University of Groningen
Genetic and lifestyle risks of cardiovascular disease
Said, M. Abdullah
DOI:
10.33612/diss.157192207
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Publication date: 2021
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Said, M. A. (2021). Genetic and lifestyle risks of cardiovascular disease. University of Groningen. https://doi.org/10.33612/diss.157192207
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Cardiovascular disease is the leading cause of morbidity and mortality worldwide1.
Major cardiovascular disorders include coronary artery disease, heart failure, stroke, atrial fibrillation, and hypertension. Of these, coronary artery disease and stroke are responsible for the majority of deaths1. Over the past 5 decades, substantial efforts
have been put into the identification and modification of risk factors leading to cardiovascular diseases. This allowed better primary and secondary prevention, but has also led to the development of pharmacological and interventional therapies, such as percutaneous coronary interventions, that have helped reduce the cardiovascular mortality rates2. Despite these advancements, the pathophysiological mechanisms
underlying cardiovascular diseases remain poorly understood.
As a cornerstone of prevention, behavioral or lifestyle changes are emphasized in current guidelines to reduce the risk of cardiovascular diseases. These changes include cessation of tobacco smoking, regular physical activity, not being overweight or obese, and adhering to a diet with an appropriate energy balance3. Adherence to such
healthy lifestyle factors remains important with the increasingly older population that is at higher risk of cardiovascular disease. However, it is also important for the younger generations, as trends of increasing obesity and type 2 diabetes rates in progressively younger populations4 will very likely result in a future increase of the cardiovascular
disease burden5. This challenge calls for innovative and improved preventive strategies,
for which a better understanding of the pathophysiological mechanisms leading to the development of cardiovascular disease is necessary. Studying the genetic architecture of cardiovascular diseases and their risk factors may aid us in this undertaking.
Over the last two decades, the field of human genetics has provided novel insights in the risk and development of cardiovascular diseases through analyses of genetic variations, biological pathways, and investigations of potential causal links between risk factors and the development of disease. Since the first draft of the human genome was completed in 2003 (Human Genome Project6), there has been a steady progress in
our understanding of the contribution of common genetic variants in the development of cardiovascular disease. Genetic variants, or single nucleotide polymorphisms, are randomly distributed at conception across the genome and have a lifelong effect. It was first assumed that a limited number of common genetic variants would explain much of the risk of non-communicable diseases such as coronary artery disease7,8. Contrary to
these expectations, since 2006, thousands of genetic variants have been identified and put forward by genome wide association studies9. Genome wide association studies test
millions of genetic variants across the genome for their association with a disease or trait of interest. This lead to the recognition of the polygenic nature of complex (cardiovascular) diseases and traits, with both heritable and environmental contributions10, and with
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small effect sizes for the majority of identified genetic variants11. This is the case for not
only the diseases themselves, but also of cardiovascular risk factors. These analyses have helped to increase our understanding of the genetic architecture of many complex diseases and traits. The advancements in the field of genome wide association studies have been aided by the emergence of extremely large biobanks harboring genetic data. Examples are the UK Biobank with ~500.000 participants12 or the Million Veterans
Program with currently over 300.000 participants13, but also international collaborations
of cohort studies that bundle disease- or trait specific data. In addition, the development of high-density genotyping arrays and novel techniques to perform whole exome and genome sequencing allow the accurate determination of millions of variants or entire sequence at a fraction of the costs and time of the Human Genome Project, which cost nearly $3 billion and took 13 years14. These efforts have made it possible to perform
well-powered genome wide association studies to detect variants, both common and rare, associated with complex diseases and traits.
An advantage of the GWAS approach, in comparison to candidate gene studies, is that there are no assumptions about potential causal genes or genetic regions. This allows the potential discovery of new biology. The identification of causal genetic variants and biological pathways may aid not only in our understanding of the pathophysiological mechanisms leading to cardiovascular diseases, but also in risk stratification and development of novel therapies15. An example of how these analyses can lead to novel
therapies is the finding of low lipid levels in individuals of African descent with nonsense variants in the PCSK9 gene16, with consequently reduced risks of myocardial infarction17.
This has made PCSK9 an attractive drug target. Currently, PCSK9-inhibiting monoclonal antibodies have been developed that effectively reduce LDL-C by 50-70%, and also reduce the risk of myocardial infarction and all-cause mortality18. A next generation
of drugs targeting PCSK9 is underway in the form of small interfering RNA (siRNA) molecules, which selectively prevent the intracellular translation of PCSK9 messenger RNA to an actual protein19. Clinical trials with these siRNA molecules show promising
results with long-lasting LDL-C lowering effects20,21.
Furthermore, Mendelian randomization analyses, which use genetic variants that are found in genome wide association studies as instrumental variables, can be performed to investigate the causal relationship between risk factors and diseases22. Hereby it is
possible to determine the direction of effect, but also to estimate the causal effect of the risk factor on the disease development. As a prerequisite for Mendelian randomization, the genetic variants that are used as instrumental variables must be strongly associated with the risk factor of interest23. The correct identification of genetic variants can
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Compared to diseases such as coronary artery disease, these traits and disorders have less strict definitions, which hampers the genome wide association analyses. Nonetheless, behavioral and lifestyle traits are important risk factors of cardiovascular disease. A better understanding of the biology underlying these traits as well as the interplay between genetic variations and lifestyle factors may provide us even more insight into their contributions to the development of cardiovascular disease.
AIMS OF THIS THESIS
The aims of this thesis are to identify novel genetic variants associated with known or suspected risk factors of cardiovascular diseases through genome wide association studies, and to use these genetic variants to investigate potential causal links between these risk factors and cardiovascular disease using Mendelian randomization analyses. This thesis furthermore aims to investigate the interplay between genetic variants and lifestyle factors, and their contributions to the risk of developing cardiovascular disease.
Part I - Genetics of cardiovascular risk factors
In part I of this thesis, I study the potential causal relationship between a variety of known cardiovascular risk factors with cardiovascular disease, and specifically coronary artery disease. In chapter 2, I explore the potential causal link between genetically determined longer telomere lengths and the risk of developing cardiovascular disease, but also cancer. Telomere attrition has been proposed to reflect biological ageing, as the telomeres shorten with each mitotic division26. Shorter telomere length has been
associated with various cardiovascular diseases, including coronary artery disease27,
abdominal aneurysms28, and heart failure29. It has also been associated with cardiovascular
risk factors such as hypertension29, diabetes29, and smoking29. Whether the shortening
of telomeres is the cause or consequence of these diseases and risk factors is however unclear. Using genetic variants identified in a previous genome wide association study, I perform Mendelian randomization analyses to provide further insight into this matter. In chapter 3, I investigate the genetic architecture of lipoprotein(a) concentrations and its causal links with coronary artery disease. Lipoprotein(a) is a LDL-like particle with an apo(a) tail attached via a disulfide bond30. Epidemiological studies and Mendelian
randomization analyses have found associations between higher concentrations of lipoprotein(a) and an increased risk of coronary artery disease31. It is however unknown
whether the potential causal relationship with coronary artery disease is independent of LDL-cholesterol. Lipoprotein(a) concentrations are under the strictest genetic control of all lipoproteins, as the variance is genetically determined for >90%32. So far, however,
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gene locus. This leaves approximately 30% of the variance that remains to be explained, as well as a gap in our knowledge of the causal variants underlying the variance. In this chapter, I therefore characterize the genetic variants associated with lipoprotein(a) concentrations across the entire genome and assess whether the proposed causal link between lipoprotein(a) and coronary artery disease is independent of LDL-C using multivariable Mendelian randomization analyses. Additionally, I perform statistical fine-mapping of the LPA gene locus to identify potential causal variants associated with lipoprotein(a). In Chapter 4, I assess the evidence for a potential causal link between iron parameters and the development of coronary artery disease. The role of iron in the development of cardiovascular disease has been postulated as early as in 1981 in the “iron hypothesis”, in which a protective role of iron depletion in the development of ischemic heart diseases was proposed33. However, epidemiological studies have
provided inconsistent results on this matter, and a recent Mendelian randomization suggested a protective effect of higher iron levels on the development of coronary artery disease34. In this chapter, I further explore the association between iron parameters and
coronary artery disease, using Mendelian randomization analyses with more genetic variants and larger cohorts to provide more insight into the direction of effect.
Part II - Interplay of genetics and lifestyle with cardiovascular disease
In part II, I investigate the interplay between genetic and lifestyle risk components of cardiovascular diseases. In chapter 5, I discuss the current knowledge on the contributions of lifestyle and genetic risk factors on coronary artery disease, review approaches to study their interplay, and suggest potential future perspectives. In
chapter 6, I investigate the added value of combined lifestyle and health behaviours
with genetic risk scores in their association to cardiovascular diseases. It was previously shown that individuals with a high genetic risk of coronary artery disease had a lower relative risk of developing the disease if they adhered to a healthy lifestyle, compared to an unhealthy lifestyle35. This risk modifying effect of lifestyle may however also apply
to other disease. I explore this hypothesis and investigate the risks associated with new-onset coronary artery disease, atrial fibrillation, hypertension, type 2 diabetes, and stroke. In chapter 7 and chapter 8, I continued investigating the risk conferred by lifestyle factors through analyses of the associated genetic variants and causal associations with disease. In chapter 7, I explore the genetic architecture of leisure sedentary behaviors and utilize the identified variants in Mendelian randomization analyses to test for causal links with coronary artery disease. A similar approach is implemented in chapter 8, where I investigate genetic variants associated with caffeine intake. I investigate the
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association between observational caffeine intake with coronary artery disease and type 2 diabetes, but also the association between genetically determined caffeine intake with these disease outcomes through Mendelian randomization analyses.
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