Abstract 151: A Polymorphic T-Rich Element in ATP1B1 Is Associated with Blood Pressure and Regulates Alternative Polyadenylation
Genome-wide linkage and association studies of hypertension (HTN) aim to uncover loci that are involved in blood pressure (BP) regulation and the pathophysiology of HTN. However, even when such loci are successfully identified, the mechanism by which the implicated genes increase HTN susceptibility is not well understood. ATP1B1, which encodes the beta subunit of Na+, K+ ATPase, a co-transporter involved in multiple BP-regulating physiological processes, is located within a well-established BP linkage peak. Although a single nucleotide polymorphism (rs12079745) in the 3’UTR of ATP1B1 has previously been shown to be associated with BP levels, the molecular mechanism underlying this association is unknown. We identified a multi-allelic T-rich element (TRE) in the 3’UTR of ATP1B1 that varies in length and sequence composition (T22-27 and T12GT3GT6). The 3’UTR of ATP1B1 contains 2 functional polyadenylation signals and the TRE is downstream of the proximal site (A2). Because U-rich elements (UREs) in 3’UTRs are known to play a role in the cleavage and polyadenylation of mRNA, and ATP1B1 transcripts with shorter 3’UTRs are translationally more efficient, we hypothesized that alleles of this TRE might influence ATP1B1 expression by regulating alternative polyadenylation. Consistent with our hypothesis, the A2-polyadenylated mRNA isoform was more abundant in human kidneys with at least one copy of T12GT3GT6 than in those homozygous for the T22-27 alleles. Functionally, in vitro, we demonstrated that the T12GT3GT6 allele has greater luciferase activity than the T22 allele and that the T12GT3GT6 allele shows increased polyadenylation at the A2 site than the T22 allele. In addition, the TRE element is associated with systolic BP in European Americans of the GenNet network of the NHLBI Family Blood Pressure Program, with the T12GT3GT6 allele being associated with higher BP (effect size = 2.4 mmHg SBP, P = 0.003). Sharing strong linkage disequilibrium with rs12079745, this TRE is likely the functional site underlying the original association. In summary, we have identified a novel multi-allelic TRE in the 3’UTR of ATP1B1. Alleles at this site are associated with HTN and may mediate their effect on BP by regulating polyadenylation of the ATP1B1 mRNA.
- © 2012 by American Heart Association, Inc.