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 result from a deficiency or malfunctioning of this maintenance. Currently, congenic strains were systematically constructed using Dahl salt-sensitive (DSS) and Lewis (LEW) rats not only to define QTLs (i.e. in DSS background), 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 lowered BP on the DSS background, their BP-increasing DSS alleles failed to influence BP in the LEW background. To further prove that the LEW background is resistant and the DSS background is susceptible to the effects of QTLs, BP-increasing alleles of a QTL on Chr 2 were introgressed into the DSS background, and its BP-decreasing alleles into the LEW background. Indeed, there was no BP-decreasing effect on the LEW background while demonstrating a BP-increasing effect on the DSS background. Thus, a genetic regulation of BP QTLs 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 good evidence that a lack of regulation for functions of BP QTLs is a potential underlying cause of hypertension.

Abstract-Quantitative trait loci (QTLs) for blood pressure (BP) were found on chromosome 10 of Dahl salt-sensitive rats and are potentially important to human essential hypertension. But their identities and how they influence BP together were not known. Presently, we first fine mapped existing QTLs, C10QTL1, C10QTL2, and C10QTL3, by constructing congenic strains. In the process, a new QTL, C10QTL4, was identified. Because the intervals harboring C10QTL1 and C10QTL4 contain a maximum of 16 and 10 possible genes, respectively, a limited number of specific gene targets has been identified to be QTLs residing in human homologous regions on chromosome 17. Moreover, because none of these candidates encodes a gene known to influence BP, the 2 QTLs will represent novel genes for BP regulations. Second, we used congenic strains with QTL combinations to analyze the interactions between the QTLs. Consequently, a double combination of C10QTL4 and C10QTL1 possessed the same BP as each of the 2 QTLs alone. BP of a triple combination of C10QTL4, C10QTL1, and C10QTL3 was not different from BP of the C10QTL4 and C10QTL1 double combination. These results demonstrate that C10QTL4, C10QTL1, and C10QTL3 are epistatic to one another in their BP effects. In contrast, when adding C10QTL2 into the triple formation of the 3 QTLs above to create a quadruple QTL combination, BP increased proportionately, indicating that C10QTL2 acts independently of C10QTL4, C10QTL1, and C10QTL3.

Blood pressure (BP) is largely determined by quantitative trait loci (QTLs) in Dahl salt-sensitive (DSS) rats. Little is known about QTLs controlling kidney (K), cardiac (C), and aortic (A) mass (i.e. Km, Cm, and Am, respectively) of DSS rats independent of BP. Their identification can facilitate our understanding of end organ damage. In this work, 36 congenic strains were employed to define QTLs for Km, Cm, and Am either independent of or associated with BP. Five new QTLs, i.e., KmQTLs, that influence Km independent of Cm, Am, and BP were defined. Four new CakmQTLs were defined for Cm, Am, and Km independent of BP. Among them, the CakmC10QTL1 interval contained 13 genes and undefined loci, and none was known to influence the phenotypes in question, paving the way for a novel gene discovery. Among 17 individual QTLs for BP, 14 also affected Cm, Km, and Am, i.e., they are BpcakmQTLs. In contrast, one BpQTL had no effect on Cm, Am, and Kam. Therefore, BP and Cm, Am, and Km have distinct and shared genetic determinants. The discovery of individual Km and Cakm QTLs will likely facilitate the identification of mechanisms underlying renal, cardiac, and/or aortic hypertrophy independent of hypertension.

We studied three possible genotypes at 10 well-defined blood pressure (BP) QTLs using congenic rat lines. The central question was whether the hypertensive or normotensive allele is dominant, or whether there is partial dominance. The congenic strains were employed to investigate the BP effects of alleles originating from normotensive rats in the background of hypertensive Dahl salt-sensitive (DSS) rats. The normotensive alleles at eight QTLs were fully dominant over DSS alleles, which we tentatively interpreted as indicating that DSS rats incurred a loss of function at these loci and that the QTLs produced BP-reducing agents. In contrast, the normotensive allele of only one QTL was recessive over its DSS counterpart, implying a gain of function at this QTL or a null allele involved in generating a BP-elevating agent. Only one locus, C17QTL, had alleles exhibiting partial dominance. These estimates of dominance differ considerably from those obtained by QTL analysis in a F2 cross. This disagreement demonstrates the importance of establishing a cause-effect relationship between a QTL and its phenotypic effect via congenic strains. The dominance relationships suggest pertinent strategies for gene identification and pharmaceutical intervention.