Abstract
Complex diseases such as coronary heart disease or diabetes mellitus are influenced by a large number of genes and environmental factors. Therefore, in most cases the contribution of a single gene is small. The identification of these genes requires a large number of well characterized patients and controls. Alternatively, the investigation of intermediate phenotypes instead of these complex endpoints seems to be more promising. An intermediate phenotype which is usually already well known or suspected to be associated with the investigated disease, is heritable and represents an aspect among others in the pathogenesis of the complex disease. This results in an accentuation of the phenotype and reduction of genetic heterogeneity. The investigation of the genetics of the intermediate phenotype instead of investigating the genetics of the final endpoints allows the elucidation of this aspect of the disease. Optimal intermediate phenotypes are quantitative, easy to measure biochemical parameters. This results in an increased statistical power in contrast to qualitative phenotypes.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Kronenberg F, Heid IM (2007) Genetik intermediärer Phänotypen. Medizinische Genetik 19:304–308
Prentice RL (1989) Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 8:431–440
Baron RM, Kenny DA (1986) The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 51:1173–1182
Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645
Kiechl S, Willeit J, The Bruneck Study Group (1999) The natural course of atherosclerosis. Part I: incidence and progression. Arterioscler Thromb Vasc Biol 19:1484–1490
Kiechl S, Willeit J, The Collaborative Study Group (1999) The natural course of atherosclerosis. Part II: vascular remodeling. Arterioscler Thromb Vasc Biol 19:1491–1498
Lamina C, Meisinger C, Heid IM et al (2006) Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13-years of follow-up. Eur Heart J 27:2580–2587
Suhre K, Wallaschofski H, Raffler J et al (2011) A genome-wide association study of metabolic traits in human urine. Nat Genet 43:565–569
Illig T, Gieger C, Zhai G et al (2010) A genomewide perspective of genetic variation in human metabolism. Nat Genet 42:137–141
Gieger C, Geistlinger L, Altmaier E et al (2008) Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet 4:1000282
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 40:189–197
Aulchenko YS, Ripatti S, Lindquist I et al (2009) Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 41:47–55
Teslovich TM, Musunuru K, Smith AV et al (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466:707–713
WTCCC (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678
Kronenberg F (2010) Association of bilirubin with cardiovascular outcomes: more hype than substance? Circ Cardiovasc Genet 3:308–310
Hunt SC, Wu LL, Hopkins PN, Williams RR (1996) Evidence for a major gene elevating serum bilirubin concentration in Utah pedigrees. Arterioscler Thromb Vasc Biol 16:912–917
Kronenberg F, Coon H, Gutin A et al (2002) A genome scan for loci influencing anti-atherogenic serum bilirubin levels. Eur J Hum Genet 10:539–546
Lin JP, Cupples LA, Wilson PW, Heard-Costa N, O’Donnell CJ (2003) Evidence for a gene influencing serum bilirubin on chromosome 2q telomere: a genomewide scan in the Framingham study. Am J Hum Genet 72:1029–1034
Lin J-P, Schwaiger JP, Cupples LA et al (2009) Conditional linkage and genome-wide association studies identify UGT1A1 as major gene for anti-atherogenic serum bilirubin levels – a Framingham Heart Study. Atherosclerosis 206:228–233
Bosma PJ, Chowdhury JR, Bakker C et al (1995) The genetic basis of the reduced expression of bilirubin UDP- glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333:1171–1175
Lin J-P, O’Donnell CJ, Schwaiger JP et al (2006) Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation 114:1476–1481
Lingenhel A, Kollerits B, Schwaiger JP et al (2008) Serum bilirubin levels, UGT1A1 polymorphisms and risk for coronary artery disease. Exp Gerontol 43:1102–1107
Rantner B, Kollerits B, Anderwald-Stadler M et al (2008) Association between the UGT1A1 TA-repeat polymorphism and bilirubin concentration in patients with intermittent claudication: results from the CAVASIC Study. Clin Chem 54:851–857
Katan MB (1986) Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet 1:507–508
Davey SG, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32:1–22
Sandholzer C, Saha N, Kark JD et al (1992) Apo(a) isoforms predict risk for coronary heart disease: a study in six populations. Arterioscler Thromb 12:1214–1226
Kronenberg F, Kronenberg MF, Kiechl S et al (1999) Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck Study. Circulation 100:1154–1160
Erqou S, Thompson A, Di AE et al (2010) Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol 55:2160–2167
Erqou S, Kaptoge S, Perry PL et al (2009) Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302:412–423
Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG (2009) Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301:2331–2339
Kronenberg F (2004) Epidemiology, pathophysiology and therapeutic implications of lipoprotein(a) in kidney disease. Expert Rev Cardiovasc Ther 2:729–743
Kraft HG, Köchl S, Menzel HJ, Sandholzer C, Utermann G (1992) The apolipoprotein(a) gene: a transcribed hypervariable locus controlling plasma lipoprotein(a) concentration. Hum Genet 90:220–230
Kraft HG, Lingenhel A, Köchl S et al (1996) Apolipoprotein(a) Kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol 16:713–719
Schunkert H, Konig IR, Kathiresan S et al (2011) Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43:333–338
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Kronenberg, F. (2012). Metabolic Traits as Intermediate Phenotypes. In: Suhre, K. (eds) Genetics Meets Metabolomics. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1689-0_15
Download citation
DOI: https://doi.org/10.1007/978-1-4614-1689-0_15
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-1688-3
Online ISBN: 978-1-4614-1689-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)