Genetic mapping of two new blood pressure quantitative trait loci in the rat by genotyping endothelin system genes.

The endothelin system, consisting of a series of potent vasoconstrictor peptides and their receptors, is potentially important in the control of blood pressure. We found that the gene coding for endothelin-2 (ET2), also known as vasoctive intestine peptide, cosegregated strongly with systolic blood pressure in a F2 population [F2(S x LEW)] derived from a cross of the Dahl salt-sensitive (S) rat and the Lewis (LEW/NCrlBR) (LEW) rat. The ET2 locus was assigned to rat chromosome 5. The testis-specific histone (HITH) locus also strongly cosegregated with blood pressure in the F2(S x LEW) population and was assigned to rat chromosome 17. Genetic maps of the regions containing the quantitative trait loci (QTL) for blood pressure on chromosomes 5 and 17 were constructed and the QTL were localized using the MAPMAKER/QTL program. The rat genes for endothelin-1, endothelin-3, and endothelin receptor A did not cosegregate with blood pressure in several F2 populations tested and were assigned to rat chromosomes 17, 3, and 19, respectively. Endothelin receptor B cosegregated weakly with blood pressure and was provisionally assigned to rat chromosome 15. We conclude that, in the rat, one new blood pressure QTL is located on chromosome 5 marked by the ET2 locus and another new QTL is located on chromosome 17 near the HITH locus.

[1]  N. Iwai,et al.  Identification of a candidate gene responsible for the high blood pressure of spontaneously hypertensive rats , 1992, Journal of hypertension.

[2]  T. Masaki,et al.  Cloning and expression of rat preproendothelin-3 cDNA. , 1992, Biochemical and biophysical research communications.

[3]  J. Rapp,et al.  Effect of genetic background on cosegregation of renin alleles and blood pressure in Dahl rats. , 1990, American journal of hypertension.

[4]  M. Soller,et al.  Detecting marker-QTL linkage and estimating QTL gene effect and map location using a saturated genetic map. , 1993, Genetics.

[5]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[6]  M. Yanagisawa,et al.  Chromosomal assignments of the human endothelin family genes: the endothelin-1 gene (EDN1) to 6p23-p24, the endothelin-2 gene (EDN2) to 1p34, and the endothelin-3 gene (EDN3) to 20q13.2-q13.3. , 1991, American journal of human genetics.

[7]  R. Alexander,et al.  Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor , 1991, Nature.

[8]  T. Kurtz,et al.  Cosegregation of the renin allele of the spontaneously hypertensive rat with an increase in blood pressure. , 1990, The Journal of clinical investigation.

[9]  M. Lokhandwala,et al.  Cardiovascular dopamine receptors: physiological, pharmacological and therapeutic implications. , 1982, Journal of autonomic pharmacology.

[10]  T. Kurtz,et al.  Linkage of 11β-hydroxylase mutations with altered steroid biosynthesis and blood pressure in the Dahl rat , 1993, Nature Genetics.

[11]  T. Kurtz,et al.  Genetic analysis of alpha2-adrenergic receptors and blood pressure using Dahl salt‐sensitive rats , 1994 .

[12]  D. Ganten,et al.  Molecular genetics of the SA-gene: cosegregation with hypertension and mapping to rat chromosome 1 , 1993, Journal of hypertension.

[13]  G. Levan,et al.  Gene mapping in the rat by mouse-rat somatic cell hybridization: synteny of the albumin and alpha-fetoprotein genes and assignment to chromosome 14. , 1984, Cytogenetics and cell genetics.

[14]  T. Ogihara,et al.  Dahl's salt-resistant normotensive rat has mutations in cytochrome P450(11 beta), but the salt-sensitive hypertensive rat does not. , 1993, The Journal of biological chemistry.

[15]  R. Elston,et al.  Use of the robust sib-pair method to screen for single-locus, multiple-locus, and pleiotropic effects: application to traits related to hypertension. , 1991, American journal of human genetics.

[16]  Sadao Kimura,et al.  A novel potent vasoconstrictor peptide produced by vascular endothelial cells , 1988, Nature.

[17]  R. Eddy,et al.  cDNA cloning and chromosomal assignment of the endothelin 2 gene: vasoactive intestinal contractor peptide is rat endothelin 2. , 1991, Genomics.

[18]  T. Sakurai,et al.  Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor , 1990, Nature.

[19]  J. Rapp,et al.  Renin gene nucleotide sequence of coding and regulatory regions in Dahl rats. , 1993, Clinical and experimental hypertension.

[20]  T. Kurtz,et al.  Cosegregation of Blood Pressure with a Kallikrein Gene Family Polymorphism , 1991, Hypertension.

[21]  G. Lathrop,et al.  Rat gene mapping using PCR-analyzed microsatellites. , 1992, Genetics.

[22]  J. Rapp,et al.  Seven renin alleles in rats and their effects on blood pressure , 1994, Journal of hypertension.

[23]  J. Rapp,et al.  Development and characteristics of inbred strains of Dahl salt-sensitive and salt-resistant rats. , 1985, Hypertension.

[24]  Eric S. Lander,et al.  Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat , 1991, Cell.

[25]  J. Rapp,et al.  Possible Role of 18-Hydroxy-deoxy-corticosterone in Hypertension , 1972, Nature.

[26]  M. Leppert,et al.  The human endothelin-1 gene (EDN1) encoding a peptide with potent vasoactive properties maps distal to HLA on chromosome arm 6p in close linkage to D6S89. , 1993, Cytogenetics and cell genetics.

[27]  Y. Yamori,et al.  A new genetic locus cosegregating with blood pressure in F2 progeny obtained from stroke-prone spontaneously hypertensive rats and Wistar-Kyoto rats , 1993, Journal of hypertension.

[28]  J. Rapp,et al.  Cosegregation of blood pressure with angiotensin converting enzyme and atrial natriuretic peptide receptor genes using Dahl salt–sensitive rats , 1992, Nature Genetics.

[29]  G. Levan,et al.  The gene map of the Norway rat (Rattus norvegicus) and comparative mapping with mouse and man. , 1991, Genomics.

[30]  J. Rapp,et al.  A genetic polymorphism in the renin gene of Dahl rats cosegregates with blood pressure. , 1989, Science.

[31]  T. Ogihara,et al.  A neuropeptide Y locus on chromosome 4 cosegregates with blood pressure in the spontaneously hypertensive rat. , 1993, Biochemical and biophysical research communications.

[32]  M. Yanagisawa,et al.  cDNA cloning, sequence analysis and tissue distribution of rat preproendothelin-1 mRNA. , 1991, Biochemical and biophysical research communications.

[33]  A. Dannenberg,et al.  Progress in the battle against hypertension. Changes in blood pressure levels in the United States from 1960 to 1980. , 1987, Hypertension.

[34]  E. Lander,et al.  Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. , 1989, Genetics.

[35]  T. Kurtz,et al.  Further evidence of the SA gene as a candidate gene contributing to the hypertension in spontaneously hypertensive rat. , 1992, Biochemical and biophysical research communications.

[36]  K. Huebner,et al.  Cloning and chromosomal localization of a human endothelin ETA receptor. , 1991, Biochemical and biophysical research communications.

[37]  P. Insel,et al.  Peripheral adrenergic receptors in hypertension. , 1990, Hypertension.

[38]  E. L. Harris,et al.  SA gene and blood pressure cosegregation using Dahl salt-sensitive rats. , 1993, American journal of hypertension.

[39]  M. Turner,et al.  The hypertensive Y chromosome elevates blood pressure in F11 normotensive rats. , 1993, Hypertension.

[40]  J. Rapp,et al.  Mendelian inheritance of 18- and ll beta-steroid hydroxylase activities in the adrenals of rats genetically susceptible or resistant to hypertension. , 1972, Endocrinology.

[41]  G. M. Lathrop,et al.  Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats , 1991, Nature.

[42]  Jacques S. Beckmann,et al.  Genetic determinants of diastolic and pulse pressure map to different loci in Lyon hypertensive rats , 1993, Nature Genetics.

[43]  T. Ogihara,et al.  Hypotensive effect associated with a phospholipase C-delta 1 gene mutation in the spontaneously hypertensive rat. , 1992, Biochemical and biophysical research communications.

[44]  S. Nakanishi,et al.  Organization, structure, chromosomal assignment, and expression of the gene encoding the human endothelin-A receptor. , 1992, The Journal of biological chemistry.

[45]  P. Hamet,et al.  Restriction Fragment Length Polymorphism Of hsp70 Gene, Localized In The Rt1 Complex, Is Associated With Hypertension In Spontaneously Hypertensive Rats , 1992, Hypertension.

[46]  勝谷 友宏.  Hypotensive effect associated with a phospholipase C-δ1 gene mutation in the spontaneously hypertensive rat , 1993 .

[47]  H. Lodish,et al.  Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.