Locating a Blood Pressure Quantitative Trait Locus Within 117 kb on the Rat Genome

Abstract

Abstract-Previously, a blood pressure (BP) quantitative trait locus (QTL) on rat chromosome 9 (RNO9) was localized to a Ͻ2.4 cM interval using congenic strains generated by introgressing segments of RNO9 from the Dahl salt-resistant (R) rat into the background of the Dahl salt-sensitive (S) rat. Renal gene expression using Affymetrix gene chips was profiled on S and a congenic strain spanning the 2.4-cM BP QTL interval. This analysis identified 20 differentially expressed genes/expressed sequence tags. Of these, the locus with the greatest differential expression (30-to 35-fold) was regulated endocrine-specific protein 18 (Resp18), which also mapped in the 2.4-cM BP QTL interval. Additional substitution mapping located the QTL to Ͻ0.4 cM or Ϸ493 kb. This newly defined QTL region still included Resp18. Nucleotide variants were identified between S and R genomic DNA of Resp18 in the coding, 5Ј regulatory and 3Ј untranslated regions. The coding sequence variation (T/C) occurs in exon 2 and predicts an amino acid change (Ile/Val) in the protein product. Resp18 was considered a differentially expressed positional candidate for the QTL. To fine-map the BP QTL, we constructed a congenic strain with a smaller introgressed region. Compared with the S rat, this strain (1) had significantly lower BP, (2)

Are IA-2 and RESP18 Involved in Trait of Blood Pressure?

“…3,4 (2) Resp18 and IA-2 may possess an additive effect on BP. This speculation is contrary to the data provided in our report, 1 wherein we have demonstrated that the effects of the QTL gene within the 117-kb region and that of Resp18 are not additive. 1 The amino acid substitution of Resp18 is correct in our report (ie, the sequence variation is from Isoleucine [Ile] to Valine [Val]).…”

“…This speculation is contrary to the data provided in our report, 1 wherein we have demonstrated that the effects of the QTL gene within the 117-kb region and that of Resp18 are not additive. 1 The amino acid substitution of Resp18 is correct in our report (ie, the sequence variation is from Isoleucine [Ile] to Valine [Val]). However, there is a discrepancy in the location of nucleotide coding for this amino acid substitution.…”

“…1 Garrett et al recently demonstrated that a blood pressure (BP) quantitative trait locus (QTL) exists within a newly defined 117-kb QTL region on rat chromosome 9. 2 By using microarray technology, the authors first found that the mRNA of Resp18 (endocrine-specific protein 18) is Ϸ7.27-fold lower in the kidney of S.R(9)x3A congenic rats (Dahl salt-resistant) than that of S rats (Dahl salt-sensitive).…”

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

“…Attempts to identify BP QTLs by gene profiling again proved to be disappointing in experiments based on the comparison of renal gene expression of congenic and DSS strains. In these cases, differentially expressed candidates fell outside the precisely defined QTL intervals in the congenic strains (Moujahidine et al, 2004;Garrett et al, 2005). Thus, they could not be the QTLs in question.…”

“…The search for differential gene expression has recently received considerable attention as a means of finding candidate genes for QTLs (Liang et al, 2003;McBride et al, 2003;Moujahidine et al, 2004;Garrett et al, 2005;Hubner et al, 2005;Yagil et al, 2005). It is easy to understand the tantalizing appeal of such an approach, because it generates gene candidates directly, rapidly and immediately, with apparent performance differentials.…”