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Although variants in many genes have previously been shown to be associated with blood pressure (BP) levels, the molecular mechanism underlying these associations are mostly unknown. We identified a multi-allelic T-rich sequence (TRS) in the 3’UTR of  ATP1B1  that varies in length and sequence composition (T 22-27  and T 12 GT  3 GT 6 ). The 3’UTR of  ATP1B1  contains 2 functional polyadenylation signals and the TRS is downstream of the proximal polyadenylation site (A2). Therefore, we hypothesized that alleles of this TRS might influence  ATP1B1  expression by regulating alternative polyadenylation.  In vitro , the T 12 GT  3 GT 6  allele increases polyadenylation at the A2 polyadenylation site as compared to the T 23  allele. Consistent with our hypothesis, the relative abundance of the A2-polyadenylated  ATP1B1  mRNA was higher in human kidneys with at least one copy of the T 12 GT  3 GT 6  allele than in those lacking this allele. The T 12 GT  3 GT 6  allele is also associated with higher systolic BP (beta = 3.3 mmHg,  p  = 0.014) and diastolic BP (beta = 2.4 mmHg,  p  = 0.003) in a European-American population. Therefore, we have identified a novel multi-allelic TRS in the 3’UTR of  ATP1B1  that is associated with higher BP and may mediate its effect by regulating the polyadenylation of the  ATP1B1  mRNA.

A Polymorphic 3’UTR Element in ATP1B1 Regulates Alternative Polyadenylation and Is Associated with Blood Pressure