Genetic loci for diet-induced atherosclerotic lesions and plasma lipids in mice (original) (raw)

Abstract

Genetic factors independent of those affecting plasma lipid levels are a major contributor to risk for atherosclerosis in humans, yet the basis for these is poorly understood. This study examined plasma lipids and diet-induced atherosclerosis in 16-month-old female mice of strains C56BL/6J and DBA/2J. Mice of the parental strains, from recombinant inbred strains derived from these (BXD RI), and F2 progeny were fed an atherogenic diet for 16 weeks, beginning at 1 year of age. This induced atherosclerotic lesion formation in both parental strains, accompanied by increased plasma LDL levels. However, individual BXD RI strains and the BXD F2 mice demonstrated a range of atherosclerotic lesion formation that was not or at best weakly correlated with plasma lipid levels. Quantitative trait locus (QTL) analysis of the BXD F2 mice identified a locus with significant linkage (lod 4.5) for aortic lesion size on Chromosome (Chr) 10 that was independent of plasma lipids. Other loci with suggestive or significant linkage for various plasma lipid measures were identified on Chr 2, 3, 4, 5, 6, 7, 11, and 17. In this intercross, the genes primarily influencing atherosclerosis are distinct from those controlling plasma lipid levels.

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References

  1. CJ WB Basten Z-B Zeng (1994) Zmap-a QTL cartographer. GJ Smith J Benkel W Chesnais JP Fairfull BW Kennedy (Eds)et al. 5th World Congress on Genetics Applied to Livestock Production: Computing Strategies and Software Organizing Committee, 5th World Congress on Genetics Applied to Livestock Production Guelph, Ontario, Canada 65–66
    Google Scholar
  2. CJ WB Basten Z-B Zeng (2002) QTL Cartographer. Department of Statistics, North Carolina State University Raleigh, N.C.
    Google Scholar
  3. JA Berliner M Navab AM Fogelman JS Frank LL Demer_et al._ (1995)ArticleTitleAtherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics.Circulation 91 2488–2496Occurrence Handle1:CAS:528:DyaK2MXlvFCrsrY%3DOccurrence Handle7729036
    CAS PubMed Google Scholar
  4. ML Brennan MM Anderson DM Shih XD Qu X Wang_et al._ (2001)ArticleTitleIncreased atherosclerosis in myeloperoxidase-deficient mice.J Clin Invest 107 419–430Occurrence Handle1:CAS:528:DC%2BD3MXhtlWktLs%3DOccurrence Handle11181641
    CAS PubMed Google Scholar
  5. HM Dansky P Shu M Donavan J Montagno_et al._ (2002)ArticleTitleA phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse.Genetics 160 1599–1608Occurrence Handle1:CAS:528:DC%2BD38XktFahtr4%3DOccurrence Handle11973313
    CAS PubMed Google Scholar
  6. TA Drake K Hannani JM Kabo V Villa K Krass_et al._ (2001a)ArticleTitleGenetic loci influencing natural variations in femoral bone morphometry in mice.J Orthop Res 19 511–517Occurrence Handle1:CAS:528:DC%2BD3MXmvVaiurw%3D
    CAS Google Scholar
  7. TA Drake E Schadt K Hannani JM Kabo K Krass_et al._ (2001b)ArticleTitleGenetic loci determining bone density in mice with diet-induced atherosclerosis.Physiol Genomics 5 205–215Occurrence Handle1:CAS:528:DC%2BD3MXjs12quro%3D
    CAS Google Scholar
  8. DL Ellsworth P Sholinsky C Jaquish RR Fabsitz TA Manolio (1999)ArticleTitleCoronary heart disease. At the interface of molecular genetics and preventive medicine.Am J Prev Med 16 122–133Occurrence Handle10.1016/S0749-3797(98)00138-XOccurrence Handle1:STN:280:DyaK1M3nsFemtQ%3D%3DOccurrence Handle10343889
    Article CAS PubMed Google Scholar
  9. OA Iakoubova CL Olsson KM Dains DA Ross A Andalibi_et al._ (2001)ArticleTitleGenome-tagged mice (GTM): two sets of genome-wide congenic strains.Genomics 74 89–104Occurrence Handle10.1006/geno.2000.6497Occurrence Handle1:CAS:528:DC%2BD3MXjslKhtbo%3DOccurrence Handle11374905
    Article CAS PubMed Google Scholar
  10. AJ Lusis (2000)ArticleTitleAtherosclerosis.Nature 407 233–241Occurrence Handle10.1038/35025203Occurrence Handle1:CAS:528:DC%2BD3cXmvVSlsrk%3DOccurrence Handle11001066
    Article CAS PubMed Google Scholar
  11. A Lusis A Weinreb TA Drake (1998) Genetics of atherosclerosis. E Topol (Eds) Textbook of Cardiovascular Medicine. Lippincott-Raven Publishers Philadelphia 2389–2414
    Google Scholar
  12. D Machleder B Ivandic C Welch L Castellani K Reue_et al._ (1997)ArticleTitleComplex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism.J Clin Invest 99 1406–1419Occurrence Handle1:CAS:528:DyaK2sXitVWktLo%3DOccurrence Handle9077551
    CAS PubMed Google Scholar
  13. KF Manly JM Olson (1999)ArticleTitleOverview of QTL mapping software and introduction to map manager QT.Mamm Genome 10 327–334Occurrence Handle10087288
    PubMed Google Scholar
  14. M Mehrabian JH Qiao R Hyman D Ruddle C Laughton_et al._ (1993)ArticleTitleInfluence of the apoA-II gene locus on HDL levels and fatty streak development in mice.Arterioscler Thromb 13 1–10Occurrence Handle1:CAS:528:DyaK3sXkt1GksL0%3DOccurrence Handle8422330
    CAS PubMed Google Scholar
  15. M Mehrabian J Wong X Wang Z Jiang W Shi_et al._ (2001)ArticleTitleGenetic locus in mice that blocks development of atherosclerosis despite extreme hyperlipidemia.Circ Res 89 125–130Occurrence Handle1:CAS:528:DC%2BD3MXlsFWhu7s%3DOccurrence Handle11463718
    CAS PubMed Google Scholar
  16. KJ Moore DL Nagle (2000)ArticleTitleComplex trait analysis in the mouse: the strengths, the limitations and the promise yet to come.Annu Rev Genet 34 653–686Occurrence Handle1:CAS:528:DC%2BD3MXlvFOjuw%3D%3DOccurrence Handle11092842
    CAS PubMed Google Scholar
  17. JL Mu JK Naggert KL Svenson GB Collin JH Kim_et al._ (1999)ArticleTitleQuantitative trait loci analysis for the differences in susceptibility to atherosclerosis and diabetes between inbred mouse strains C57BL/6J and C57BLKS/J.J Lipid Res 40 1328–1335Occurrence Handle1:CAS:528:DyaK1MXksVKiu70%3DOccurrence Handle10393218
    CAS PubMed Google Scholar
  18. PM Nishina J Wang W Toyofuku FA Kuypers BY Ishida_et al._ (1993)ArticleTitleAtherosclerosis and plasma and liver lipids in nine inbred strains of mice.Lipids 28 599–605Occurrence Handle1:CAS:528:DyaK3sXmt1ehsLc%3DOccurrence Handle8355588
    CAS PubMed Google Scholar
  19. PM Nishina JK Naggert J Verstuyft B Paigen (1994)ArticleTitleAtherosclerosis in genetically obese mice: the mutants obese, diabetes, fat, tubby, and lethal yellow.Metabolism 43 554–558Occurrence Handle1:CAS:528:DyaK2cXitFChsbs%3DOccurrence Handle8177043
    CAS PubMed Google Scholar
  20. B Paigen (1995)ArticleTitleGenetics of responsiveness to high-fat and high-cholesterol diets in the mouse.Am J Clin Nutr 62 458S–462SOccurrence Handle1:CAS:528:DyaK2MXnsV2qs7o%3DOccurrence Handle7625360
    CAS PubMed Google Scholar
  21. WA Pitman MH Hunt C McFarland B Paigen (1998)ArticleTitleGenetic analysis of the difference in diet-induced atherosclerosis between the inbred mouse strains SM/J and NZB/BINJ.Arterioscler Thromb Vasc Biol 18 615–620Occurrence Handle1:STN:280:DyaK1c3hsFWmsA%3D%3DOccurrence Handle9555867
    CAS PubMed Google Scholar
  22. MK Purcell JL Mu DC Higgins R Elango H Whitmore_et al._ (2001)ArticleTitleFine mapping of Ath6, a quantitative trait locus for atherosclerosis in mice.Mamm Genome 12 495–500Occurrence Handle10.1007/s00335001-0006-9Occurrence Handle1:CAS:528:DC%2BD3MXks1ajsrg%3DOccurrence Handle11420610
    Article CAS PubMed Google Scholar
  23. JH Qiao PZ Xie MC Fishbein J Kreuzer TA Drake_et al._ (1994)ArticleTitlePathology of atheromatous lesions in inbred and genetically engineered mice. Genetic determination of arterial calcification.Arterioscler Thromb 14 1480–1497Occurrence Handle1:CAS:528:DyaK2cXmt1OktbY%3DOccurrence Handle8068611
    CAS PubMed Google Scholar
  24. K Robinson J Loscalzo (1998) Other risk factors for coronary artery disease: homocysteine, lipoprotein(a), fibrinogen, and plasminogen activator inhibitor. E. Topol (Eds) Textbook of Cardiovascular Medicine. Philadelphia Lippincott-Raven Publishers 231–248
    Google Scholar
  25. DM Shih YR Xia XP Wang E Miller LW Castellani_et al._ (2000)ArticleTitleCombined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis.Biol Chem 275 17527–17535Occurrence Handle10.1074/jbc.M910376199Occurrence Handle1:CAS:528:DC%2BD3cXktFaksbk%3D
    Article CAS Google Scholar
  26. CH Warden JS Fisler MJ Pace KL Svenson AJ Lusis (1993)ArticleTitleCoincidence of genetic loci for plasma cholesterol levels and obesity in a multifactorial mouse model.J Clin Invest 92 773–779Occurrence Handle1:CAS:528:DyaK2cXkslWjug%3D%3DOccurrence Handle8349816
    CAS PubMed Google Scholar
  27. CL Welch S Bretschger N Latib M Bezouevski Y Guo_et al._ (2001)ArticleTitleLocalization of atherosclerosis susceptibility loci to Chrs 4 and 6 using the Ldlr knockout mouse model.Proc Natl Acad Sci USA 98 7946–7951Occurrence Handle10.1073/pnas.141239098Occurrence Handle1:CAS:528:DC%2BD3MXlt1KntL0%3DOccurrence Handle11438740
    Article CAS PubMed Google Scholar
  28. RW Williams J Gu S Qi L Lu (2001)ArticleTitleThe genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis.Genome Biol 2 Occurrence Handle11521680
    PubMed Google Scholar
  29. ZB Zeng CH Kao CJ Basten (1999)ArticleTitleEstimating the genetic architecture of quantitative traits.Genet Res 74 279–289Occurrence Handle1:STN:280:DC%2BD3c7lsVeqtw%3D%3DOccurrence Handle10689805
    CAS PubMed Google Scholar

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Acknowledgements

The assistance of Larry Castellani, Sharda Charungundla, Marjon Jahromi, Kathy Salcedo, and Yishou Shi is gratefully acknowledged. This work was supported by NIH grant HL30568 (A.J. Lusis and T.A. Drake) and by the Laubisch Fund, UCLA.

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Authors and Affiliations

  1. Department of Microbiology, Immunology and Molecular Genetics, University of California-Los Angeles, Los Angeles, California 90095, USA
    Veronica V. Colinayo, Kelly L. Krass & Aldons J. Lusis
  2. Department of Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, California 90095, USA
    Jian-Hua Qiao & Thomas A. Drake
  3. Department of Medicine, University of California-Los Angeles, Los Angeles, California 90095, USA
    Xuping Wang & Aldons J. Lusis
  4. Department of Human Genetics, University of California, Los Angeles, California 90095, USA
    Aldons J. Lusis
  5. Rosetta Inpharmatics, Kirkland, LCC, Washington 98034, USA
    Eric Schadt

Authors

  1. Veronica V. Colinayo
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  2. Jian-Hua Qiao
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  3. Xuping Wang
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  4. Kelly L. Krass
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  5. Eric Schadt
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  6. Aldons J. Lusis
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  7. Thomas A. Drake
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Corresponding author

Correspondence toThomas A. Drake.

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Colinayo, V.V., Qiao, JH., Wang, X. _et al._Genetic loci for diet-induced atherosclerotic lesions and plasma lipids in mice .Mamm Genome 14, 464–471 (2003). https://doi.org/10.1007/s00335-002-2187-2

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