Genetic Loci Influencing Plasma High Density Lipoprotein Cholesterol Concentrations in Humans



The majority of variation in HDL cholesterol observed at the population level is of polygenic origin and is the result of the complex interaction between genetic and environmental factors. For many years, genotype-phenotype associations were explored by evaluating a single common variant in a candidate gene. Although important genetic determinants of HDL cholesterol variation have been identified in such studies, this approach does not take into account the multifactorial nature of this complex trait. With the advent of genome-wide association (GWA) technology, it is now possible to study relationships between complex genetic traits, such as HDL cholesterol, and common variants in numerous loci in large populations. Over the past few years, GWA analysis has led to the discovery of novel, as well as confirmation of previously known, common genetic determinants of plasma lipoproteins. This review summarizes the results of GWA studies reported from 2007 to present that have identified common genetic loci associated with plasma HDL cholesterol concentrations in humans.


Complex trait genetics High density lipoproteins Genome-wide association Single nucleotide polymorphism 


  1. 1.
    Miller GJ, Miller NE (1975) Plasma high density lipoprotein concentration and development of ischaemic heart-disease. Lancet 1:16–25CrossRefPubMedGoogle Scholar
  2. 2.
    Gordon DJ, Probstfield JL, Garrison RJ et al (1989) High density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation 79:8–15PubMedGoogle Scholar
  3. 3.
    Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH (1991) A prospective study of cholesterol, apolipoproteins and the risk of myocardial infarction. N Engl J Med 325:373–381CrossRefPubMedGoogle Scholar
  4. 4.
    Goldbourt U, Yaari S, Medalie JH (1997) Isolated low HDL cholesterol as a risk factor for coronary heart disease. Arterioscler Thromb Vasc Biol 17:107–113PubMedGoogle Scholar
  5. 5.
    Heller DA, DeFaire D, Pedersen NL, Dahlen G, McClearn GE (1993) Genetic and environmental influences on serum lipid levels in twins. N Engl J Med 328:1150–1156CrossRefPubMedGoogle Scholar
  6. 6.
    Kathiresan S, Musunuru K, Orho-Melander M (2008) Defining the spectrum of alleles that contribute to blood lipid concentrations in humans. Curr Opin Lipid 19:122–127CrossRefGoogle Scholar
  7. 7.
    Hegele RA (2009) Plasma lipoproteins: genetic influences and clinical implications. Nat Rev Genet 10:109–121CrossRefPubMedGoogle Scholar
  8. 8.
    Kathiresan S, Manning AK, Demissie S et al (2007) A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study. BMC Med Genet 8(Suppl 1):S17CrossRefPubMedGoogle Scholar
  9. 9.
    Herbert A, Gerry NP, McQueen MB et al (2006) A common genetic variant is associated with adult and childhood obesity. Science 312:279–283CrossRefPubMedGoogle Scholar
  10. 10.
    Wallace C, Newhouse SJ, Braund P et al (2008) Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet 82:139–149CrossRefPubMedGoogle Scholar
  11. 11.
    Saxena R, Voight BF, Lyssenko V et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336CrossRefPubMedGoogle Scholar
  12. 12.
    Chasman DI, Pare G, Zee RYL et al (2008) Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and apolipoprotein B among 6382 white women in genome-wide analysis with replication. Circ Cardiovasc Genet 1:21–30CrossRefPubMedGoogle Scholar
  13. 13.
    Willer CJ, Sanna S, Jackson AU et al (2008) Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40:161–169CrossRefPubMedGoogle Scholar
  14. 14.
    Kathiresan S, Melander O, Guiducci C et al (2008) Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40:189–197CrossRefPubMedGoogle Scholar
  15. 15.
    Sabatti C, Service SK, Hartikainen AL et al (2009) Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 41:35–46CrossRefPubMedGoogle Scholar
  16. 16.
    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser 57:289–300Google Scholar
  17. 17.
    Lanktree MB, Anand SS, Yusuf S, Hegele RA (2009) Replication of genetic associations with plasma lipoprotein traits in a multiethnic sample. J Lipid Res 50:1487–1496CrossRefPubMedGoogle Scholar
  18. 18.
    Keating BJ, Tischfield S, Murray SS et al (2008) Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS One 3:e3583CrossRefPubMedGoogle Scholar
  19. 19.
    Scott LJ, Mohlke KL, Bonnycastle LL et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345CrossRefPubMedGoogle Scholar
  20. 20.
    Pilia G, Chen WM, Scuteri A et al (2006) Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2:e132CrossRefPubMedGoogle Scholar
  21. 21.
    Kathiresan S, Willer CJ, Peloso GM et al (2009) Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41:56–65CrossRefPubMedGoogle Scholar
  22. 22.
    The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320CrossRefGoogle Scholar
  23. 23.
    Kooner JS, Chambers JC, Aguilar-Salinas CA et al (2008) Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet 40:149–151CrossRefPubMedGoogle Scholar
  24. 24.
    Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C (2004) Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol 24:e13-e18CrossRefPubMedGoogle Scholar
  25. 25.
    Heid IM, Boes E, Muller M et al (2008) Genome-wide association analysis of high-density lipoprotein cholesterol in the population-based KORA study sheds new light on intergenic regions. Circ Cardiovasc Genet 1:10–20CrossRefPubMedGoogle Scholar
  26. 26.
    Aulchenko YS, Ripatti S, Lindqvist I et al (2009) Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 41:47–55CrossRefPubMedGoogle Scholar
  27. 27.
    Edmondson AC, Brown RJ, Kathiresan S et al (2009) Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. J Clin Invest 119:1042–1050PubMedGoogle Scholar
  28. 28.
    Yoshida K, Shimizugawa T, Ono M, Furukawa H (2002) Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J Lipid Res 43:1770–1772CrossRefPubMedGoogle Scholar
  29. 29.
    Romeo S, Pennacchio LA, Fu Y et al (2007) Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 39:513–516CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Novartis Institutes for Biomedical Research, IncCambridgeUSA

Personalised recommendations