Scholar 

  29. Health Survey for England (1998) (http://www.official-documents.co.uk/document/doh/survey98/hset3-69.htm)

  30. Kotze MJ, de Villiers JN, Loubser O, Thiart R, Scholtz CL, Raal FJ (1997) A double mutant LDL receptor allele in a Cypriot family with heterozygous familial hypercholesterolemia. Hum Genet 100(1):101–103

    Article  PubMed  CAS  Google Scholar 

  31. Gudnason V, Day INM, Humphries SE (1994) Effect on plasma lipid levels of different classes of mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolaemia. Arteriosclerosis 14:1717–1722

    CAS  Google Scholar 

  32. Graham CA, McClean E, Ward AJ, Beattie ED, Martin S, O’Kane M, Young IS, Nicholls DP (1999) Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia. Atherosclerosis 147(2):309–316

    Article  PubMed  CAS  Google Scholar 

  33. Webb JC, Sun X-M, Patel DD, McCarthy SN, Knight BL, Soutar AK (1992) Characterization of two new point mutations in the low density lipoprotein receptor genes of an English patient with homozygous familial hypercholesterolemia. J Lipid Res 33:689–698

    PubMed  CAS  Google Scholar 

  34. Sun X-M, Patel DD, Bhatnagar D, Knight BL, Soutar AK (1995) Characterization of a splice-site mutation in the gene for the LDL receptor associated with an unpredictably severe clinical phenotype in English patients with heterozygous FH. Arterioscler Thromb Vasc Biol 15(2):219–227

    PubMed  CAS  Google Scholar 

  35. Lee WK, Haddad L, Macleod MJ, Wilson DJ, Gaffney D, Humphries SE, Dominiczak AF (1998) Identification of a common density lipoprotein receptor mutation (C163Y) in the west of Scotland. J Med Genet 35:573–578

    PubMed  CAS  Google Scholar 

  36. Day INM, Haddad L, O’Dell SD, Day LB, Whittall RA, Humphries SE (1997) Identification of a common low density lipoprotein receptor mutation (R329X) in the south of England: complete linkage disequilibrium with an allele of microsatellite D19S394. J Med Genet 34:111–116

    Article  PubMed  CAS  Google Scholar 

  37. Neil HAW, Seagroatt V, Betteridge DJ, Cooper MP, Durrington PN, Miller JP, Seed M, Naoumova RP, Thompson GR, Huxley R, Humphries SE (2004) Established and emerging coronary risk factors in patients with heterozygous familial hypercholesterolaemia. Heart 90:1431–1437

    Article  PubMed  CAS  Google Scholar 

  38. Villeger L, Abifadel M, Allard D, Rabes JP, Thiart R, Kotze MJ, Beroud C, Junien C, Boileau C, Varret M (2002) The UMD-LDLR database: additions to the software and 490 new entries to the database. Hum Mutat 20(2):81–87

    Article  PubMed  CAS  Google Scholar 

  39. Esser V, Limbird LE, Brown MS, Goldstein JL, Russell DW (1988) Mutational analysis of the ligand binding domain of the low density lipoprotein receptor. J Biol Chem 263:13282–13290

    PubMed  CAS  Google Scholar 

  40. Davis CG, Goldstein JL, Südhof TC, Anderson RGW, Russell DW, Brown MS (1987) Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region. Nature 326:760–765

    Article  PubMed  CAS  Google Scholar 

  41. Tybjaerg-Hansen A, Gallagher J, Vincent J, Houlston R, Talmud P, Dunning AM, Seed M, Hamsten A, Humphries SE, Myant NB (1990) Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases. Atherosclerosis 80:235–242

    Article  PubMed  CAS  Google Scholar 

  42. Sun X-M, Webb JC, Gudnason V, Humphries SE, Seed M, Thompson GR, Knight BL, Soutar AK (1992) Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom. Arterioscler Thromb 12:762–770

    PubMed  CAS  Google Scholar 

  43. Jensen HK, Jensen LG, Hansen PS, Færgeman O, Gregerson N (1996) High sensitivity of the single-strand conformation polymorphism method for detecting sequence variations in the low-density lipoprotein receptor gene validated by DNA sequencing. Clin Chem 42:1140–1146

    PubMed  CAS  Google Scholar 

  44. Mogensen J, Bahl A, Kubo T, Elanko N, Taylor R, McKenna WJ (2003) Comparison of fluorescent SSCP and denaturing HPLC analysis with direct sequencing for mutation screening in hypertrophic cardiomyopathy. J Med Genet 40(5):e59

    Article  PubMed  CAS  Google Scholar 

  45. Lombardi P, Sijbrands EJG, van de Giessen K, Smelt AHM, Kastelein JJP, Frants RR, Havekes LM (1995) Mutations in the low density lipoprotein receptor gene of familial hypercholesterolaemic patients detected by denaturing gradient gel electrophoresis and direct sequencing. J Lipid Res 36:860–867

    PubMed  CAS  Google Scholar 

  46. Ward AJ, O’Kane M, Young I, Nicholls DP, Nevin NC, Graham CA (1995) Three novel mutations in the EGF-precursor homology domain of the low-density lipoprotein receptor gene in Northern Irish patients with familial hypercholesterolemia. Hum Mutat 6:254–256

    Article  PubMed  CAS  Google Scholar 

  47. Sun XM, Neuwirth C, Patel DD, Knight BL, Soutar AK with the Familial Hypercholesterolaemia Regression Study Group (1997) Comparison of the genetic defect with LDL-receptor activity in culture cells from patients with a clinical diagnosis of heterozygous familial hypercholesterolaemia. Arterioscler Thromb Vasc Biol 17:3092–3101

    PubMed  CAS  Google Scholar 

  48. Heath KE, Gudnason V, Humphries SE, Seed M (1999) The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia (FH). Atherosclerosis 143:41–54

    Article  PubMed  CAS  Google Scholar 

  49. Sun X-M, Patel DD, Knight BL, Soutar AK (1998) Influence of genotype at the low density lipoprotein (LDL) receptor gene locus on the clinical phenotype and response to lipid-lowering drug therapy in heterozygous familial hypercholesterolaemia. Atherosclerosis 136:175–185

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The GRAFT study is supported by the Welcome Trust, and additional financial support was from British Heart Foundation (grants PG2000015). SEH acknowledges support from the UK Departments of Health and of Trade and Industry for the IDEAS Genetics Knowledge Park. We thank the patients who participated in this study.

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Correspondence to Steve E. Humphries.

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Humphries, S.E., Cranston, T., Allen, M. et al. Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. J Mol Med 84, 203–214 (2006). https://doi.org/10.1007/s00109-005-0019-z

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  • DOI: https://doi.org/10.1007/s00109-005-0019-z

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