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Mammalian Genome

, Volume 16, Issue 6, pp 414–423 | Cite as

QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival

  • Ferrin C. Wheeler
  • Liliana Fernandez
  • Kerri M. Carlson
  • Matthew J. Wolf
  • Howard A. Rockman
  • Douglas A. MarchukEmail author
Article

Abstract

The progression from myocardial hypertrophy to heart failure is a complex process, involving genetic and environmental factors. Elucidating the genetic components contributing to heart failure has been difficult, largely because of the heterogeneity of human populations. We have employed a strategy to map genetic loci that modify the heart failure phenotype in a transgenic mouse model of cardiomyopathy caused by cardiac-specific overexpression of calsequestrin. Strain-specific differences in both cardiac function and survival are observed when the transgene is moved into different inbred mouse strains. We have previously reported linkage results from mapping in reciprocal backcrosses between C57/BL6 (BL6) and DBA/2J (DBA) and a backcross between DBA/AKR and AKR. Here we report the results of a genome-wide linkage scan in the reciprocal backcross between DBA/AKR and DBA. We identified one novel locus on Chromosome (Chr) 18 that affects heart function and a second on Chr 3 that shows significant linkage to both survival and heart function. Intriguingly, the Chr 3 allele of AKR shows a susceptibility effect on phenotype, whereas the overall effect of the AKR genetic background is protective. The Chr 3 locus also completely overlaps the Hrtfm2 locus, which was previously mapped in crosses between DBA and BL6. Mapping the same QTL in two different crosses allowed us to use ancestral haplotypes to narrow the candidate gene interval from 9 to 2 Mb. Identification of the genes at these QTLs in the mouse will provide novel candidate genes that can be evaluated for their role in human heart failure.

Keywords

Heart Function Haplotype Block Likelihood Ratio Statistic Human Heart Failure Reciprocal Backcross 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors thank Dr. Lan Mao for her expert technique of echocardiography and Christopher Clayton, Kristine Porter, and Holly Roberts for their technical assistance with mouse handling. This work was supported by NIH grants R01-HL-69230 and R01-HL-68963 and American Heart Association Fellowship 0425520U (F.C.W.).

References

  1. Balke CW, Shorofsky SR (1998) Alterations in calcium handling in cardiac hypertrophy and heart failure. Cardiovasc Res 37: 290–299CrossRefPubMedGoogle Scholar
  2. Cho MC, Rapacciuolo A, Koch WJ, Kobayashi Y, Jones LR, et al. (1999) Defective beta-adrenergic receptor signaling precedes the development of dilated cardiomyopathy in transgenic mice with calsequestrin overexpression. J Biol Chem 274: 22251–2225 6CrossRefPubMedGoogle Scholar
  3. Cooper RS, Simmons BE, Castaner A, Santhanam V, Ghali J, et al. (1990) Left ventricular hypertrophy is associated with worse survival independent of ventricular function and number of coronary arteries severely narrowed. Am J Cardiol 65: 441–445CrossRefPubMedGoogle Scholar
  4. Cormier RT, Hong KH, Halberg RB, Hawkins TL, Richardson P, et al. (1997) Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nat Genet 17: 88–91CrossRefPubMedGoogle Scholar
  5. Cormier RT, Bilger A, Lillich AJ, Halberg RB, Hong KH et al. (2000) The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene 19: 3182–3192CrossRefPubMedGoogle Scholar
  6. Darvasi A (1997) The effect of selective genotyping on QTL mapping accuracy. Mamm Genome 8: 67–68CrossRefPubMedGoogle Scholar
  7. Dietrich WF, Lander ES, Smith JS, Moser AR, Gould KA, et al. (1993) Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia hi the mouse. Cell 75: 631–639CrossRefPubMedGoogle Scholar
  8. Doerge RW, Churchill GA (1996) Permutation tests for multiple loci affecting a quantitative character. Genetics 142: 285–294PubMedGoogle Scholar
  9. Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11: 241–247CrossRefPubMedGoogle Scholar
  10. Le Corvoisier P, Park HY, Carlson KM, Marchuk DA, Rockman HA (2003) Multiple quantitative trait loci modify the heart failure phenotype in murine cardiomyopathy. Hum Mol Genet 12: 3097–3107CrossRefPubMedGoogle Scholar
  11. Lee TH, Hamilton MA, Stevenson LW, Moriguchi JD, Fonarow GC, et al. (1993) Impact of left ventricular cavity size on survival in advanced heart failure. Am J Cardiol 72: 672–676CrossRefPubMedGoogle Scholar
  12. Manly KF, Cudmore RH Jr, Meer JM (2001) Map Manager QTX, cross-platform software for genetic mapping. Mamm Genome 12: 930–932CrossRefPubMedGoogle Scholar
  13. Nabar A, Rodriguez LM, Batra RK, Timmermans C, Cheriex E, (2002) Echocardiographic predictors of survival in patients undergoing radiofrequency ablation of postinfarct clinical ventricular tachycardia. J Cardiovasc Electrophysiol 13: S118–121CrossRefPubMedGoogle Scholar
  14. Nadeau JH (2001) Modifier genes hi mice and humans. Nat Rev Genet 2: 165–174CrossRefPubMedGoogle Scholar
  15. Pletcher MT, McClurg P, Batalov S, Su AI, Barnes SW, et al. (2004) Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse. PLoS Biol 2: e393CrossRefPubMedGoogle Scholar
  16. Shoemaker AR, Moser AR, Midgley CA, Clipson L, Newton MA, et al. (1998) A resistant genetic background leading to incomplete penetrance of intestinal neoplasia and reduced loss of heterozygosity in ApcMin/+ mice. Proc Natl Acad Sci USA 95: 10826–10831CrossRefPubMedGoogle Scholar
  17. Suzuki M, Carlson KM, Marchuk DA, Rockman HA (2002) Genetic modifier loci affecting survival and cardiac function in murine dilated cardiomyopathy. Circulation 105: 1824–1829CrossRefPubMedGoogle Scholar
  18. Zhao Y, Meng XM, Wei YJ, Zhao XW, Liu DQ, et al. (2003) Cloning and characterization of a novel cardiac-specific Idnase that interacts specifically with cardiac troponin I. J Mol Med 81: 297–304PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Inc. 2005

Authors and Affiliations

  • Ferrin C. Wheeler
    • 1
  • Liliana Fernandez
    • 2
  • Kerri M. Carlson
    • 1
  • Matthew J. Wolf
    • 2
  • Howard A. Rockman
    • 1
    • 2
  • Douglas A. Marchuk
    • 1
    Email author
  1. 1.Department of Molecular Genetics and MicrobiologyDuke University Medical CenterDurhamUSA
  2. 2.Department of MedicineDuke University Medical CenterDurhamUSA

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