Dissecting Epistatic QTL for Blood Pressure in Rats: Congenic Strains versus Heterogeneous Stocks, a Reality Check

Both linkage and use of congenic strains have shown that a chromosome region near the gene for the Na-K-ATPase α1-subunit ( Atp1a1) contained a quantitative trait locus (QTL) for blood pressure (BP). Currently, two congenic strains, designated S.M5 and S.M6, were made by replacing a segment of the Dahl salt-sensitive SS/Jr (S) rat by the homologous region of the Milan normotensive rat (MNS). In S.M5, the gene for Atp1a1 is from the MNS strain; whereas in S.M6, Atp1a1 is from the S strain. The baseline activity of the α1-Na-K-ATPase and its stoichiometry were evaluated by an assay of ouabain-sensitive inwardly and outwardly directed 86Rb and 22Na fluxes in erythrocytes. The two congenic strains showed a similar BP, but both had a BP lower than that of S rats ( P < 0.0001). Neither the α1-Na-K-ATPase activity nor its stoichiometry was affected by the substitution of the Atp1a1 alleles of S by those of MNS. Thus the BP-lowering effects observed in S.M5 and S.M6 could not be attributed to the α1-Na-K-ATPase activity or its stoichiometry. Atp1a1 is not supported as a candidate to be a BP QTL.

Download Full-text

Genome Scan and Congenic Strains for Blood Pressure QTL Using Dahl Salt-Sensitive Rats

Genome Research ◽

10.1101/gr.8.7.711 ◽

1998 ◽

Vol 8 (7) ◽

pp. 711-723 ◽

Cited By ~ 119

Author(s):

Michael R. Garrett ◽

Howard Dene ◽

Roxanne Walder ◽

Qian-Yun Zhang ◽

George T. Cicila ◽

...

Keyword(s):

Blood Pressure ◽

Genome Scan ◽

Congenic Strains

Download Full-text

Reciprocal rat chromosome 2 congenic strains reveal contrasting blood pressure and heart rate QTL

Physiological Genomics ◽

10.1152/physiolgenomics.00065.2002 ◽

2002 ◽

Vol 10 (3) ◽

pp. 199-210 ◽

Cited By ~ 25

Author(s):

Adamu Alemayehu ◽

Laura Breen ◽

Drahomira Krenova ◽

Morton P. Printz

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Spontaneously Hypertensive Rat ◽

Cardiovascular Responses ◽

Chromosome 2 ◽

Spontaneously Hypertensive ◽

Congenic Strains ◽

Multiple Blood ◽

Wistar Kyoto ◽

Chromosome Segments

Evidence exists implying multiple blood pressure quantitative trait loci (QTL) on rat chromosome 2. To examine this possibility, four congenic strains and nine substrains were developed with varying size chromosome segments introgressed from the spontaneously hypertensive rat (SHR/lj) and normotensive Wistar-Kyoto rat (WKY/lj) onto the reciprocal genetic background. Cardiovascular phenotyping was conducted with telemetry over extended periods during standard salt (0.7%) and high-salt (8%) diets. Our results are consistent with at least three independent pressor QTL: transfer of SHR/lj alleles to WKY/lj reveals pressor QTL within D2Rat21-D2Rat27 and D2Mgh10-D2Rat62, whereas transfer of WKY/lj D2Rat161-D2Mit8 to SHR/lj reveals a depressor locus. Our results also suggest a depressor QTL in SHR/lj located within D2Rat161-D2Mgh10. Introgressed WKY/lj segments also reveal a heart rate QTL within D2Rat40-D2Rat50 which abolished salt-induced bradycardia, dependent upon adjoining SHR/lj alleles. This study confirms the presence of multiple blood pressure QTL on chromosome 2. Taken together with our other studies, we conclude that rat chromosome 2 is rich in alleles for cardiovascular and behavioral traits and for coordinated coupling between behavior and cardiovascular responses.

Download Full-text

Complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl rat chromosome 17

Physiological Genomics ◽

10.1152/physiolgenomics.00275.2004 ◽

2005 ◽

Vol 21 (1) ◽

pp. 112-116 ◽

Cited By ~ 19

Author(s):

Myrian Grondin ◽

Vasiliki Eliopoulos ◽

Raphaelle Lambert ◽

Yishu Deng ◽

Anita Ariyarajah ◽

...

Keyword(s):

Blood Pressure ◽

Quantitative Trait Locus ◽

Quantitative Trait ◽

Congenic Strain ◽

Chromosome 17 ◽

Congenic Strains ◽

Genome Wide ◽

A Genome ◽

Trait Locus ◽

Negative Controls

Linkage studies suggested that a quantitative trait locus (QTL) for blood pressure (BP) was present in a region on chromosome 17 (Chr 17) of Dahl salt-sensitive (DSS) rats. A subsequent congenic strain targeting this QTL, however, could not confirm it. These conflicting results called into question the validity of localization of a QTL by linkage followed by the use of a congenic strain made with an incomplete chromosome coverage. To resolve this issue, we constructed five new congenic strains, designated C17S.L1 to C17S.L5, that completely spanned the ±2 LOD confidence interval supposedly containing the QTL. Each congenic strain was made by replacing a segment of the DSS rat by that of the normotensive Lewis (LEW) rat. The only section to be LL homozygous is the region on Chr 17 specified in a congenic strain, as evidenced by a total genome scan. The results showed that BPs of C17S.L1 and C17S.L2 were lower ( P < 0.04) than that of DSS rats. In contrast, BPs of C17S.L3, C17S.L4, and C17S.L5 were not different ( P > 0.6) from that of DSS rats. Consequently, a BP QTL must be located in an interval of ∼15 cM shared between C17S.L1 and C17S.L2 and unique to them both, as opposed to C17S.L3, C17S.L4, and C17S.L5. The present study illustrates the importance of thorough chromosome coverage, the necessity for a genome-wide screening, and the use of “negative” controls in physically mapping a QTL by congenic strains.

Download Full-text

Chromosome 2 Reciprocal Congenic Strains to Evaluate the Effect of the Genetic Background on Blood Pressure

Scottish Medical Journal ◽

10.1177/003693300204700104 ◽

2002 ◽

Vol 47 (1) ◽

pp. 7-9 ◽

Cited By ~ 3

Author(s):

F.J. Carr ◽

C.D. Negrin ◽

J.S. Clark ◽

D Graham ◽

M.W. Mcbride ◽

...

Keyword(s):

Blood Pressure ◽

Genetic Background ◽

Chromosome 2 ◽

Congenic Strains

Download Full-text

DISSECTING QUANTITATIVE TRAIT LOCI INTO OPPOSITE BLOOD PRESSURE EFFECTS ON DAHL RAT CHROMOSSOME 8 BY CONGENIC STRAINS

Journal of Hypertension ◽

10.1097/00004872-200402001-00528 ◽

2004 ◽

Vol 22 (Suppl. 1) ◽

pp. S124

Author(s):

A. Ariyarajah ◽

A. Palijan ◽

J. Dutil ◽

A. Deng

Keyword(s):

Blood Pressure ◽

Quantitative Trait Loci ◽

Quantitative Trait ◽

Pressure Effects ◽

Congenic Strains ◽

Trait Loci ◽

Blood Pressure Effects

Download Full-text

Multiple blood pressure loci on rat chromosome 13 attenuate development of hypertension in the Dahl S hypertensive rat

Physiological Genomics ◽

10.1152/physiolgenomics.00280.2006 ◽

2007 ◽

Vol 31 (2) ◽

pp. 228-235 ◽

Cited By ~ 59

Author(s):

Carol Moreno ◽

Mary L. Kaldunski ◽

Tao Wang ◽

Richard J. Roman ◽

Andrew S. Greene ◽

...

Keyword(s):

Blood Pressure ◽

Renal Damage ◽

High Salt ◽

Male Rats ◽

Brown Norway ◽

High Salt Diet ◽

Salt Diet ◽

Chromosome 13 ◽

Congenic Strains ◽

Multiple Blood

Previous studies have indicated that substitution of chromosome 13 of the salt-resistant Brown Norway BN/SsNHsdMcwi (BN) rat into the genomic background of the Dahl salt-sensitive SS/JrHsdMcwi (SS) rat attenuates the development of salt-sensitive hypertension and renal damage. To identify the regions within chromosome 13 that attenuate the development of hypertension during a high-salt diet in the SS rat, we phenotyped a series of overlapping congenic lines covering chromosome 13, generated from an intercross between the consomic SS-13BN rat and the SS rat. Blood pressure was determined in chronically catheterized rats after 2 wk of high-salt diet (8% NaCl) together with microalbuminuria as an index of renal damage. Four discrete regions were identified, ranging in size from 4.5 to 16 Mbp, each of which independently provided significant protection from hypertension during high-salt diet, reducing blood pressure by 20–29 mmHg. Protection was more robust in female than male rats in some of the congenic strains, suggesting a sex interaction with some of the genes determining blood pressure during high-salt diet. Among the 23 congenic strains, several regions overlapped. When three of the “protective” regions were combined onto one broad congenic strain, no summation effect was seen, obtaining the same decrease in blood pressure as with each one independently. We conclude from these studies that there are four regions within chromosome 13 containing genes that interact epistatically and influence arterial pressure.

Download Full-text