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Closely linked non-additive blood pressure quantitative trait loci

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Abstract

There is enough evidence through linkage and substitution mapping to indicate that rat chromosome 1 harbors multiple blood pressure (BP) quantitative trait loci (QTLs). Of these, BP QTL1b was previously reported from our laboratory using congenic strains derived by introgressing normotensive alleles from the LEW rat onto the genetic background of the hypertensive Dahl salt-sensitive (S) rat. The region spanned by QTL1b is quite large (20.92 Mb), thus requiring further mapping with improved resolution so as to facilitate systematic identification of the underlying genetic determinant(s). Using congenic strains containing the LEW rat chromosomal segments on the Dahl salt-sensitive (S) rat background, further iterations of congenic substrains were constructed and characterized. Collective data obtained from this new iteration of congenic substrains provided evidence for further fragmentation of QTL1b with improved resolution. At least two separate genetic determinants of blood pressure underlie QTL1b. These are within 7.40 Mb and 7.31 Mb and are known as the QTL1b1 region and the QTL1b2 region, respectively. A genetic interaction was detected between the two BP QTLs. Interestingly, five of the previously reported differentially expressed genes located within the newly mapped QTL1b1 region remained differentially expressed. The congenic strain S.LEW(D1Mco36-D1Mco101), which harbors the QTL1b1 region alone but not the QTL1b2 region, serves as a genetic tool for further dissection of the QTL1b1 region and validation of Nr2f2 as a positional candidate gene. Overall, this study represents an intermediary yet obligatory progression towards the identification of genetic elements controlling BP.

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References

  • Aitman TJ, Glazier AM, Wallace CA, Cooper LD, Norsworthy PJ et al (1999) Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nat Genet 21:76–83

    Article  PubMed  CAS  Google Scholar 

  • Arbilly M, Pisante A, Devor M, Darvasi A (2006) An integrative approach for the identification of quantitative trait loci. Anim Genet 37(Suppl 1):7–9

    Article  PubMed  CAS  Google Scholar 

  • Cervino AC, Darvasi A, Fallahi M, Mader CC, Tsinoremas NF (2007) An integrated in silico gene mapping strategy in inbred mice. Genetics 175:321–333

    Article  PubMed  CAS  Google Scholar 

  • Cicila GT, Lee SJ (1998) Identifying candidate genes for blood pressure quantitative trait loci using differential gene expression and a panel of congenic strains. Hypertens Res 21:289–296

    Article  PubMed  CAS  Google Scholar 

  • Clemitson JR, Pratt JR, Frantz S, Sacks S, Samani NJ (2002) Kidney specificity of rat chromosome 1 blood pressure quantitative trait locus region. Hypertension 40:292–297

    Article  PubMed  CAS  Google Scholar 

  • Clemitson JR, Dixon RJ, Haines S, Bingham AJ, Patel BR et al (2007) Genetic dissection of a blood pressure quantitative trait locus on rat chromosome 1 and gene expression analysis identifies SPON1 as a novel candidate hypertension gene. Circ Res 100:992–999

    Article  PubMed  CAS  Google Scholar 

  • Cowley AW Jr (2006) The genetic dissection of essential hypertension. Nat Rev Genet 7:829–840

    Article  PubMed  CAS  Google Scholar 

  • Cui ZH, Ikeda K, Kawakami K, Gonda T, Nabika T et al (2003) Exaggerated response to restraint stress in rats congenic for the chromosome 1 blood pressure quantitative trait locus. Clin Exp Pharmacol Physiol 30:464–469

    Article  PubMed  CAS  Google Scholar 

  • Cui ZH, Ikeda K, Kawakami K, Gonda T, Masuda J et al (2004) Exaggerated response to cold stress in a congenic strain for the quantitative trait locus for blood pressure. J Hypertens 22:2103–2109

    Article  PubMed  CAS  Google Scholar 

  • Darvasi A (2003) Genomics: Gene expression meets genetics. Nature 422:269–270

    Article  PubMed  CAS  Google Scholar 

  • Deng AY (2007) Genetic basis of polygenic hypertension. Hum Mol Genet 16:R195–202

    Article  PubMed  CAS  Google Scholar 

  • DiPetrillo K, Wang X, Stylianou IM, Paigen B (2005) Bioinformatics toolbox for narrowing rodent quantitative trait loci. Trends Genet 21:683–692

    Article  PubMed  CAS  Google Scholar 

  • Flint J, Mott R (2001) Finding the molecular basis of quantitative traits: successes and pitfalls. Nat Rev Genet 2:437–445

    Article  PubMed  CAS  Google Scholar 

  • Frantz SA, Kaiser M, Gardiner SM, Gauguier D, Vincent M et al (1998) Successful isolation of a rat chromosome 1 blood pressure quantitative trait locus in reciprocal congenic strains. Hypertension 32:639–646

    PubMed  CAS  Google Scholar 

  • Frantz S, Clemitson JR, Bihoreau MT, Gauguier D, Samani NJ (2001) Genetic dissection of region around the Sa gene on rat chromosome 1: evidence for multiple loci affecting blood pressure. Hypertension 38:216–221

    PubMed  CAS  Google Scholar 

  • Garrett MR, Rapp JP (2002) Two closely linked interactive blood pressure QTL on rat chromosome 5 defined using congenic Dahl rats. Physiol Genomics 8:81–86

    PubMed  CAS  Google Scholar 

  • Garrett MR, Meng H, Rapp JP, Joe B (2005) Locating a blood pressure quantitative trait locus within 117 kb on the rat genome: substitution mapping and renal expression analysis. Hypertension 45:451–459

    Article  PubMed  CAS  Google Scholar 

  • Glazier AM, Nadeau JH, Aitman TJ (2002) Finding genes that underlie complex traits. Science 298:2345–2349

    Article  PubMed  CAS  Google Scholar 

  • Gu L, Dene H, Deng AY, Hoebee B, Bihoreau M-T et al (1996) Genetic mapping of two blood pressure quantitative trait loci on rat chromosome l. J Clin Invest 97:777–778

    Article  PubMed  CAS  Google Scholar 

  • Hubner N, Lee YA, Lindpaintner K, Ganten D, Kreutz R (1999) Congenic substitution mapping excludes Sa as a candidate gene locus for a blood pressure quantitative trait locus on rat chromosome 1. Hypertension 34:643–648

    PubMed  CAS  Google Scholar 

  • Hubner N, Wallace CA, Zimdahl H, Petretto E, Schulz H et al (2005) Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat Genet 37:243–253

    Article  PubMed  CAS  Google Scholar 

  • Iwai N, Tsujita Y, Kinoshita M (1998) Isolation of a chromosome 1 region that contributes to high blood pressure and salt sensitivity. Hypertension 32:636–638

    PubMed  CAS  Google Scholar 

  • Jacob HJ, Kwitek AE (2002) Rat genetics: attaching physiology and pharmacology to the genome. Nat Rev Genet 3:33–42

    Article  PubMed  CAS  Google Scholar 

  • Joe B, Garrett MR (2005) Substitution mapping: Using congenic strains to detect genes controlling blood pressure. In: Raizada MK, Kasparov S, Katovich MJ (eds) Cardiovascular Genomics. Totowa, NJ, Humana Press pp 41–58

    Google Scholar 

  • Joe B, Garrett MR (2006) Genetic analysis of inherited hypertension in the rat. In: Dominiczak A, Connell J (eds) Genetics of Hypertension. Amrsteram, The Netherlands, Elsevier Science pp 177–200

    Google Scholar 

  • Joe B, Garrett MR, Dene H, Rapp JP (2003) Substitution mapping of a blood pressure quantitative trait locus to a 2.73 Mb region on rat chromosome 1. J Hypertens 21:2077–2084

    Article  PubMed  CAS  Google Scholar 

  • Joe B, Letwin NE, Garrett MR, Dhindaw S, Frank B et al (2005) Transcriptional profiling with a blood pressure QTL interval-specific oligonucleotide array. Physiol Genomics 23:318–326

    Article  PubMed  CAS  Google Scholar 

  • Kato N, Nabika T, Liang Y-Q, Mashimo T, Inomata H et al (2003) Isolation of a chromosome region affecting blood pressure and vascular disease traits in the stroke-prone rat model. Hypertension 42:1191–1197

    Article  PubMed  CAS  Google Scholar 

  • Kloting I, Voigt B, Kovacs P (1998) Metabolic features of newly established congenic diabetes-prone BB.SHR rat strains. Life Sci 62:973–979

    Article  PubMed  CAS  Google Scholar 

  • Krushkal J, Ferrell R, Mockrin SC, Turner ST, Sing CF et al (1999) Genome-wide linkage analyses of systolic blood pressure using highly discordant siblings. Circulation 99:1407–1410

    PubMed  CAS  Google Scholar 

  • Lee SJ, Cicila GT (2002) Functional genomics in rat models of hypertension: using differential expression and congenic strains to identify and evaluate candidate genes. Crit Rev Eukaryot Gene Expr 12:297–316

    Article  PubMed  CAS  Google Scholar 

  • Lee SJ, Liu J, Qi N, Guarnera RA, Lee SY et al (2003) Use of a panel of congenic strains to evaluate differentially expressed genes as candidate genes for blood pressure quantitative trait loci. Hypertens Res 26:75–87

    Article  PubMed  CAS  Google Scholar 

  • Lee SJ, Liu J, Westcott AM, Vieth JA, DeRaedt SJ et al (2006) Substitution mapping in Dahl rats identifies two distinct blood pressure quantitative trait loci within 1.12- and 1.25-Mb intervals on chromosome 3. Genetics 174:2203–2213

    Article  PubMed  CAS  Google Scholar 

  • Lee NH, Haas BJ, Letwin NE, Frank BC, Luu TV et al (2007) Cross-talk of expression quantitative trait loci within two interacting blood pressure quantitative trait loci. Hypertension 50:1126-1133

    Article  PubMed  CAS  Google Scholar 

  • Liang M, Yuan B, Rute E, Greene AS, Zou AP et al (2002) Renal medullary genes in salt-sensitive hypertension: a chromosomal substitution and cDNA microarray study. Physiol Genomics 8:139–149

    PubMed  CAS  Google Scholar 

  • Liang M, Yuan B, Rute E, Greene AS, Zou AP et al (2003) Insights into Dahl salt-sensitive hypertension revealed by temporal patterns of renal medullary gene expression. Physiol Genomics 12:229-237

    PubMed  CAS  Google Scholar 

  • Malek RL, Wang HY, Kwitek AE, Greene AS, Bhagabati N et al (2006) Physiogenomic resources for rat models of heart, lung and blood disorders. Nat Genet 38:234–239

    Article  PubMed  CAS  Google Scholar 

  • Meng H, Garrett MR, Dene H, Rapp JP (2003) Localization of a blood pressure QTL to a 2.4-cM interval on rat chromosome 9 using congenic strains. Genomics 81:210–220

    Article  PubMed  CAS  Google Scholar 

  • Monti J, Plehm R, Schulz H, Ganten D, Kreutz R et al (2003) Interaction between blood pressure quantitative trait loci in rats in which trait variation at chromosome 1 is conditional upon a specific allele at chromosome 10. Hum Mol Genet 12:435–439

    Article  PubMed  CAS  Google Scholar 

  • Petretto E, Mangion J, Dickens NJ, Cook SA, Kumaran MK et al (2006a) Heritability and tissue specificity of expression quantitative trait loci. PLoS Genet 2:e172

  • Petretto E, Mangion J, Pravanec M, Hubner N, Aitman TJ (2006b) Integrated gene expression profiling and linkage analysis in the rat. Mamm Genome 17:480–489

    Google Scholar 

  • Pravenec M, Kurtz TW (2007) Molecular genetics of experimental hypertension and the metabolic syndrome. From gene pathways to new therapies. Hypertension 49:941–952

    Article  PubMed  CAS  Google Scholar 

  • Pravenec M, Landa V, Zidek V, Musilova A, Kren V et al (2001) Transgenic rescue of defective CD36 ameliorates insulin resistance in spontaneously hypertensive rats. Nat Genet 27:156–158

    Article  PubMed  CAS  Google Scholar 

  • Rapp JP, Garrett MR, Deng AY (1998) Construction of a double congenic strain to prove an epistatic interaction on blood pressure between rat chromosomes 2 and 10. J Clin Invest 101:1591–1595

    Article  PubMed  CAS  Google Scholar 

  • Saad Y, Garrett MR, Lee SJ, Dene H, Rapp JP (1999) Localization of a blood pressure QTL on rat chromosome 1 using Dahl rat congenic strains. Physiol Genomics 1:119–125

    PubMed  CAS  Google Scholar 

  • Saad Y, Garrett MR, Rapp JP (2001) Multiple blood pressure QTL on rat chromosome 1 defined by Dahl rat congenic strains. Physiol Genomics 4:201–214

    PubMed  CAS  Google Scholar 

  • Saad Y, Garrett MR, Manickavasagam E, Yerga-Woolwine S, Farms P et al (2007a) Fine-mapping and comprehensive transcript analysis reveals nonsynonymous variants within a novel 1.17 Mb blood pressure QTL region on rat chromosome 10. Genomics 89:343–353

    Google Scholar 

  • Saad Y, Yerga-Woolwine S, Saikumar J, Farms P, Manickavasagam E et al (2007b) Congenic interval mapping of RNO10 reveals a complex cluster of closely-linked genetic determinants of blood pressure. Hypertension 50:891–898

    Google Scholar 

  • St Lezin E, Griffin KA, Picken M, Churchill MC, Churchill PC et al (1999) Genetic isolation of a chromosome 1 region affecting susceptibility to hypertension-induced renal damage in the spontaneously hypertensive rat. Hypertension 34:187–191

    PubMed  CAS  Google Scholar 

  • Stoll M, Kwitek-Black AE, Cowley AW Jr, Harris EL, Harrap SB et al (2000) New target regions for human hypertension via comparative genomics. Genome Res 10:473–482

    Article  PubMed  CAS  Google Scholar 

  • Weder AB, Delgado MC, Zhu X, Gleiberman L, Kan D et al (2003) Erythrocyte sodium-lithium countertransport and blood pressure: a genome-wide linkage study. Hypertension 41:842–846

    Article  PubMed  CAS  Google Scholar 

  • Xu X, Rogus JJ, Terwedow HA, Yang J, Wang Z et al (1999a) An extreme-sib-pair genome scan for genes regulating blood pressure. Am J Hum Genet 64:1694–1701

    Google Scholar 

  • Xu X, Yang J, Rogus J, Chen C, Schork N (1999b) Mapping of a blood pressure quantitative trait locus to chromosome 15q in a Chinese population. Hum Mol Genet 8:2551–2555

    Google Scholar 

  • Yagil C, Hubner N, Kreutz R, Ganten D, Yagil Y (2003) Congenic strains confirm the presence of salt-sensitivity QTLs on chromosome 1 in the Sabra rat model of hypertension. Physiol Genomics 12:85–95

    PubMed  CAS  Google Scholar 

  • Yao H, Cui ZH, Masuda J, Nabika T (2007) Congenic removal of a QTL for blood pressure attenuates infarct size produced by middle cerebral artery occlusion in hypertensive rats. Physiol Genomics 30:69–73

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Funding from NHLBI/NIH (RO1HL075414) to B. Joe and N. H. Lee is gratefully acknowledged. The authors thank John P. Rapp and George T. Cicila for critical comments on the manuscript.

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Authors and Affiliations

  1. Physiological Genomics Laboratory, Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, OH, 43614, USA

    Edward J. Toland, Yasser Saad, Shane Yerga-Woolwine, Steven Ummel, Phyllis Farms, Ramona Ramdath & Bina Joe

  2. Department of Pharmacology and Physiology, George Washington University, Washington, DC, 20037, USA

    Bryan C. Frank & Norman H. Lee

Authors
  1. Edward J. Toland
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  2. Yasser Saad
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  3. Shane Yerga-Woolwine
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  4. Steven Ummel
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  5. Phyllis Farms
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  6. Ramona Ramdath
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  7. Bryan C. Frank
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  8. Norman H. Lee
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  9. Bina Joe
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Corresponding author

Correspondence to Bina Joe.

Additional information

E. J. Toland and Y. Saad contributed equally to this work.

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Toland, E.J., Saad, Y., Yerga-Woolwine, S. et al. Closely linked non-additive blood pressure quantitative trait loci. Mamm Genome 19, 209–218 (2008). https://doi.org/10.1007/s00335-008-9093-1

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  • DOI: https://doi.org/10.1007/s00335-008-9093-1

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