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

Abstract

An F 2 population (n = 151) derived from Dahl salt-sensitive (S) and Lewis rats was raised on a 8% NaCl diet for 9 weeks and analyzed for blood pressure quantitative trait loci (QTL) by use of a whole genome scan. Chromosomes 5 and 10 yielded lod scores for linkage to blood pressure that were significant; chromosomes 1, 2, 3, 8, 16, 17, and 18 gave lod scores suggestive for linkage. Chromosome 7 gave a significant signal for heart weight with a lesser effect on blood pressure. Congenic strains were constructed by introgressing Lewis low-blood-pressure QTL alleles for chromosomes 1, 5, 10, and 17 into the S genetic background. Congenic strains for chromosomes 1, 5, and 10 had significantly lower blood pressure than S, proving the existence of QTL on these chromosomes, but the chromosome 17 congenic strain failed to trap a contrasting QTL allele. The QTL allele increasing blood pressure originated from S rats for all QTL except those on chromosomes 2 and 7 in which the Lewis allele increased blood pressure. Interactions between each QTL and every other locus in the genome scan yielded significant interactions between chromosomes 10 and 4, and between chromosomes 2 and 3.More than 30 years ago, Dahl et al. (1963) selectively bred rats for sensitivity (S rats) and resistance (R rats) to the hypertensive effect of a high-salt (NaCl) diet. Inbred strains of S and R rats were subsequently developed from Dahl's selectively bred lines (Rapp and Dene 1985). These strains are the prototypic animal model for studying salt-induced hypertension.S rats develop hypertension even on a low-salt diet, but this is markedly exacerbated by increased salt intake (Dahl et al. 1963;Rapp and Dene 1985). Chromosomal regions containing blood pressure quantitative trait loci (QTL) have been detected by the candidate gene approach starting in 1972 with a biochemical genetic marker for steroid 11␤-hydroxylase Dahl 1972a, 1976), and then in 1989 when restriction fragment-length polymorphisms first became available (Rapp et al. 1989). More recently, additional chromosomal regions containing blood pressure QTL were identified around candidate genes by use of Dahl rats and more modern genetic markers

Congenic Rats For Hypertension: How Useful Are They For The Hunting Of Hypertension Genes?

“…To clarify this point, it is essential to make congenics with transferred regions wide enough to entrap QTL, as was done for several QTL of DS. [12][13][14] In this context, we constructed a congenic rat in which we transferred a large segment covering a 100 : 1 support interval of the chromosome 1 QTL (Fig. 2b).…”

“…[12][13][14] However, not much experimental data are available with which to evaluate this hypothesis; only two sets of reciprocal congenics have been studied to date. 4,5,9 One of them was made for the Sa locus using SHR and WKY rats.…”

Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

“…In brief, male Garrett et al (1998) Abbreviations: Chr, chromosome; DSS, Dahl salt-sensitive strain; LEW, Lewis strain; MNS, Milan normotensive strain. Norm strain refers to the contrasting normotensive rat strain involved in localizing the QTL.…”

“…Consequently, F 2 linkage analysis cannot reveal how many QTLs are present within such a 20-cM intervals: it is incapable of separating closely linked QTLs. For example, our previous work revealed the presence of a QTL in a 46-cM region on rat Chr 10 (Deng and Rapp, 1995;Garrett et al, 1998), whereas, in fact, there are four QTLs in this segment. Three of them are clustered within a section of less than 15 cM (Palijan et al, 2003b;Charron et al, 2005a).…”

“…One of these models is Dahl salt-sensitive (DSS) rats (Dahl et al, 1962). We previously (Garrett et al, 1998) analyzed a single F 2 population derived from crosses of DSS with normotensive Lewis (LEW) rats and localized multiple QTLs, each of which accounted for 4.8-17.8% of total variance in the population. These results suggested that certain QTLs might have minor (e.g.…”