Collections > Electronic Theses and Dissertations > Genetic and Pharmacogenetic Associations with Heart Failure Patient Survival

Heart failure (HF) is an enormous public health problem. Survival and beta-blocker response rates in HF patients are highly variable and cannot be accurately predicted by clinical characteristics alone. The sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) dually contribute to HF pathophysiology, and inhibition of these systems by beta-blockers, on average, significantly prolongs HF patient survival. Common, functional genetic variants affect the activity of the SNS and RAAS, but their association with HF patient outcomes has not been fully characterized. Therefore the collective objective of this doctoral dissertation research was to determine the association of common, functional genetic variants in the SNS and RAAS with HF patient survival and beta-blocker survival benefit. Eleven variants from nine genes in the SNS and RAAS were genotyped in 722 HF patients with fluorescent, electrophoretic, and mass spectrometric methods. No variants were independently associated with HF patient survival, but ADBR1 Ser49Gly was significantly associated with beta-blocker survival benefit. Beta-blocker use at baseline was associated with a statistically significant 46% reduction in mortality in Ser49-homozygotes and a non-significant 38% increase in Gly49-carriers. Simple and internally-weighted genetic risk scores were used to assess the additive association of the SNS and RAAS variants with HF patient survival and beta-blocker survival benefit. The genetic risk scores were not associated with either outcome, did not add to the predictability of clinical risk factors, or reclassify HF patients into new mortality risk categories. A recursive partitioning data mining method was used to detect gene-gene interactions associated with HF patient survival and beta-blocker survival benefit. No gene-gene interactions were associated with outcome in all of the patients or specifically the African-Americans, but in the non-African-Americans ADRB1 Ser49-Arg389/ Gly49-Arg389 diplotype interacted with AGTR1 A1166C. In the patients aged less than 60 and treated with beta-blockers, the mortality rate was approximately 3-fold higher if patients had the ADRB1 Ser49-Arg389/Gly49-Arg389 diplotype and carried AGTR1 1166C. The findings in this dissertation research have profound clinical implications. HF patients with a genetic predisposition for high mortality risk or beta-blocker ineffectiveness could be targeted for closer clinical monitoring and/or additional/alternative pharmacologic therapies.