The angiotensin II receptor (Agtr1a): functional regulatory polymorphisms in a locus genetically linked to blood pressure variation in the mouse

Hypertension is a complex trait with multiple genetic determinants. A previous genome-wide linkage study of systolic blood pressure in a mouse genetic backcross implicated a region of chromosome 13 (LOD = 3.3 at 16.0 cM) as a determinant of blood pressure differences between a hereditary low blood pressure strain of Mus musculus (BPL/1) and Mus spretus (SPRET); at this locus, the unexpected effect of the BPL/1 allele was to increase blood pressure. A plausible candidate locus encoding angiotensin II receptor isoform 1a (Agtr1a) is also located at 16.0 cM on chromosome 13. We therefore investigated structural and functional differences at Agtr1a between BPL/1 and SPRET, as well as the BPH/2 strain. Resequencing Agtr1a in the three strains established the exon/intron and proximal promoter structure of the mouse gene. Coding exon 3 spanned 1,960 bp (with 26 SNPs), including the 1,077-bp/359-amino acid ORF (with 5 cSNPs, all of which were synonymous). Promoter sequences revealed a consensus TATA box, conserve...