A polymorphic 3'UTR element in ATP1B1 regulates alternative polyadenylation and is associated with blood pressure

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 co...

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Bibliographic Details
Published in:PloS one 2013-10, Vol.8 (10), p.e76290-e76290
Main Authors: Prasad, Megana K, Bhalla, Kavita, Pan, Zhen Hua, O'Connell, Jeffrey R, Weder, Alan B, Chakravarti, Aravinda, Tian, Bin, Chang, Yen-Pei C
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Adolescent
Adult
Alleles
Binding sites
Biochemistry
Blood
Blood pressure
Blood Pressure - genetics
Dentistry
Diabetes
Electrolytes
Endocrinology
Gene expression
Genes
Genetic Association Studies
Humans
Hypertension
Kidneys
Medicine
Middle Aged
Molecular biology
Molecular chains
mRNA
Nucleotide Motifs
Nutrition
Polyadenylation
Polymorphism, Genetic
Regulatory Sequences, Nucleic Acid
Relative abundance
RNA
RNA, Messenger - genetics
Rodents
Signal transduction
Sodium-Potassium-Exchanging ATPase - genetics
Young Adult
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Summary: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 (T22-27 and T12GT 3GT6). 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 T12GT 3GT6 allele increases polyadenylation at the A2 polyadenylation site as compared to the T23 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 T12GT 3GT6 allele than in those lacking this allele. The T12GT 3GT6 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0076290