Congenic Interval Mapping of RNO10 Reveals a Complex Cluster of Closely-Linked Genetic Determinants of Blood Pressure

Abstract

Abstract-Genetic dissection of the rat genome for identifying alleles that cause abnormalities in blood pressure (BP) resulted in the mapping of a significant number of BP quantitative trait loci (QTLs). In this study we mapped at least one such BP QTL on rat chromosome 10 (RNO10) as being within the introgressed segment of a S.LEW congenic strain S.LEWx12x2x3x8 spanning 1.34 Mb from 70 725 437 bp to 72 063 232 bp. BP of 3 congenic strains that span shorter segments of this region was additionally examined. Results obtained indicate that LEW alleles that comprise a 375-kb introgressed segment of the congenic strain S.LEWx12x2x3x5 (70 725 437 bp to 71 100 513 bp) increase BP. The magnitude of change in BP exhibited by the 2 strains, S.LEWx12x2x3x8 and S.LEWx12x2x3x5, is the net phenotypic effect of the underlying genetic determinants of BP. In this respect, the current data are superior to previous QTL localization of BP QTL1, which was hypothesized based on differential congenic segments. Genetic dissection using these 2 congenic strains as tools is expected to facilitate further dissection of the regions. Meanwhile, differential congenic segments were used to predict and thereby prioritize regions for candidate gene analysis. Using this approach, 2 distinct regions of 401 kb and 409 kb within S.LEWx12x2x3x8 and a 104 kb region within S.LEWx12x2x3x5 were prioritized for further consideration. Because all of these genetic elements are located within a 1.06-Mb region of RNO10, our study has revealed a remarkable insight into a genomic module comprising very closely-linked, opposing genetic determinants of BP. espite the description of a number of blood pressure (BP) quantitative trait loci (QTLs) in humans, rats, and mice, identities of the underlying genetic determinants conferring susceptibility to hypertension in any species remain largely unknown, [1][2][3][4] with the exception of rat 11-␤-hydroxylase 5,6 and CD36. 7 Linkage analysis and substitution mapping using various rat strain comparisons provide conclusive evidence for the existence of multiple genetic determinants of BP on rat chromosome 10 (RNO10). 8 -32 Located on this chromosome are genes coding for angiotensin-I converting enzyme, nerve growth factor receptor, skeletal myosin heavy polypeptide 3, nitric oxide synthase-2, ATPase-Na ϩ /K ϩ transporting-␤ 2 polypeptide, nicotiniccholinergic receptor-beta polypeptide 1, and protein kinaselysine deficient 4, all of which are appealing candidates for causally controlling BP. However, fine-mapping and/or DNA sequencing has not provided evidence for most of these genes as candidates for BP QTLs, implicating that the identities of the genetic determinants of BP on RNO10 remain elusive. 8 -31 By replacing progressively shorter segments of RNO 10 of the hypertensive Dahl Salt-sensitive (S) rat with corresponding segments from the Lewis (LEW) rat genome, we have previously fine-mapped a BP quantitative trait locus (S.LEW BP QTL1) to a 1.17-Mb region containing 18 genes. 32 None of these genes have any kn...

Blood pressure and proteinuria effects of multiple quantitative trait loci on rat chromosome 9 that differentiate the spontaneously hypertensive rat from the Dahl salt-sensitive rat

“…The effect of these 'protective' alleles is overcome by the effect of the susceptibility alleles, thereby resulting in the phenotype of hypertension. The existence of such protective alleles in both S/jr and SHR rats is well documented by independent laboratories [19,26,27]. These studies also provide proof for the existence of differential causative mechanisms for the observed high BP in each of these hypertensive strains.…”

“…Hypertensive strains also contain alleles that confer resistance to the development of high BP. For example, using congenic strains, the S/jr rat was found to contain genetic elements that account for a lowering BP effect [19,26]. The effect of these 'protective' alleles is overcome by the effect of the susceptibility alleles, thereby resulting in the phenotype of hypertension.…”

Salt Sensitivity of Blood Pressure

“…111 Furthermore, chromosomal regions without coding variants or with variants in intronic segments that may have possible regulatory functions have also been associated with hypertension, but the mechanism of the association remains obscure. [112][113][114] Results of this approach make it clear that the SS phenotype of rats is determined by multiple different genes or by the combination of their effects into a polygenic form of inheritance. An additional contribution of this methodology has been the understanding that components of the SS phenotype (eg, insulin resistance 115 ) or the magnitude of its cardiac 98,116 and renal 99,[117][118][119] target organ damage may be determined by genetic influences distinct from those that control the hypertensive response to salt.…”

Investigating the effect of genetic background on proteinuria and renal injury using two hypertensive strains

“…In either case, the larger the phenotypic effect between the congenic and control animals, the greater the ability to track these differences when performing further congenic strain analysis (i.e., substrains). This is advantageous because the unfortunate reality is that QTL are likely to contain multiple loci that each contribute small-to-modest effects or interact with other loci, making the process of positional cloning difficult (22,38,50). Nevertheless, with persistence, the process from QTL to gene identification is valuable and achievable (2,12,45).…”