Human Genetics

, Volume 120, Issue 3, pp 371–380 | Cite as

Genome-wide linkage scans for loci affecting total cholesterol, HDL-C, and triglycerides: the Family Blood Pressure Program

  • Suzette J. Bielinski
  • Weihong Tang
  • James S. Pankow
  • Michael B. Miller
  • Thomas H. Mosley
  • Eric Boerwinkle
  • Richard A. Olshen
  • J. David Curb
  • Cashell E. Jaquish
  • D. C. Rao
  • Alan Weder
  • Donna K. Arnett
Original Investigation

Abstract

Atherosclerosis accounts for 75% of all deaths from cardiovascular disease and includes coronary heart disease (CHD), stroke, and other diseases of the arteries. More than half of all CHD is attributable to abnormalities in levels and metabolism of lipids. To locate genes that affect total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides, genome-wide linkage scans for quantitative trait loci were performed using variance components methods as implemented in SOLAR on a large diverse sample recruited as part of the Family Blood Pressure Program. Phenotype and genetic marker data were available for 9,299 subjects in 2,953 families for total cholesterol, 8,668 subjects in 2,736 families for HDL, and 7,760 subjects in 2,499 families for triglycerides. Mean lipid levels were adjusted for the effects of sex, age, age2, age-by-sex interaction, body mass index, smoking status, and field center. HDL-C and triglycerides were further adjusted for average total alcoholic drinks per week and estrogen use. Significant linkage was found for total cholesterol on chromosome 2 (LOD = 3.1 at 43 cM) in Hispanics and for HDL-C on chromosome 3 (LOD = 3.0 at 182 cM) and 12 (LOD = 3.5 at 124 cM) in Asians. In addition, there were 13 regions that showed suggestive linkage (LOD ≥ 2.0); 7 for total cholesterol, 4 for HDL, and 2 for triglycerides. The identification of these loci affecting lipid phenotypes and the apparent congruence with previous linkage results provides increased support that these regions contain genes influencing lipid levels.

Notes

Acknowledgments

We are grateful for resources from the University of Minnesota Supercomputing Institute, the NIH Training Grant in Cardiovascular Disease Genetic Epidemiology (#5 T32 HL007972), and the National Heart Lung and Blood Institute Family Blood Pressure Program including networks GenNet (U01 HL54512, U01 HL54508, U01 HL54485, U01 HL54466, U01 HL64777), GENOA (U01 HL54481, U01 HL54504, U01 HL54463, U01 HL54526, U01 HL54457, U01 HL54464), HyperGEN (U01 HL54471, U01 HL54472, U01 HL54495, U01 HL54497, U01 HL54509, U01 HL54496, U01 HL54473), and SAPPHIRe (U01 HL54527, U01 HL54498). http://www.biostat.wustl.edu/fbpp/Acknowledgments.html

Supplementary material

References

  1. FBPP investigators (2002) Multi-center genetic study of hypertension: the Family Blood Pressure Program (FBPP). Hypertension 39:3–9Google Scholar
  2. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101PubMedCrossRefGoogle Scholar
  3. Abu-Elheiga L, Matzuk MM, Kordari P, Oh W, Shaikenov T, Gu Z, Wakil SJ (2005) Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci USA 102:12011–12016PubMedCrossRefGoogle Scholar
  4. Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198–1211PubMedCrossRefGoogle Scholar
  5. Arya R, Duggirala R, Almasy L, Rainwater DL, Mahaney MC, Cole S, Dyer TD, Williams K, Leach RJ, Hixson JE, MacCluer JW, O’Connell P, Stern MP, Blangero J (2002) Linkage of high-density lipoprotein–cholesterol concentrations to a locus on chromosome 9p in Mexican Americans. Nat Genet 30:102–105PubMedCrossRefGoogle Scholar
  6. Association AH (2005) Heart Disease and Stroke Statisitics—2005 Update. American Heart Association, Dallas TexasGoogle Scholar
  7. Beekman M, Heijmans BT, Martin NG, Pedersen NL, Whitfield JB, DeFaire U, van Baal GC, Snieder H, Vogler GP, Slagboom PE, Boomsma DI (2002) Heritabilities of apolipoprotein and lipid levels in three countries. Twin Res 5:87–97PubMedCrossRefGoogle Scholar
  8. Blangero J, Williams JT, Almasy L (2001) Variance component methods for detecting complex trait loci. Adv Genet 42:151–181PubMedGoogle Scholar
  9. Bo S, Cavallo-Perin P, Scaglione L, Pagano G (1997) Heritability of cardiovascular risk parameters in subjects with increased susceptibility to non-insulin-dependent diabetes mellitus. Acta Diabetol 34:280–284PubMedCrossRefGoogle Scholar
  10. Christian JC, Feinleib M, Hulley SB, Castelli WP, Fabsitz RR, Garrison RJ, Borhani NO, Rosenman RH, Wagner J (1976) Genetics of plasma cholesterol and triglycerides: a study of adult male twins. Acta Genet Med Gemellol (Roma) 25:145–149Google Scholar
  11. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–401PubMedCrossRefGoogle Scholar
  12. 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 21:1969–1976PubMedCrossRefGoogle Scholar
  13. Freeman MS, Mansfield MW, Barrett JH, Grant PJ (2002) Heritability of features of the insulin resistance syndrome in a community-based study of healthy families. Diabet Med 19:994–999PubMedCrossRefGoogle Scholar
  14. Friedlander Y, Cohen T, Stenhouse N, Davies AM, Stein Y (1982) Familial aggregation of total cholesterol, triglyceride and high-density lipoprotein–cholesterol in an Israeli population sample. Isr J Med Sci 18:1137–1143PubMedGoogle Scholar
  15. Hayden MR, Clee SM, Brooks-Wilson A, Genest J Jr, Attie A, Kastelein JJ (2000) Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency. Curr Opin Lipidol 11:117–122PubMedCrossRefGoogle Scholar
  16. Heath SC, Snow GL, Thompson EA, Tseng C, Wijsman EM (1997) MCMC segregation and linkage analysis. Genet Epidemiol 14:1011–1016PubMedCrossRefGoogle Scholar
  17. Horne BD, Malhotra A, Camp NJ (2003) Comparison of linkage analysis methods for genome-wide scanning of extended pedigrees, with application to the TG/HDL-C ratio in the Framingham Heart Study. BMC Genet 4(Suppl 1):S93PubMedCrossRefGoogle Scholar
  18. Hunt SC, Hasstedt SJ, Kuida H, Stults BM, Hopkins PN, Williams RR (1989) Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. Am J Epidemiol 129:625–638PubMedGoogle Scholar
  19. 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 20:2651–2656PubMedGoogle Scholar
  20. Kelley DE, Simoneau JA (1994) Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Invest 94:2349–2356PubMedCrossRefGoogle Scholar
  21. Kotchen TA, Kotchen JM, Grim CE, George V, Kaldunski ML, Cowley AW, Hamet P, Chelius TH (2000) Genetic determinants of hypertension: identification of candidate phenotypes. Hypertension 36:7–13PubMedGoogle Scholar
  22. Miller MB (2003) MER2SOL: translating MERLIN or Loki IBD Data to SOLAR Format. Genetic Epidemiol 25:261–262Google Scholar
  23. Muoio DM, Lynis Dohm G (2002) Peripheral metabolic actions of leptin. Best Pract Res Clin Endocrinol Metab 16:653–666PubMedCrossRefGoogle Scholar
  24. Pollin TI, Hsueh WC, Steinle NI, Snitker S, Shuldiner AR, Mitchell BD (2004) A genome-wide scan of serum lipid levels in the Old Order Amish. Atherosclerosis 173:89–96PubMedCrossRefGoogle Scholar
  25. Program NCE (2002) Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). National Institutes of HealthGoogle Scholar
  26. Rosmond R, Chagnon YC, Holm G, Chagnon M, Perusse L, Lindell K, Carlsson B, Bouchard C, Bjorntorp P (2000) Hypertension in obesity and the leptin receptor gene locus. J Clin Endocrinol Metab 85:3126–3131PubMedCrossRefGoogle Scholar
  27. Sistonen P, Ehnholm C (1980) On the heritability of serum high density lipoprotein in twins. Am J Hum Genet 32:1–7PubMedGoogle Scholar
  28. Snieder H, van Doornen LJ, Boomsma DI (1997) The age dependency of gene expression for plasma lipids, lipoproteins, and apolipoproteins. Am J Hum Genet 60:638–650PubMedGoogle Scholar
  29. Spiekerkoetter U, Khuchua Z, Yue Z, Bennett MJ, Strauss AW (2004) General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatr Res 55:190–196PubMedCrossRefGoogle Scholar
  30. Tang H, Quertermous T, Rodriguez B, Kardia SL, Zhu X, Brown A, Pankow JS, Province MA, Hunt SC, Boerwinkle E, Schork NJ, Risch NJ (2005) Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet 76:268–275PubMedCrossRefGoogle Scholar
  31. Trayhurn P, Hoggard N, Mercer JG, Rayner DV (1999) Leptin: fundamental aspects. Int J Obes Relat Metab Disord 23(Suppl 1):22–28PubMedCrossRefGoogle Scholar
  32. Ukkola O, Tremblay A, Despres JP, Chagnon YC, Campfield LA, Bouchard C (2000) Leptin receptor Gln223Arg variant is associated with a cluster of metabolic abnormalities in response to long-term overfeeding. J Intern Med 248:435–439PubMedCrossRefGoogle Scholar
  33. Wauters M, Mertens I, Rankinen T, Chagnon M, Bouchard C, Van Gaal L (2001) Leptin receptor gene polymorphisms are associated with insulin in obese women with impaired glucose tolerance. J Clin Endocrinol Metab 86:3227–3232PubMedCrossRefGoogle Scholar
  34. Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS (2001) The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab 86:4434–4439PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Suzette J. Bielinski
    • 1
  • Weihong Tang
    • 1
  • James S. Pankow
    • 1
  • Michael B. Miller
    • 1
  • Thomas H. Mosley
    • 2
  • Eric Boerwinkle
    • 3
  • Richard A. Olshen
    • 4
  • J. David Curb
    • 5
  • Cashell E. Jaquish
    • 6
  • D. C. Rao
    • 7
  • Alan Weder
    • 8
  • Donna K. Arnett
    • 1
    • 9
  1. 1.University of MinnesotaDivision of Epidemiology and Community HealthMinneapolisUSA
  2. 2.Department of Medicine (Geriatrics)University of Mississippi Medical CenterJacksonUSA
  3. 3.Human Genetics CenterUniversity of Texas–Houston Health Science CenterHoustonUSA
  4. 4.Division of BiostatisticsStanford University School of MedicineStanfordUSA
  5. 5.Pacific Health Research InstituteHonoluluUSA
  6. 6.Division of Epidemiology and Clinical ApplicationsNational Heart, Lung, and Blood InstituteBethesdaUSA
  7. 7.Division of BiostatisticsWashington University School of MedicineSt. LouisUSA
  8. 8.University of Michigan HospitalsAnn ArborUSA
  9. 9.Department of EpidemiologyUniversity of AlabamaBirminghamUSA

Personalised recommendations