Studies on the genetics of heart failure

Perttu Päiviö Salo

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Heart failure is a complex clinical syndrome, most often caused by ischemic, hypertensive, and valvular heart disease. In this thesis, we studied how genetic variation contributes to hypertension and acute coronary syndrome, the most frequent causes of heart failure. We also studied the role of genetic variation in Takotsubo cardiomyopathy, a disease which still remains poorly understood and often presents with transient heart failure. To identify trait-associated genetic variants, we analyzed several population-based samples of Finns using genetic association tests. Three of the four publications constituting this thesis are genome-wide association studies (GWAS). In the first study, we identified variants near the PRDM6 gene, which associated with both higher systolic blood pressure and a higher risk of intracranial aneurysms. This result was one of the first to show a shared genetic background for blood pressure and intracranial aneurysms. Based on data on the function of PRDM6 and other trait associations in the locus, we hypothesize that the genetic variants at this locus increase systolic blood pressure and aneurysm risk via an effect on the proliferation of smooth muscle cells in the arterial wall. In the second study, we performed a GWAS separately on the two subtypes of myocardial infarction in acute coronary syndrome, the ST- segment elevation and non-ST-segment elevation myocardial infarctions (STEMI and NSTEMI). Genetic variation near DRAM2, encoding a protein participating in the regulation of autophagy, increased the risk of NSTEMI with little to no effect on the risk of STEMI. This finding is rather surprising, given that both infarction types are mostly the result of the same disease process, namely coronary heart disease. The third study addressed atrial and B-type natriuretic peptides (ANP and BNP), which are secreted by cardiomyocytes, both during normal homeostasis and especially during acute heart failure. We identified a new locus near the calcineurin subunit gamma gene PPP3CC, which was 7associated with the ratio of the circulating concentrations of active BNP and the N-terminal fragment of the proBNP prohormone. Based on the genetic results, we also showed that the data specifically supports the blood- pressure-lowering effect of ANP in the general population, and not that of BNP. In the fourth study, we studied the possible genetic background of Takotsubo cardiomyopathy. The cause of this condition is currently unknown but a contribution of genetic variation has been suggested in previous literature. We could not replicate previous genetic findings in the disease to show that if genetic predisposition exists, it is similar to that of complex diseases, such as acute coronary syndromes, with small absolute risks conferred by each of multiple genetic risk variants. The results of this thesis provide new information on the molecular basis of the two most common causes of heart failure: hypertension and acute coronary syndromes. They also limit plausible genetic models that are compatible with observational data for Takotsubo cardiomyopathy.
Original languageEnglish
Supervisors/Advisors
  • Perola, Markus, Supervisor
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-4170-5
Electronic ISBNs978-951-51-4171-2
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • Heart Failure
  • +genetics
  • Non-ST Elevated Myocardial Infarction
  • ST Elevation Myocardial Infarction
  • Acute Coronary Syndrome
  • Intracranial Aneurysm
  • Hypertension
  • Takotsubo Cardiomyopathy
  • Blood Pressure
  • Natriuretic Peptides
  • Natriuretic Peptide, Brain
  • Atrial Natriuretic Factor
  • Muscle Proteins
  • Transcription Factors
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • 3121 Internal medicine
  • 3111 Biomedicine

Cite this

Salo, P. P. (2018). Studies on the genetics of heart failure. Helsinki: Helsingin yliopisto.
Salo, Perttu Päiviö. / Studies on the genetics of heart failure. Helsinki : Helsingin yliopisto, 2018. 125 p.
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year = "2018",
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Salo, PP 2018, 'Studies on the genetics of heart failure', Helsinki.

Studies on the genetics of heart failure. / Salo, Perttu Päiviö.

Helsinki : Helsingin yliopisto, 2018. 125 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Studies on the genetics of heart failure

AU - Salo, Perttu Päiviö

N1 - M1 - 125 s. + liitteet

PY - 2018

Y1 - 2018

N2 - Heart failure is a complex clinical syndrome, most often caused by ischemic, hypertensive, and valvular heart disease. In this thesis, we studied how genetic variation contributes to hypertension and acute coronary syndrome, the most frequent causes of heart failure. We also studied the role of genetic variation in Takotsubo cardiomyopathy, a disease which still remains poorly understood and often presents with transient heart failure. To identify trait-associated genetic variants, we analyzed several population-based samples of Finns using genetic association tests. Three of the four publications constituting this thesis are genome-wide association studies (GWAS). In the first study, we identified variants near the PRDM6 gene, which associated with both higher systolic blood pressure and a higher risk of intracranial aneurysms. This result was one of the first to show a shared genetic background for blood pressure and intracranial aneurysms. Based on data on the function of PRDM6 and other trait associations in the locus, we hypothesize that the genetic variants at this locus increase systolic blood pressure and aneurysm risk via an effect on the proliferation of smooth muscle cells in the arterial wall. In the second study, we performed a GWAS separately on the two subtypes of myocardial infarction in acute coronary syndrome, the ST- segment elevation and non-ST-segment elevation myocardial infarctions (STEMI and NSTEMI). Genetic variation near DRAM2, encoding a protein participating in the regulation of autophagy, increased the risk of NSTEMI with little to no effect on the risk of STEMI. This finding is rather surprising, given that both infarction types are mostly the result of the same disease process, namely coronary heart disease. The third study addressed atrial and B-type natriuretic peptides (ANP and BNP), which are secreted by cardiomyocytes, both during normal homeostasis and especially during acute heart failure. We identified a new locus near the calcineurin subunit gamma gene PPP3CC, which was 7associated with the ratio of the circulating concentrations of active BNP and the N-terminal fragment of the proBNP prohormone. Based on the genetic results, we also showed that the data specifically supports the blood- pressure-lowering effect of ANP in the general population, and not that of BNP. In the fourth study, we studied the possible genetic background of Takotsubo cardiomyopathy. The cause of this condition is currently unknown but a contribution of genetic variation has been suggested in previous literature. We could not replicate previous genetic findings in the disease to show that if genetic predisposition exists, it is similar to that of complex diseases, such as acute coronary syndromes, with small absolute risks conferred by each of multiple genetic risk variants. The results of this thesis provide new information on the molecular basis of the two most common causes of heart failure: hypertension and acute coronary syndromes. They also limit plausible genetic models that are compatible with observational data for Takotsubo cardiomyopathy.

AB - Heart failure is a complex clinical syndrome, most often caused by ischemic, hypertensive, and valvular heart disease. In this thesis, we studied how genetic variation contributes to hypertension and acute coronary syndrome, the most frequent causes of heart failure. We also studied the role of genetic variation in Takotsubo cardiomyopathy, a disease which still remains poorly understood and often presents with transient heart failure. To identify trait-associated genetic variants, we analyzed several population-based samples of Finns using genetic association tests. Three of the four publications constituting this thesis are genome-wide association studies (GWAS). In the first study, we identified variants near the PRDM6 gene, which associated with both higher systolic blood pressure and a higher risk of intracranial aneurysms. This result was one of the first to show a shared genetic background for blood pressure and intracranial aneurysms. Based on data on the function of PRDM6 and other trait associations in the locus, we hypothesize that the genetic variants at this locus increase systolic blood pressure and aneurysm risk via an effect on the proliferation of smooth muscle cells in the arterial wall. In the second study, we performed a GWAS separately on the two subtypes of myocardial infarction in acute coronary syndrome, the ST- segment elevation and non-ST-segment elevation myocardial infarctions (STEMI and NSTEMI). Genetic variation near DRAM2, encoding a protein participating in the regulation of autophagy, increased the risk of NSTEMI with little to no effect on the risk of STEMI. This finding is rather surprising, given that both infarction types are mostly the result of the same disease process, namely coronary heart disease. The third study addressed atrial and B-type natriuretic peptides (ANP and BNP), which are secreted by cardiomyocytes, both during normal homeostasis and especially during acute heart failure. We identified a new locus near the calcineurin subunit gamma gene PPP3CC, which was 7associated with the ratio of the circulating concentrations of active BNP and the N-terminal fragment of the proBNP prohormone. Based on the genetic results, we also showed that the data specifically supports the blood- pressure-lowering effect of ANP in the general population, and not that of BNP. In the fourth study, we studied the possible genetic background of Takotsubo cardiomyopathy. The cause of this condition is currently unknown but a contribution of genetic variation has been suggested in previous literature. We could not replicate previous genetic findings in the disease to show that if genetic predisposition exists, it is similar to that of complex diseases, such as acute coronary syndromes, with small absolute risks conferred by each of multiple genetic risk variants. The results of this thesis provide new information on the molecular basis of the two most common causes of heart failure: hypertension and acute coronary syndromes. They also limit plausible genetic models that are compatible with observational data for Takotsubo cardiomyopathy.

KW - Heart Failure

KW - +genetics

KW - Non-ST Elevated Myocardial Infarction

KW - ST Elevation Myocardial Infarction

KW - Acute Coronary Syndrome

KW - Intracranial Aneurysm

KW - Hypertension

KW - Takotsubo Cardiomyopathy

KW - Blood Pressure

KW - Natriuretic Peptides

KW - Natriuretic Peptide, Brain

KW - Atrial Natriuretic Factor

KW - Muscle Proteins

KW - Transcription Factors

KW - Genome-Wide Association Study

KW - Genetic Predisposition to Disease

KW - 3121 Internal medicine

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-4170-5

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - Helsingin yliopisto

CY - Helsinki

ER -

Salo PP. Studies on the genetics of heart failure. Helsinki: Helsingin yliopisto, 2018. 125 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 20/2018).