A loss of genome buffering capacity of Dahl salt-sensitive model to modulate blood pressure as a cause of hypertension

Essential hypertension is a complex trait influenced by multiple genes known as quantitative trait loci (QTLs)for blood pressure (BP). It is not clear, however, what roles these QTLs play in maintaining normotension.Insights gained toward the maintenance of normotension will shed light on how hypertension can resultfrom a deficiency or malfunctioning of this maintenance. Currently, congenic strains were systematicallyconstructed using Dahl salt-sensitive (DSS) and Lewis (LEW) rats not only to define QTLs (i.e. in DSS back-ground), but also to ascertain effects of the same QTLs in preserving normotension (i.e. in LEW background),a first such study. Results showed that although LEW alleles for two QTLs on Chromosome (Chr) 18 loweredBP on the DSS background, their BP-increasing DSS alleles failed to influence BP in the LEW background. Tofurther prove that the LEW background is resistant and the DSS background is susceptible to the effectsof QTLs, BP-increasing alleles of a QTL on Chr 2 were introgressed into the DSS background, and itsBP-decreasing alleles into the LEW background. Indeed, there was no BP-decreasing effect on the LEW back-ground while demonstrating a BP-increasing effect on the DSS background. Thus, a genetic regulation of BPQTLs in the LEW genome inhibits BP changes by nullifying the effects of BP-altering QTLs. In comparison,the DSS genome must have lost the buffering capacity for stabilizing BP. The current work presents goodevidence that a lack of regulation for functions of BP QTLs is a potential underlying cause of hypertension.INTRODUCTIONComplex traits such as hypertension are controlled by multiplegenes (1). It has been believed that each individual geneknown as quantitative trait locus (QTL) exerts a certain amountof blood pressure (BP) effect and multiple of them willaccumulatively contribute to BP (1,2). An added complexityamong BP QTLs was woven by epistatic QTL–QTLinteractions (3–6). However, genetic regulations of BPQTLs themselves are little noticed, and even less understood.A reason for this lack of information on QTL regulationscomes from the fact that a majority of QTLs were localized bythe use of animal models especially the rat employing the con-genic strategy (1,7). So far, almost all congenic strains havebeen generated by replacing a chromosome segment of Dahlsalt-sensitive (DSS) rats with its homologue of a normotensivestrain (8). Few congenic constructions in the oppositedirection have been attempted, i.e. replacing QTL allelesfrom a normotensive strain by those of DSS.There are certain values attributable to congenic strainsso constructed. First, if an insight into the pathogenesis ofhypertension can be gained by studying individual QTLs ofa hypertensive model, the opposite should also be informative,i.e. an insight into the preservation of BP by the same QTL ina normotensive model. Secondly, genetic research of hyper-tension to this day has been mostly confined to locatingQTLs causing hypertension. Mechanisms of retaining normo-tension can provide invaluable insights into what can resisthypertension, and if missing or malfunctioning, can lead tohypertension.With these considerations in mind, we designed currentexperiments. The goal is to define QTL intervals, to establish