RGD Reference Report - Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats. - Rat Genome Database

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Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats.

Authors: Kantachuvesiri, S  Haley, CS  Fleming, S  Kurian, K  Whitworth, CE  Wenham, P  Kotelevtsev, Y  Mullins, JJ 
Citation: Kantachuvesiri S, etal., Kidney Int 1999 Aug;56(2):414-20.
RGD ID: 619627
Pubmed: PMID:10432379   (View Abstract at PubMed)
DOI: DOI:10.1046/j.1523-1755.1999.00571.x   (Journal Full-text)

BACKGROUND: Genetic background has a major influence on the manifestation of multifactorial diseases such as hypertension in which severe complications may be caused through an interaction with additional factors, which may be genetically determined. We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2-27), in which the phenotype is dependent on the genetic background. METHODS: Using a single homozygous TGRmRen2-27 male as transgene donor, we produced two F1 populations with (a) 100% penetrance of MH in progeny heterozygous for the Fischer F344 genetic background and (b) 58.5% penetrance in progeny heterozygous for the Lewis genetic background. To identify the modifier loci affecting the phenotype, a cohort of 252 males was produced by breeding the same single male with Fischer-Lewis F1 females. The progeny were phenotyped for clinical and pathological features of MH. RESULTS: Genome-wide screening and quantitative trait loci (QTL) analysis identified two loci, on chromosome 10 (LOD 4.4) and on chromosome 17 (LOD 3.9) close to the Ace and At1 genes, respectively, which contribute to the lethal MH phenotype. Their influence on mortality was consistent with a multiplicative effect of the two loci. In addition, we found higher plasma angiotensin-converting enzyme activity in progeny receiving the Fischer allele than in progeny receiving the Lewis allele (123.5 +/- 9.5 vs. 91.8 +/- 4.9 U/liter, P < 0.01), suggesting the association of angiotensin-converting enzyme and MH. CONCLUSIONS: Our study demonstrates the application of a transgene as a "major gene" to facilitate the identification of modifier loci, which can affect the phenotype of MH, and reveals Ace and At1 as candidate genes involved in the manifestation of the MH phenotype.



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Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Bp342Rathypertension no_associationIAGP  RGD 
Bp343Rathypertension no_associationIAGP  RGD 
Bp342Ratmalignant hypertension  IAGP  RGD 
Bp343Ratmalignant hypertension  IDA  RGD 
Bp343Ratmalignant hypertension  IAGP  RGD 
Bp342RatPolyuria  IAGP  RGD 
Bp343RatPolyuria  IAGP  RGD 
Bp342Ratvisual epilepsy  IAGP  RGD 
Bp343Ratvisual epilepsy  IAGP  RGD 
1 to 9 of 9 rows

1 to 14 of 14 rows
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Bp342Ratabnormal induced morbidity/mortality  IDA  RGD 
Bp343Ratabnormal induced morbidity/mortality  IDA  RGD 
Bp342Ratabnormal pilomotor reflex  IDA  RGD 
Bp343Ratabnormal pilomotor reflex  IDA  RGD 
Bp342Ratincreased systemic arterial blood pressure no_associationIDA  RGD 
Bp343Ratincreased systemic arterial blood pressure no_associationIDA  RGD 
Bp342Ratlethargy  IDA  RGD 
Bp343Ratlethargy  IDA  RGD 
Bp342Ratmortality/aging  IDA  RGD 
Bp343Ratmortality/aging  IDA  RGD 
Bp342Ratseizures  IDA  RGD 
Bp343Ratseizures  IDA  RGD 
Bp342Ratweight loss  IDA  RGD 
Bp343Ratweight loss  IDA  RGD 
1 to 14 of 14 rows

QTLs
Bp342  (Blood pressure QTL 342) Bp343  (Blood pressure QTL 343)

Strains
LEW/NHsd  (NA) SD-Tg(Ren2)27  (NA)