Current Atherosclerosis Reports

, Volume 1, Issue 1, pp 70–78 | Cite as

Common mutations of the lipoprotein lipase gene and their clinical significance

  • Siegmund Gehrisch


The accumulation of triglyceride-rich lipoproteins is an independent factor for an increased risk for premature arteriosclerosis. Common mutations in the lipoprotein lipase (LPL) gene are at least in part inherited susceptibility factors involved in the age- and sex-dependent phenotypic expression of hypertriglyceridemia. It can be estimated that about 20% of patients with hypertriglyceridemia are carriers of common LPL gene mutations (Asp9Asn, Asn291Ser, Trp86Arg, Gly188Glu, Pro207Leu, Asp250Asn) associated with the HLP. Genotyping of these LPL gene mutations is recommended especially in patients with high risk for premature arteriosclerosis. A comparably high number of individuals are carriers of common mutations (Ser447X) or silent mutations (Thr361) associated with low favorable lipids.


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  1. 1.
    Austin MA, Hokanson JE, Edwards KL: Hypertriglyceridemia as cardiovascular risk factor. Am J Cardiol 1998, 81:7B-12B.PubMedCrossRefGoogle Scholar
  2. 2.
    Grundy SM: Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol 1998, 81:18B-25B.PubMedCrossRefGoogle Scholar
  3. 3.
    Assmann G, Schulte H, Funke H, von Eckardtstein A: The emergence of triglycerides as a significant independent risk factor in coronary artery disease. Eur Heart J 1998, 19:M8-M14.PubMedGoogle Scholar
  4. 4.
    Thompson GJ, Wilson PW: Clinical manifestation of coronary heart disease. In Coronary Risk Factors and Their Assessment. Edited by Thompson GJ, Wilson PW. London: Science Press; 1992:1–3.Google Scholar
  5. 5.
    Assmann G, Cullen P, Schulte H: The Muenster heart study (PROCAM): Results of follow-up at 8 years. Eur Heart J 1998, 19:A2-A11.PubMedGoogle Scholar
  6. 6.
    Jaross W, Assmann G, Bergmann S, DRECAN Team: Comparision of of risk factors for coronary heart disease in Dresden and Muenster. Eur J Epidemiol 1994, 10:307–315.PubMedCrossRefGoogle Scholar
  7. 7.
    Chait A, Brunzell JD: Chylomicronemia syndrome. Adv Intern Med 1991, 37:249–273.Google Scholar
  8. 8.
    Beisiegel U: Receptors for triglyceride-rich lipoproteins and their role in lipoprotein metabolism. Curr Opin Lipidol 1995, 6:117–122.PubMedGoogle Scholar
  9. 9.
    Santamarina-Fojo S, Dugi KA: Structure, function and role of lipoprotein lipase in lipoprotein metabolism. Curr Opin Lipidol 1994, 5:117–125.PubMedCrossRefGoogle Scholar
  10. 10.
    Henderson AD, Richmond W, Elkeles RS: Hepatic and lipoprotein lipases selectively assayed in postheparin plasma. Clin Chem 1993, 39:218–223.PubMedGoogle Scholar
  11. 11.
    Olivecrona G, Olivecrona T: Triglyceride lipases and atherosclerosis. Curr Opin Lipidol 1995, 6:291–305.PubMedCrossRefGoogle Scholar
  12. 12.
    Babirak SP, Brown BG, Brunzell JD: Familial combined hyperlipidemia and abnormal lipoprotein lipase. Arterioscler Thromb 1992, 12:1176–1183.PubMedGoogle Scholar
  13. 13.
    Seed M, Mailly F, Vallance D, et al.: Lipoprotein lipase activity in patients with combined hyperlipidemia. Clin Investigator 1994, 72:100–106.Google Scholar
  14. 14.
    Wion KL, Kirchgessner TG, Lusis AJ, et al.: Human lipoprotein lipase complementary DNA sequence. Science 1987, 235:1638–1641.PubMedCrossRefGoogle Scholar
  15. 15.
    Deeb SS, Peng R: Structure of the human lipoprotein lipase gene. Biochemistry 1989, 28:4131–4135.PubMedCrossRefGoogle Scholar
  16. 16.
    Kirchgessner TG, Chuat J-C, Heinzmann C, et al.: Organization of the human lipoprotein lipase gene and evolution of the lipase gene family. Proc Natl Acad Sci U S A 1989, 86:9647–9651.PubMedCrossRefGoogle Scholar
  17. 17.
    Chuat JC, Raisonnier A, Etienne J, Galibert F: The lipoprotein lipase-encoding human gene: Sequence from intron-6 to intron-9 and presence of a 40-million-year-old Alu sequence. Gene 1992, 110:257–261.PubMedCrossRefGoogle Scholar
  18. 18.
    Nickerson DA, Taylor SL, Weiss KM, et al.: DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet 1998, 19:233–240.PubMedCrossRefGoogle Scholar
  19. 19.
    Bey L, Etienne J, Tse C, et al.: Cloning, sequencing and structural analysis of 976 base pairs of the promoter sequence for the rat lipoprotein lipase gene: Comparison with the mouse and human sequences. Gene 1998, 209:31–38.PubMedCrossRefGoogle Scholar
  20. 20.
    Santamarina-Fojo S: Genetic dyslipoproteinemias: Role of lipoprotein lipase and apolipoprotein C-II. Curr Opin Lipidol 1992, 3:186–195.CrossRefGoogle Scholar
  21. 21.
    Santamarina-Fojo S, Brewer HB Jr: Lipoprotein lipase: Structure, function and mechanism of action. Int J Clin Lab Res 1994, 24:143–147.PubMedCrossRefGoogle Scholar
  22. 22.
    Hayden MR, Ma Y: Molecular genetics of human lipoprotein lipase deficiency. Mol Cell Biochem 1992, 113:171–176.PubMedCrossRefGoogle Scholar
  23. 23.
    Wiebusch H, Funke H, Kastelein JJP, et al.: Mutations in the lipoprotein lipase gene are not restricted to patients with type I hyperlipidemia. Circulation 1992, 86:609.Google Scholar
  24. 24.
    Mailly F, Palmen J, Muller DPR, et al.: Familial lipoprotein lipase (LPL) deficiency: A catalogue of LPL gene mutations identified in 20 patients from the UK, Sweden, and Italy. Hum Mutat 1997, 10:465–473.PubMedCrossRefGoogle Scholar
  25. 25.
    Antonarakis SE, Nomenclature Working Group: Recommendations for a nomenclature system for human gene mutations. Hum Mutat 1998, 11:1–3.PubMedCrossRefGoogle Scholar
  26. 26.
    Ehrenborg E, Clee SM, Pimstone SN, et al.: Ethnic variantion and in vivo effects of the −93t->g promotor variant in the lipoprotein lipase gene. Arterioscl Thromb Vasc Biol 1997, 17:2672–2678.PubMedGoogle Scholar
  27. 27.
    Kastelein JJP, Groenemeyer BE, Hallman DM, The Regress Study Group, et al.: The Asn9 variant of lipoprotein lipase is associated with the -93G promoter mutation and an increased risk of coronary artery disease. Clin Genet 1998, 52:27–33.CrossRefGoogle Scholar
  28. 28.
    Hall S, Chu G, Miller G, et al.: A common mutation in the lipoprotein lipase gene promoter, −93T/G, is associated with lower plasma triglyceride levels and increased promoter activity in vitro. Arterioscler Thromb Vasc Biol 1997, 17:1969–1976.PubMedGoogle Scholar
  29. 29.
    Zhang HF, Henderson H, Gagne SE, et al.: Common sequence variants of lipoprotein lipase: Standardized studies of in vitro expression and catalytic function. Biochim Biophys Acta 1996, 1302:159–166.PubMedGoogle Scholar
  30. 30.
    Fisher RM, Humphries SE, Talmud PJ: Common variation in the lipoprotein lipase gene: Effects on plasma lipids and risk of atherosclerosis. Atherosclerosis 1997, 135:145–159.PubMedCrossRefGoogle Scholar
  31. 31.
    Gehrisch S, Kostka H, Julius U, Hanefeld M, Jaross W: Suszeptibilitaetsallele der Lipoproteinlipase (LPL) und der Hepatischen Lipase (HL) als genetisch bedingte Ursachen einer atherogenen Hyperlipidaemie (HLP). In Die Bedeutung von Proteoglykanen, Lipoproteinen und Lipasen fuer die Atherogenese. Edited by Heinle H, Schulte H, Siegel G. Deutsche Gesellschaft fuer Arterioskleroseforschung. Stuttgart: W. Kohlhammer; 1998:45–49.Google Scholar
  32. 32.
    Gehrisch S, Jaross W: Relevance of mutations in genes of the lipoprotein lipase (LPL) and the hepatic lipase (HL). In Advances in Lipoprotein and Atherosclerosis Research, Diagnostics and Treatment. Edited by Hanefeld M, Leonhardt W, Jaross W, Dude H. Jena: Gustav Fischer Verlag; 1998:173–179.Google Scholar
  33. 33.
    Rouis M, Lohse P, Dugi KA, et al.: Homozygosity for two point mutations in the lipoprotein lipase (LPL) gene in a patient with familial LPL deficiency: LPL(Asp(9)→Asn, Tyr (262)→His). J Lipid Res 1996, 37:651–661.PubMedGoogle Scholar
  34. 34.
    Hokanson JE: Lipoprotein lipase gene variants and risk of coronary disease: A quantitative analysis of population-based studies. Int J Clin Lab Res 1997, 27:24–34.PubMedGoogle Scholar
  35. 35.
    Wittekoek ME, Moll E, Pimstone SN, et al.: A common mutation in the lipoprotein lipase gene (D9N) and FH: Evidence for gene-gene interaction. In Abstracts 70th EAS Congress 1998. Geneva: European Atherosclerosis Society 1998:9.Google Scholar
  36. 36.
    Gaudet D, Vohl M-C, Julien P, et al.: Relative contribution of low-density lipoprotein receptor and lipoprotein lipase gene mutations to angiographically assessed coronary artery disease among French Canadians. Am J Cardiol 1998, 82:299–305.PubMedCrossRefGoogle Scholar
  37. 37.
    Debruin TWA, Mailly F, Vanbarlingen HHJJ, et al.: Lipoprotein lipase gene mutations D9N and N291S in four pedigrees with familial combined hyperlipidaemia. Eur J Clin Invest 1996, 26:631–639.Google Scholar
  38. 38.
    Hoffer MJV, Bredie SJH, Snieder H, et al.: Gender-related association between the −93T→G/D9N haplotype of the lipoprotein lipase gene and elevated lipid levels in familial combined hyperlipidemia. Atherosclerosis 1998, 138:91–99.PubMedCrossRefGoogle Scholar
  39. 39.
    Kostka H, Gehrisch S, Freidt M, et al.: Point mutations in the lipoprotein lipase gene are likely susceptibility alleles for familial combined hyperlipidemia. Clin Lab 1997, 43:893–897.Google Scholar
  40. 40.
    Yang WS, Nevin DN, Iwasaki L, et al.: Regulatory mutations in the human lipoprotein lipase gene in patients with familial combined hyperlipidemia and coronary artery disease. J Lipid Res 1996, 37:2627–2637.PubMedGoogle Scholar
  41. 41.
    Monsalve MV, Henderson H, Roederer G, et al.: A missense mutation at codon 188 of the human lipoprotein lipase gene is a frequent cause of lipoprotein lipase deficiency in persons of different ancestries. J Clin Invest 1990, 86:728–734.PubMedGoogle Scholar
  42. 42.
    Ma Y, Henderson HE, Ven Murthy MR, et al.: A mutation in the human lipoprotein lipase gene as the most common cause of familial chylomicronemia in French Canadians. N Engl J Med 1991, 324:1761–1766.PubMedCrossRefGoogle Scholar
  43. 43.
    Ma Y, Wilson BI, Bijovet S, et al.: A missense mutation Asp250Asn in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries. Genomics 1992, 13:649–653.PubMedCrossRefGoogle Scholar
  44. 44.
    Bergeron J, Normand T, Bharucha A, et al.: Prevalence, geopraphical distribution and genealogical investigations of mutation 188 of lipoprotein lipase gene in the French Canadian population of Quebec. Clin Genet 1992, 41:206–210.PubMedCrossRefGoogle Scholar
  45. 45.
    Bijvoet S, Gagne SE, Moorjani S, et al.: Alterations in plasma lipoproteins and apolipoproteins before the age of 40 in heterozygotes for lipoprotein lipase deficiency. J Lipid Res 1996, 37:640–650.PubMedGoogle Scholar
  46. 46.
    Minnich A, Baloukas J, Roederer G, et al.: Lipoprotein lipase gene mutation in coronary artery disease. Can J Cardiol 1998, 14:711–716.PubMedGoogle Scholar
  47. 47.
    Nordestgaard BB, Reeler S, Steffensen R, Tybjaerg-Hansen A: Clinical expression in the heterozygote state of the Gly188Glu mutation in the lipoprotein lipase gene: Screening among 1000 heart patients and 5400 persons from general population (the Copenhagen City Heart Study). Atherosclerosis 1994, 109:205–206.CrossRefGoogle Scholar
  48. 48.
    Funke H, Assmann G: The low down on lipoprotein lipase. Nat Genet 1995, 10:6–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Hoffer MJV, Bredie SJH, Boomsma DI, et al.: The lipoprotein lipase (Asn291 → Ser) mutation is associated with elevated lipid levels in families with familial combined hyperlipidaemia. Atherosclerosis 1996, 119:159–167.PubMedCrossRefGoogle Scholar
  50. 50.
    Bijvoet AM, Bruin T, Kastelein JJP: The familial hyperchylomicronemia syndrome. Neth J Med 1993, 42:36–44.PubMedGoogle Scholar
  51. 51.
    Reymer PWA, Groenemeyer BE, Gagne E, et al.: A frequently occurring mutation in the lipoprotein lipase gene (Asn291Ser) contributes to the expression of familial combined hyperlipidemia. Hum Mol Genet 1995, 4:1543–1549.PubMedCrossRefGoogle Scholar
  52. 52.
    Degraaf J, Stalenhoef AFH: Defects of lipoprotein metabolism in familial combined hyperlipidaemia. Curr Opin Lipidol 1998, 9:189–196.CrossRefGoogle Scholar
  53. 53.
    Wittrup HH, Tybjaerg-Hansen A, Abildgaard S, et al.: A common substitution (Asn291Ser) in lipoprotein lipase is associated with increased risk of ischemic heart disease. J Clin Invest 1997, 99:1606–1613.PubMedCrossRefGoogle Scholar
  54. 54.
    Wittekoek ME, Pimstone SN, Reymer PWA, et al.: A common mutation in the lipoprotein lipase gene (N291S) alters the lipoprotein phenotype and risk for cardiovascular disease in patients with familial hypercholesterolemia. Circulation 1998, 97:729–735.PubMedGoogle Scholar
  55. 55.
    Huang P, Kostulas K, Huang WX, et al.: Lipoprotein lipase gene polymorphisms in ischaemic stroke and carotid stenosis. Eur J Clin Invest 1997, 27:740–742.PubMedCrossRefGoogle Scholar
  56. 56.
    Baum L, Chen L, Masliah E, et al.: Lipoprotein lipase mutations and Alzheimer’s disease. Am J Med Genet 1999, 88:136–139.PubMedCrossRefGoogle Scholar
  57. 57.
    Hata A, Robertson M, Emi M, Lalouel J-M: Direct detection and automated sequencing of individuall alleles after electrophoretic strand separation: Identification of a common nonsense mutation in exon 9 of the human lipoprotein lipase gene. Nucl Acid Res 1990, 18:5407–5411.CrossRefGoogle Scholar
  58. 58.
    Stock J, Thorn JA, Galton DJ: Lipoprotein lipase genotypes for a common premature termination codon mutation detected by PCR-mediated site-directed mutagenesis and restriction digestion. J Lipid Res 1992, 33:853–857.Google Scholar
  59. 59.
    Kobayashi J, Nishida T, Ameis D, et al.: A heterozygous mutation (the codon Ser447→ a stop codon) in lipoprotein lipase contributes to a defect in lipid interface recognition in a case wit type I hyperlipidemia. Biochem Biophys Res Commun 1992, 182:70–72.PubMedCrossRefGoogle Scholar
  60. 60.
    Humphries SE, Nicaud V, Margalef J, et al.: Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides-The European Atherosclerosis Research Study (EARS). Arterioscler Thromb Vasc Biol 1998, 18:526–534.PubMedGoogle Scholar
  61. 61.
    Murano T, Miyashita Y, Itoh Y, et al.: Incidence of lipoprotein lipase genotype for premature termination codon (Ser447-Ter) in Japanese, and association with dyslipoproteinemia. Clin Chim Acta 1998, 275:25–213.CrossRefGoogle Scholar
  62. 62.
    Peacock RE, Hamsten A, Nilson-Ehle P, Humphries SE: Associations between lipoprotein lipase gene polymorphisms and plasma correlations of lipids, lipoproteins and lipase activities in young myocardial infarction survivors and age-matched healthy individuals from Sweden. Atherosclerosis 1992, 97:171–185.PubMedCrossRefGoogle Scholar
  63. 63.
    Chikhi L, Destro-Bisol G, Bertorelle G, et al.: Clines of nuclear DNA markers suggest a large neolithic ancestry of the European gene pool. Proc Natl Acad Sci U S A 1998, 21:9053–9058.CrossRefGoogle Scholar
  64. 64.
    Faustinella F, Chang A, Van Biervlit JP, et al.: Catalytic triad residue mutation Asp156Gly causing familial lipoprotein lipase deficiency: Co-inheritance with a nonsense mutation Ser447→Ter in a Turkish family. J Biol Chem 1991, 266:14418–14424.PubMedGoogle Scholar
  65. 65.
    Mattu RK, Needham EWA, Morgan R, et al.: DNA variants at the LPL gene locus associate with angiographically defined severity of atherosclerosis and serum lipoprotein levels in a Welsh population. Arterioscler Thromb 1994, 14:1090–1097.PubMedGoogle Scholar
  66. 66.
    Nevin DN, Brunzell JD, Deeb SS: The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity. Arterioscler Thromb 1994, 14:869–873.PubMedGoogle Scholar
  67. 67.
    Elbein SC, Yeager C, Kwong LK, et al.: Molecular screening of the lipoprotein lipase gene in hypertriglyceridemic members of familial noninsulin-dependent diabetes mellitus families. J Clin Endocrinol Metab 1994, 79:1450–1456.PubMedCrossRefGoogle Scholar
  68. 68.
    Gagne E, Genest J, Zhang H, et al.: Analysis of DNA changes in the LPL gene in patients with familial combined hyperlipidemia. Arterioscler Thromb 1994, 14:1250–1257.PubMedGoogle Scholar
  69. 69.
    Zhang Q, Liu Y, Liu BW, et al.: Common genetic variants of lipoprotein lipase and apolipoprotein AI-CIII that relate to coronary artery disease: A study in Chinese and European subjects. Mol Genet Metab 1998, 64:177–183.PubMedCrossRefGoogle Scholar
  70. 70.
    Georges JL, Regisbailly A, Salah D, et al.: Family study of lipoprotein lipase gene polymorphisms and plasma triglyceride levels. Genet Epidemiol 1996, 13:179–192.PubMedCrossRefGoogle Scholar
  71. 71.
    Lahr MM, Foley RA: Toward a theory of modern human origins: Geography, demography, and diversity in recent human evolution. Am J Phys Anthropol 1998, 27:137–176.PubMedCrossRefGoogle Scholar

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© Current Science Inc 1999

Authors and Affiliations

  • Siegmund Gehrisch
    • 1
  1. 1.Institut fuer Klinische Chemie und Laboratoriumsmedizin, Direktor Prof. Dr. Werner JarossMedizinische Fakultaet der Technischen Universitaet DresdenDresdenGermany

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