Skip to main content

Advertisement

SpringerLink
Log in

Genome-wide linkage analysis replicates susceptibility locus for fasting plasma triglycerides: NHLBI Family Heart Study

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Recent reports implicate chromosomal regions linked to inter-individual variation in plasma triglycerides. We conducted genome-wide scans to replicate these linkages and/or identify other loci influencing plasma triglycerides in the NHLBI Family Heart Study (FHS). Data were obtained for 501 three-generational families. Genotyping was done by the Utah Molecular Genetics Laboratory and NHLBI Mammalian Genotyping Service; markers from both were placed on one genetic map. Analysis was done using multipoint variance components linkage. Fasting plasma triglycerides were log-transformed and age-, sex-, and field center-adjusted; suggestive linkage evidence was found on chromosome 8 (LOD=2.80 at 89 cM, marker D8S1141). Further adjustment for waist girth, BMI, diabetes, hypertension, and lipid-lowering drugs suggested linkage regions on chromosomes 6 (LOD=2.29 at 79 cM, marker D6S295) and 15 (LOD=1.85 at 43 cM, marker D15S659). Since HDL is correlated with triglycerides and because it was linked to this region on chromosome 15 in FHS, we created a composite triglyceride–HDL phenotype. The combined phenotype LOD score was 3.0 at the same marker on chromosome 15. Chromosome 15 likely harbors a susceptibility locus with an influence on triglycerides and HDL. Regions on chromosomes 6 and 8 may also contain loci contributing to inter-individual variation in plasma triglycerides.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Arnett DK, Pankow JS, Atwood LD, Sellers TA (1997) Impact of adjustments for intermediate phenotypes on the power to detect linkage. Genet Epidemiol 14:749–754

    Article  CAS  PubMed  Google Scholar 

  • Austin MA (1998) Plasma triglyceride as a risk factor for cardiovascular disease. Can J Cardiol 14(suppl B):14B–17B

    CAS  PubMed  Google Scholar 

  • Austin MA, King MC, Bawol RD, Hulley SB, Friedman GD (1987) Risk factors for coronary heart disease in adult female twins. Genetic heritability and shared environmental influences. Am J Epidemiol 125:308–318

    CAS  PubMed  Google Scholar 

  • Breslow JL (2000) Genetics of lipoprotein abnormalities associated with coronary artery disease susceptibility. Annu Rev Genet 34:233–254

    Article  CAS  PubMed  Google Scholar 

  • Coon H, Leppert MF, Eckfeldt JH, Oberman A, Myers RH, Peacock JM, Province MA, Hopkins PN, Heiss G (2001) Genome-wide linkage analysis of lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) blood pressure study. Arterioscler Thromb Vasc Biol 21:1969–1976

    CAS  PubMed  Google Scholar 

  • Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O’Connell P, Stern MP (2000) A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans. Am J Hum Genet 66:1237–1245

    Article  CAS  PubMed  Google Scholar 

  • Elbein SC, Hasstedt SJ (2002) Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q. Diabetes 51:528–535

    CAS  PubMed  Google Scholar 

  • Feitosa MF, Borecki IB, Rich SS, Arnett DK, Sholinsky P, Myers RH, Leppert M, Province MA (2002) Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart, Lung, and Blood Institute Family Heart Study. Am J Hum Genet 70:72–82

    Article  CAS  PubMed  Google Scholar 

  • Ford ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356–359

    Article  PubMed  Google Scholar 

  • Higgins M, Province M, Heiss G, Eckfeldt J, Ellison RC, Folsom AR, Rao DC, Sprafka JM, Williams R (1996) NHLBI Family Heart Study: objectives and design. Am J Epidemiol 143:1219–1228

    CAS  PubMed  Google Scholar 

  • Hinds D, Risch N (1996) The ASPEX package: affected sib-pair exclusion mapping [computer program]. Stanford University, Stanford

    Google Scholar 

  • Imperatore G, Knowler WC, Pettitt DJ, Kobes S, Fuller JH, Bennett PH, Hanson RL (2000) A locus influencing total serum cholesterol on chromosome 19p: results from an autosomal genomic scan of serum lipid concentrations in Pima Indians. Arterioscler Thromb Vasc Biol 20:2651–2656

    CAS  PubMed  Google Scholar 

  • Klos KL, Kardia SL, Ferrell RE, Turner ST, Boerwinkle E, Sing CF (2001) Genome-wide linkage analysis reveals evidence of multiple regions that influence variation in plasma lipid and apolipoprotein levels associated with risk of coronary heart disease. Arterioscler Thromb Vasc Biol 21:971–978

    CAS  PubMed  Google Scholar 

  • Kuller LH, Simkin-Silverman LR, Wing RR, Meilahn EN, Ives DG (2001) Women’s Healthy Lifestyle Project: a randomized clinical trial: results at 54 months. Circulation 103:32–37

    CAS  PubMed  Google Scholar 

  • Naoumova RP, Bonney SA, Eichenbaum-Voline S, Patel HN, Jones B, Jones EL, Amey J, Colilla S, Neuwirth CK, Allotey R, Seed M, Betteridge DJ, Galton DJ, Cox NJ, Bell GI, Scott J, Shoulders CC (2003) Confirmed locus on chromosome 11p and candidate loci on 6q and 8p for the triglyceride and cholesterol traits of combined hyperlipidemia. Arterioscler Thromb Vasc Biol 23:2070–2077

    Article  CAS  PubMed  Google Scholar 

  • Newman DL, Abney M, Dytch H, Parry R, McPeek MS, Ober C (2003) Major loci influencing serum triglyceride levels on 2q14 and 9p21 localized by homozygosity-by-descent mapping in a large Hutterite pedigree. Hum Mol Genet 12:137–144

    Article  CAS  PubMed  Google Scholar 

  • Pajukanta P, Terwilliger JD, Perola M, Hiekkalinna T, Nuotio I, Ellonen P, Parkkonen M, Hartiala J, Ylitalo K, Pihlajamaki J, Porkka K, Laakso M, Viikari J, Ehnholm C, Taskinen MR, Peltonen L (1999) Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels. Am J Hum Genet 64:1453–1463

    Article  CAS  PubMed  Google Scholar 

  • PEDSYS (1999) Southwest Foundation for Biomedical Research, San Antonio, edn. 2.0

  • Perusse L, Rice T, Despres JP, Bergeron J, Province MA, Gagnon J, Leon AS, Rao DC, Skinner JS, Wilmore JH, Bouchard C (1997) Familial resemblance of plasma lipids, lipoproteins and postheparin lipoprotein and hepatic lipases in the HERITAGE family study. Arterioscler Thromb Vasc Biol 17:3263–3269

    CAS  PubMed  Google Scholar 

  • Pratt SC, Daly MJ, Kruglyak L (2000) Exact multipoint quantitative-trait linkage analysis in pedigrees by variance components. Am J Hum Genet 66:1153–1157

    Article  CAS  PubMed  Google Scholar 

  • Rashid S, Trinh DK, Uffelman KD, Cohn JS, Rader DJ, Lewis GF (2003) Expression of human hepatic lipase in the rabbit model preferentially enhances the clearance of triglyceride-enriched versus native high-density lipoprotein apolipoprotein A-I. Circulation 107:3066–3072

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez C, Pablos-Mendez A, Palmas W, Lantigua R, Mayeux R, Berglund L (2002) Comparison of modifiable determinants of lipids and lipoprotein levels among African-Americans, Hispanics, and Non-Hispanic Caucasians > or =65 years of age living in New York city. Am J Cardiol 89:178–183

    Article  CAS  PubMed  Google Scholar 

  • Shearman AM, Ordovas JM, Cupples LA, Schaefer EJ, Harmon MD, Shao Y, Keen JD, DeStefano AL, Joost O, Wilson PW, Housman DE, Myers RH (2000) Evidence for a gene influencing the TG/HDL-C ratio on chromosome 7q32.3-qter: a genome-wide scan in the Framingham study. Hum Mol Genet 9:1315–1320

    Article  CAS  PubMed  Google Scholar 

  • Shoji T, Ishimura E, Inaba M, Tabata T, Nishizawa Y (2001) Atherogenic lipoproteins in end-stage renal disease. Am J Kidney Dis 38:S30–S33

    CAS  PubMed  Google Scholar 

  • Suter PM, Gerritsen-Zehnder M, Hasler E, Gurtler M, Vetter W, Hanseler E (2001) Effect of alcohol on postprandial lipemia with and without preprandial exercise. J Am Coll Nutr 20:58–64

    CAS  PubMed  Google Scholar 

  • The Writing Group for the PEPI Trial (1995) Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 273:199–208

    PubMed  Google Scholar 

  • Unger RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863–870

    CAS  PubMed  Google Scholar 

  • Warnick GR, Benderson J, Albers JJ (1982) Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem 28:1379–1388

    CAS  PubMed  Google Scholar 

  • Weber JL, Broman KW (2001) Genotyping for human whole-genome scans: past, present, and future. Adv Genet 42:77–96

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Support was partially provided by the National Heart, Lung, and Blood Institute cooperative agreement grants U01 HL56563, U01 HL56564, U01 HL56565, U01 HL56566, U01 HL56567, U01 HL56568, U01 HL56569. This paper is presented on behalf of the investigators of the NHLBI FHS. Participating institutions and principal staff of the study not participating as authors are as follows: Forsyth County/University of North Carolina/Wake Forest University: Gerardo Heiss, Stephen Rich, Greg Evans, H.A. Tyroler, and Amy Haire; University of Minnesota Field Center: James Pankow, James Peacock, and Greg Feitl; Boston University Framingham Field Center: Richard H. Myers, Yuqing Zhang, Andrew G. Bostom, Luc Djoussé, Jemma B. Wilk, and Greta Lee Splansky; University of Utah Field Center: Steven C. Hunt, Roger R. Williams (deceased), Paul N. Hopkins, and Jan Skuppin; Coordinating Center, Washington University, St. Louis: D.C. Rao, Ingrid B. Borecki, Mary Feitosa, Jeanne Cashman, and Avril Adelman; University of Minnesota Central Biochemistry Laboratory: Catherine Leiendecker-Foster, Michael Y. Tsai, and Greg Rynders; University of Utah Central Molecular Laboratory: Mark F. Leppert, Jean-Marc Lalouel, Tena Varvil, Lisa Baird; National Heart, Lung, & Blood Institute—Project Office: Phyliss Sholinsky, Millicent Higgins (retired), Jacob Keller (retired), Sarah Knox, and Lorraine Silsbee.

Author information

Authors and Affiliations

  1. Division of Epidemiology, University of Minnesota, 1300 South Second Street, Suite 300, Minneapolis, MN, 55454, USA

    Donna K. Arnett & Michael B. Miller

  2. Cardiovascular Genetics, University of Utah, Salt Lake City, Utah, USA

    Hilary Coon & Mark Leppert

  3. Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts, USA

    R. Curtis Ellison

  4. Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA

    Kari E. North

  5. Division of Biostatistics and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA

    Michael Province

  6. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA

    John H. Eckfeldt

Authors
  1. Donna K. Arnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael B. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hilary Coon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Curtis Ellison
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kari E. North
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Province
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark Leppert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John H. Eckfeldt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Donna K. Arnett.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arnett, D.K., Miller, M.B., Coon, H. et al. Genome-wide linkage analysis replicates susceptibility locus for fasting plasma triglycerides: NHLBI Family Heart Study. Hum Genet 115, 468–474 (2004). https://doi.org/10.1007/s00439-004-1182-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-004-1182-y

Keywords

Search

Navigation