Cross-Talk of Expression Quantitative Trait Loci Within 2 Interacting Blood Pressure Quantitative Trait Loci

Abstract

Abstract-Genetic dissection of the S rat genome has provided strong evidence for the presence of 2 interacting blood pressure quantitative trait loci (QTLs), termed QTL1 and QTL2, on rat chromosome 5. However, the identities of the underlying interacting genetic factors remain unknown. Further experiments targeted to identify the interacting genetic factors by the substitution mapping approach alone are difficult because of the interdependency of natural recombinations to occur at the 2 QTLs. We hypothesized that the interacting genetic factors underlying these 2 QTLs may interact at the level of gene transcription and thereby represent expression QTLs or eQTLs. To detect these interacting expression QTLs, a custom QTL chip containing the annotated genes within QTL1 and QTL2 was developed and used to conduct a transcriptional profiling study of S and 2 congenic strains that retain either 1 or both of the QTLs. The results uncovered an interaction between 2 transcription factor genes, Dmrta2 and Nfia. Furthermore, the "biological signature" elicited by these 2 transcription factors was differential between the congenic strain that retained Lewis alleles at both QTL1 and QTL2 compared with the congenic strain that retained Lewis alleles at QTL1 alone. A network of transcription factors potentially affecting blood pressure could be traced, lending support to our hypothesis.

Genetic determinants of hypertension: An update

“…Another use of congenic strains and expression profi ling to investigate blood pressure QTLs was performed by Lee et al [42]. Segments representing two blood pressure QTLs on chromosome 5, originally discovered in SS rats, were introduced from the Lewis rat onto a SS rat background to make congenic strains with one or both QTLs.…”

Molecular networks in Dahl salt-sensitive hypertension based on transcriptome analysis of a panel of consomic rats

“…The consomic or congenic rat strains have well-defined and often small genetic differences from the SS rat. Those strains that exhibit reduced blood pressure salt sensitivity, and/or ameliorated tissue organ injuries, compared with SS become informative model animals for studying genes and pathways involved in these disease processes (4,9,12,18).…”

Closely linked non-additive blood pressure quantitative trait loci

“…Detection of cisacting expression QTLs (eQTLs) is one way of prioritizing * p \ 0.0001 compared to S. SBP = systolic blood pressure; DBP = diastolic blood pressure; PP = pulse pressure; HR = heart rate; bpm = beats/ min candidate gene analysis (Hubner et al 2005;Petretto et al 2006a, b). This approach has been applied extensively to study the inheritance of gene expression differences in inbred, recombinant-inbred, consomic, and congenic rat strains (Aitman et al 1999, Cicila andLee 1998;Hubner et al 2005;Lee and Cicila 2002;Lee et al 2003Lee et al , 2007Liang et al 2002;Malek et al 2006;Petretto et al 2006a, b). Expression QTLs are proposed to represent prototypical targets for a new class of transcription-modulating drugs aimed at treating patients with hypertension and metabolic syndrome (Pravenec and Kurtz 2007).…”