Date of Award

5-1-2007

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Integrative Physiology

Department

Graduate School of Biomedical Sciences

First Advisor

Michael L. Smith

Second Advisor

James Caffrey

Third Advisor

Xiangrong Shi

Abstract

Thakre, Tushar P., Single Nucleotide Polymorphisms of the ATP1a2 Gene and Their Effects on Blood Pressure and Other Cardiovascular Variables in African Americans and Caucasian Americans. Doctor of Philosophy (Integrative Physiology), May 2007. Mutations in the 3’ – untranslated region (3’-UTR) of the ATP1a2 gene, which encodes the α2 subunit of Na+-K+-ATPases are reportedly associated with hypertension. This study was initiated: 1) to identify and to determine the frequency of the single nucleotide polymorphism (SNP) responsible for a 3’-UTR restriction fragment length polymorphism (RFLP) of the ATP1a2 gene in African Americans (AAs) and Caucasian Americans (CAs), 2) to test for association of these SNPs with baseline blood pressure, 3) to determine whether pressor responses of cardiovascular variables are affected by these SNPs, and 4) to test whether endothelial dysfunction is associated with these SNPs. RFLP analysis using the BglII restriction enzyme was performed on DNA obstained from 63 normotensive subjects and results were confirmed by sequencing. Responses of blood pressure, heart rate, muscle sympathetic nerve activity (MSNA) and systematic vascular resistance (SVR) to pressor stimuli of two difference origins (cold pressor and hypoxic apnea) were tested in 37 individuals. Endothelin function was tested using ultrasound imaging of the brachial artery. Six SNPs were detected in the sequenced region at mRNA positions G3756C, A3788G, T3849C, G3853A, C3913T and C3915T, of which T3849C, G3853A and C3913T are novel SNPs. Mutant allel frequencies for these SNPs were higher in AAs than in CAs. SNPs at mRNA positions G3756C, G3853A, C3919T and C3915T were associated with baseline blood pressure. The ancestral haplotype G3756G3853AC3913C3915 constructed from these 4 SNPs associated with lower blood pressure in AAs and with higher blood pressure in CAs. Haplotypes GGTT and CATT were associated with higher mean and diastolic blood pressures, respectively in AAs. Responses of blood pressure, MSNA and SVR to the pressor stimuli were not difference across haplotype (p≥0.61). Similarly, no endothelial dysfunction was associated with the SNPs (p≥0.56). Haplotype groups associated with higher baseline blood pressure tended to have higher systemic vascular resistance (SVR), suggesting increased vascular tonicity as a primary mechanism for the higher blood pressure. These data suggest that although SNPs in the 3’-UTF of the ATP1a2 gene and haplotypes constructed from the SNPs affect baseline blood pressure in an ethnic-specific manner at a young age, neither the responses to pressor stimuli nor endothelial function are affected. Thus, these SNPs and haplotypes are associated with an increased arterial pressure that is likely mediated by an increased vascular tone.

Comments

Thakre, Tushar P., Single Nucleotide Polymorphisms of the ATP1a2 Gene and Their Effects on Blood Pressure and Other Cardiovascular Variables in African Americans and Caucasian Americans. Doctor of Philosophy (Integrative Physiology), May 2007. W 4 T364S 2007

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