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CHAPTER 1

THE PROBLEM AND ITS BACKGROUND

Introduction

The Apolipoprotein A-V (APOA5) plays an important role in regulating the plasma

triglyceride levels, a major risk factor for coronary artery disease. It is a component of

high density lipoprotein and is highly similar to a rat protein that is upregulated in

response to liver injury. Coronary heart disease (CHD) is a severe condition in which

plaque builds up inside the coronary arteries. Over time, plaque hardens and narrows

the coronary arteries, eventually leading to myocardic infarction and mortality.

Triglycerides (TGs) are the major components of plaque and aberrant levels of TGs

significantly correlate with the risk of CHD (Carey 2010).

BACKGROUND OF THE STUDY

Many people nowadays are involved in one particular illness that may affect their

heart or blood vessels. The common disease that affects the heart and vessels is

Cardiovascular Disease, most of the common problem that is related to a process about

heart disease is atherosclerosis. Atherosclerosis is a disease that occurs when plaque

builds up in the arteries' walls. As a result of the buildup, the arteries narrow, making

blood flow more difficult. A blood clot can obstruct blood flow if it forms. Even the

majority of the patients of this disease cause heart attack or stroke.

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More than that there's a condition in Cardiovascular Disease (CVD) and that's

coronary heart disease (CHD). Coronary Heart Disease (CHD) is one of the most

common cardiovascular diseases, with high morbidity and mortality. CHD is sometimes

called ischaemic heart disease or coronary artery disease. Just like the terms in CVD,

CHD happens when your heart's blood supply is blocked or interrupted by a buildup of

fatty substances in the coronary arteries. To say exactly when civilization first became

aware of coronary artery disease (arterial narrowing) is difficult. However, it’s known

that Leonardo da Vinci (1452–1519) investigated coronary arteries. According to

Friedrich Hoffmann (1660–1742), chief professor of medicine at the University of Halle,

noted later that coronary heart disease started in the “reduced passage of the blood

within the coronary arteries,”. (Coleen M. (2018) The History of Heart Disease; et al.

Coronary heart Disease (2020).

Heart disease can happen at any age, according to Fisher, the traditional risk

factors for coronary heart disease are high LDL cholesterol, low HDL cholesterol, high

blood pressure, family history, diabetes, smoking, being postmenopausal for women,

and being over 45 for men. Obesity is another risk factor that should be considered.

“Coronary artery disease begins in childhood, so that by the teenage years, there

is evidence that plaques that will stay with us for life are formed in most people,”.

Furthermore CHD is related to Single Nucleotide Polymorphism (SNP) in such cases,

SNPs are the most common type of genetic variation found in humans. Each SNP

represents a variation in a single DNA building block known as a nucleotide. (Coronary

Artery Disease - Coronary Heart Disease (2015).

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One of the causes of coronary heart disease (CHD) is High lipoprotein (a) and it's

known risk factor for cardiovascular disease and atherosclerosis. The quantity of LP(a)

in your blood is carried down from our parents. Although it is not routinely measured,

screening is advised for people who are at a moderate or high risk of developing

cardiovascular disease.

(Coronary Heart Disease (2020).

Apart from that, there's any Single Nucleotide Polymorphism that is associated

with cardiovascular disease, probably this study was to determine and analyze the

particular Cardiovascular Disease which is that condition is coronary heart disease that

correlates to the genetic polymorphism. According to research, apolipoprotein A5

(APOA5) gene variants are genetic determinants of triglyceride concentrations, which

are a known risk factor for coronary heart disease (CHD). This study sought to

determine whether the APOA5 gene variants -1131T>C, S19W, and 553G>T are

associated with CHD in the populations studied using this quantitative analysis methods

it will help in this study to assess the contribution of APOA5 gene variants to CHD in

different ethnic populations. ( Jianqing, Z., Limin, X., Rong, SG., Yi, H., Yanping, L.,

Danjie, J., Xi, Y., Weifeng, X., Xiaoyan, H., Changzheng, D., Meng, Y., Jiang Fang, L.,

Shiwei, D., (2013).

This research is studying genetics through DNA sequencing and other modern

technology. We can identify the genes with significant and potential carriers of diseases

such as coronary heart disease.

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STATEMENT OF THE PROBLEM

What is the relationship between SNP and cardiovascular disease?

1. Is there a significant relationship between clinvar interpretation and proximity to risk

factor Single Nucleotide Polymorphism (SNP)?

2. Is there a significant relationship between alt. allele frequency and Coronary Artery

Disease incidence in a population?

SIGNIFICANCE OF STUDY

This research is of great significance in the field of public health because

identifying populations at higher risk of common cardiovascular illnesses could lead to

specific prevention programs that reduce people's risk of disease incidence or

continuation. Despite the fact that cardiovascular diseases are mostly preventable, they

are the primary cause of death globally, responsible for over a third of all deaths.

Furthermore, it will benefit some groups and organizations, such as environmental

health, in protecting people and providing communities with healthier environments.

Moreover, this would benefit the entire population because it will help to ensure that

everyone has access to safe and greater care.

SCOPE AND DELIMITATIONS

This study focuses on Analysis of a single nucleotide polymorphism in

apolipoprotein A5 Associated with Cardiovascular Disease. The main purpose of the

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study is to know the correlation between a single nucleotide polymorphism to

Cardiovascular Disease.

The data of this study will only come from one database. The researchers will use

the website of ncbi.nlm.nih.gov in gathering the data. The variables of this study are

single nucleotide polymorphism (snp) , gene, and disease.

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Definition of terms

Apolipoprotein A5(APOA5)- it is clinical significance at present comes largely from

genetic studies showing a consistent association with plasma triglyceride concentrations

Atherosclerosis - is the buildup of fats, cholesterol and other substances in our artery

walls.

Blood Vessel - it delivers blood to organs and tissues in our body.

Blood clot - it is a response to an injury, a cut or injured blood vessel, which stops

bleeding.

Cardiovascular Disease - are a group of disorders of the heart and blood vessels.

Clinvar Interpretation - it is interpretation of genetic change that is extremely difficult.

Deoxyribonucleic Acid (DNA) - it is a signal and information about the tissue of origin

and other.

Heart attack - occurs when the blood flow decreases or stops to the coronary artery of

the heart.

Ischemic Heart Disease- is a condition of recurring chest pain or discomfort that

occurs when a part of the heart does not receive enough blood

Low-density-lipoprotein (LDL) – cholesterol raises our risk for heart disease and

stroke.
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Morbidity - refers to a disease or to the degree that the health condition affects the

patient.

Mortality – it is the proportion of people dying during a given time interval.

Plaque - fatty substances, cholesterol

Single Nucleotide Polymorphism(SNP) - it is a variation in single base pair in a DNA

sequence.

Triglyceride - are lipids (waxy fats) that give energy to our body and the main

constituents of body fat in our body gets from foods we eat.

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References

Carey, V., Bishop L., Laranjo L., Harshfield, B., Kwiat, C., Sacks, F., (2010) Contribution

of High Plasma Triglycerides and Low High-Density Lipoprotein Cholesterol to Residual

Risk of Coronary Heart Disease After Establishment of Low-Density Lipoprotein

Cholesterol Control.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102341/
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CHAPTER 2

REVIEW OF THE RELATED LITERATURE

This chapter presents a review of the review of the related literatures to the Analysis

of single Nucleotide Polymorphism in Apolipoprotein A5 associated with Coronary

Artery Disease. This chapter will help strengthen the claim and importance of the

present study.

Related Literature

(Zhou et al., 2013) this study aims to analyze the Apolipoprotein A5 (APOA5) and the

risk factors of coronary heart disease which is otherwise known for triglycerides, the

common risk of CHD. Other than that this study sought to determine whether the single

nucleotide polymorphisms (SNPs) in the APOA5 gene variants -1131T>C, S19W, and

553G>T are associated with Coronary Heart Disease (CHD) in the populations studied

and it will assess the contribution of APOA5 gene variants to CHD in various ethnic

populations by using meta-analysis. They observed the genetic variants whether it is

significantly with triglyceride (TG) levels and the risk of CHD in different populations.

This study is a huge contribution in studying Analysis of Single Nucleotide

Polymorphism in apolipoprotein A5 Associated with Coronary Heart Disease by knowing

the risk factors. Molecular medicine reports 1175- 1182.

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(Liu, H., 2005) This study was focused on DNA variants in apolipoprotein A5 gene and

coronary heart disease in Chinese. It showed that the common and major risk factor of

cardiovascular disease is plasma triglyceride (TG). Also in this study they searched for

possible associations of the APOA5 gene polymorphisms S19W and −1131T>C with

coronary heart disease (CHD) in a Chinese population. From the observed Chinese

patients they found out that the minor allele 19W was observed only in CHD patients

and not in controls and the minor allele −1131C was significantly higher in CHD patients

than in controls. According to the result they found out that the triglyceride levels were

significantly higher in −1131C carriers than in −1131T. That's why APOA5 genes are

associated with CHD and appear to be two genetic risk factors for CHD susceptibility in

Chinese. This study is good because it shows the gene polymorphism associated with

coronary heart disease. Metabolism 54 (5), 568-572.

(Omrani-Nava V., Amjadi O., and Alizadeh-Navaei R., 2018), the genetic distribution of

TP53 Arg72Pro was significantly varried between patients with CAD and control

participants, and the proline allele has been linked to an increased risk of coronary

artery disease. CAD patients with the Pro allele (whether Pro/Pro or Arg/Pro) had

significantly lower LVEF than those with Arg/Arg. This detrimental effect could be owing

to the proline allele's inflammatory properties. The coexistence of an active acid

phosphatase locus 1 genotype (carrying *B/*C alleles: C/T in codon 43 and C/C in

codon 41) with TP53 Pro/Pro has been shown to enhance the risk of CAD dangers.

Furthermore, based on observed relationships between the two, it appears that the total

incidence of CVD is linked to TP53, the risk is increased in people who have
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autoimmune diseases. This is good because it will help or serve as a guide to better

understand especially the correlation between CAD and SNP.

(Wang Y., Wang X., Li Z., Chen L., Zhou L., Li C., and Ouyang D., 2017), between CAD

and control individuals, the gene distribution of rs2431697 and rs2910164 differed

significantly. Carriers of the T allele in rs2431697 had a higher risk of coronary artery

disease, while carriers of the G allele in rs2910164 had a lower risk. Furthermore, the

gene variation that affects miRNA expression could be a key risk factor for illness

susceptibility. The T allele of the rs2431697 gene was found to increase the risk of

coronary artery disease, which could be due to the T allele promoting miR-146a

production. In our analysis, the allele frequencies of rs2431697 are 19.6 percent and

80.4 percent, respectively, which is similar with another study on the Chinese population

(16.5 percent and 83.5 percent). Another study discovered no link between rs2431697

and miR-146a levels. Those findings were not in line with ours. As a result, the effect of

rs2431697 on miR-146a expression is equivocal, and more research is needed to

validate the SNP's role. Furthermore, rs2910164, which is found near the precursor of

miR-146a, causes low levels of mature miR-146a to be produced. The G allele of

rs2910164 was found to lower the risk of coronary artery disease by downregulating the

production of miR-146, according to multiple studies. Finally, we discovered that the T

allele of rs2431697 was associated with an increased risk of coronary artery disease in

the Chinese population. Meanwhile, we found that having the G allele of the rs2910164

gene reduced the risk of coronary artery disease. This study is well organized and has a
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great help in our research, just as it can be a guide and help in understanding well the

database we will use.

(Slov. Antropol., 2016) this study talks about the APOA5 gene variant and the risk of

Coronary Heart Disease in Slovak Population. They included two variants of APOA5

gene in conducting this study which are: -1131T>C and 553G>T, these variants were

analyzed for association of CHD. It is stated that the single nucleotide polymorphism

553G>T was found to correlate with the severity of CHD. These following variants can

be used to predict a case of cardiovascular disease. As to their results that the gene

–1131T>C is more likely to be a risk of CHD factor the gene 553G>T. This study

showed that gene -1131T>C can be a CHD risk factor in their population. This is a

good study because it can guide us more on the study that we will conduct.

(Zhai Guanghua., Li Meifen., Zhu Chaowang 2010) Functional studies suggest that the

APOA5 −1131T/C polymorphism plays an important role in triglyceride (TG)

metabolism, which is an event contributing to the pathogenesis of coronary artery

disease (CAD). The researchers performed a comprehensive meta-analysis on nine

published studies. Their findings support that the −1131T/C polymorphism of the

APOA5 gene is associated with CAD and the C allele might be a genetic risk factor that

increases susceptibility to CAD. This study can help us to understand more about gene

-1131T/C specially it is connected to coronary artery disease.

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(Shalia, Kavita; Saranath,Dhananjaya; Rayar,Jaipreet: Shah,Vinod K;Mashru,Manoj

R;Sonoji, Surendra L., et al. October 2017) this research aims to study the identification

of a single nucleotide polymorphism (SNP) indicates high risk in acute myocardial

infarction associated with Acute Myocardial Infarction (AMI) in patients using dedicated

chip and validating the identified SNPs in custom-design chips using high-throughput

microarray analysis. The researchers identified SNPs were Validated by genotyping an

additional 160 patients and 179 controls using custom-made illumina Vera Code

GoldenGate, Genotyping Assay. This research analysis was carried out using PLINK

software to pilot phase 98 SNPs preset on 94 genes that were identified with increased

risk of AMI. Five of the SNPs demonstrated association with AMI in the validation

phase. Among these, one SNP rs9978223 in interferon gamma receptor 2 significant P

value. IFNGR2 are the second subunit og the receptore for IFN-gamma, an important

cytokine in inflammatory reactions. Volume146 –issue 4 505-513

(Sekar Kathiresan, M.D., Olle Melander, M.D., Ph.D., Dragi Anevski, Ph.D., Candace

Guiducci, B.S., et al. 2008)This research aims to study if a combination of single-

nucleotide polymorphisms that are associated with blood low-density lipoprotein (LDL)

or high-density lipoprotein (HDL) cholesterol contributes to the risk of cardiovascular

disease. Upon collecting samples, validation and using Cox proportional-hazards

models to determine the time to the first cardiovascular event in relation to the genotype

score, the genotype score was associated with incident cardiovascular disease in

models adjusted for covariates including baseline lipid levels (P<0.001). The use of the

genotype score did not improve the clinical risk prediction, as assessed by the C
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statistic. With this, a genotype score validated SNPs that are associated with

modulation in levels of LDL or HDL cholesterol was an independent risk factor for

incident cardiovascular disease. This also proves that SNP can contribute to the risk of

cardiovascular disease. 358:1240-1249

(Lin., Nunez., Johns., Shiao.,Pamela K., 2017) the purpose of this study is to examine

the association of polymorphism risk subtypes of APOA5 1131 gene and potential

contributing factors of CVD risks in global populations. The results of this study showed

that the frequency of APOA5 1131 CC and TC polymorphisms in Asian populations

(22.2%–52.6%) were higher than that in other populations, including Caucasians and

Eurasians (10.0%–25.0%). The homozygous CC and heterozygous TC genotypes (both

p < .0001) were associated with increased risks for CVD and were higher in many

Western nations, including Canada, Spain, the Czech Republic, Hungary, Turkey,

Egypt, France, and Iran. The CC genotype was associated with greater risks (RR >

2.00, p < .0001) for dyslipidemia and myocardial infarction, whereas RR > 1.00 was

associated with metabolic syndrome, coronary artery disease, and stroke. This is a

great study because it helps us understand the associations among APOA5 1131

polymorphisms, air pollution, and the development of CVDs.

.
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Conceptual Framework
Research Paradigm

INPUT
Process OUTCOME
• Single
Nucleotide • To know about
• Gathering of
Polymorphis the risk factors of
data
m in APOA5 having coronary
• Analyzing and
• Coronary artery disease .
interpretation
Artery To have
of the data
Disease knowledge about
the study.

Figure 1. Research Paradigm

The diagram shows the relationship between the Single Nucleotide Polymorphism in

APOA5 and Coronary Artery Disease . The inputs are the researchers' independent and

dependent variables. First, Single Nucleotide Polymorphism as an independent

variable, and last, Coronary Artery Disease as a dependent variable.

Then, in the process, the researchers will gather the data by analyzing the given

database. The study's likely outcome has been determined by researchers. Learning

about the relationship between the two variables will help you to lower the risk of having

a coronary artery disease.

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Chapter 3

Research Methodology

This chapter presents the strategy that was used by the researchers in

conducting the research. It includes the following research design, sampling and

population, and the instruments that were used in conducting this research.

3.1 Research Design

In order to define the research design, the researchers used the Correlational

research design which studies the relationship between two variables with the help of

statistical analysis (Cresswell, 2009). Interpreting previous statistical data using different

techniques can also be undertaken in quantitative studies. This type of design is

centered on gathering statistical data to generalize it across groups of people to give

details on a particular phenomenon (Barbie, 2010). The purpose of this research is to

determine the variables that are related to the point where a change in one causes a

change in another.

Correlational findings can be used to assess prevalence and correlation between

variables, as well as predict occurrences based on current data and knowledge. It helps

us researchers in identifying the variables with the strongest associations and making

better long-term decisions. It explains our research's value and aim as well it's

application, analysis, and interpretation, with contextualization

The researchers will use a database as their research instrument to gather data to help

them find the results for this study. This study focuses to find if there is a relationship
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between the single nucleotide polymorphism in APOA5 and coronary artery disease.

With the help of the database the researchers shall know their research questions.

3.2 Sampling and Population

The researchers selected population of three countries namely: Turkmenistan,

Kyrgyzstan and Yemen. These are the three countries that the researchers will use to

conduct the database. The researchers will use a website to gather the data that is

needed. With the given database the researchers will be able to determine the

relationship between the alt. allele frequency and Coronary Heart Disease incidence in

a chosen population.

3.3 Research Instruments

To get the right data needed, they used a database from the selected population

of three countries where to conduct the database, it will be followed by alt. allele

frequency of Single Nucleotide Polymorphism to be found out the presence of a

person’s Coronary Artery Disease or the percentage of Coronary Heart Disease on

every population of the country recorded from the study. The three selected countries

were Turkmenistan, Kyrgyzstan and Yemen, these three will be used to study and

determine the significant relationship between alt. allele frequency and Coronary Heart

Disease incidence in a chosen population.

Database is the instrument used in this study because the researcher's can't use

or perform the experiment due to the presence of a pandemic. Furthermore this study is
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said to be done at a site to find out and get the said frequency and percentage of

incidence of the selected population.

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References

Lin., Nunez., Johns., Shiao.,Pamela K., (2017). APOA5 Gene Polymorphisms and

Cardiovascular Diseases Metaprediction in Global Populations.

https://journals.lww.com/nursingresearchonline/Abstract/2017/03000/APOA5_Gene_Pol

ymorphisms_and_Cardiovascular.12.aspx

Zhai Guanghua.,Li Meifen., Zhu Chaowang (2010). APOA5 −1131T/C polymorphism is

associated with coronary artery disease in a Chinese population: a meta-analysis.

https://www.degruyter.com/document/doi/10.1515/CCLM.2011.070/html

Zhou et al., (2013). Apolipoprotein A5 gene variants and the risk of coronary heart

disease: A case‑control study and meta‑analysis.

https://www.spandidos-publications.com/10.3892/mmr.2013.1642

Liu et. Al., (2005). Association between DNA variant sites in the apolipoprotein A5 gene

and coronary heart disease in Chinese.

https://www.sciencedirect.com/science/article/abs/pii/S0026049504004330

Slov. Antropol.,(2016). APOA5 gene variant and the risk of Coronary Heart Disease in

Slovak Population.

https://fns.uniba.sk/fileadmin/prif/biol/kan/SlovAntrop_casopis/2016_19_1/Slovenska_A

ntropologia_19_1.pdf#page=4
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Shalia, Kavita; Saranath,Dhananjaya; Rayar,Jaipreet: Shah,Vinod K;Mashru,Manoj

R;Sonoji, Surendra L., et al. (October 2017) Identification of a single nucleotide

polymorphism indicative of high risk in acute myocardial infarction

https://journals.lww.com/ijmr/Fulltext/2017/46040/Identification_of_a_single_nucleotide_

polymorphism.10.aspx

Sekar Kathiresan, M.D., Olle Melander, M.D., Ph.D., Dragi Anevski, Ph.D., Candace

Guiducci, B.S., et al. (2008) Polymorphisms Associated with Cholesterol and Risk of

Cardiovascular Events

https://www.nejm.org/doi/full/10.1056/NEJMoa0706728

Omrani-Nava V., Amjadi O., and Alizadeh-Navaei R., (2018). TP53 single nucleotide

polymorphism (RS1042522)in Iranian patients with coronary artery disease.

https://www.researchgate.net/publication/326130169_TP53_single_nucleotide_polymor

phism_RS1042522in_Iranian_patients_with_coronary_artery_diseaseWang Y., Wang

X., Li Z., Chen L., Zhou L., Li C., and Ouyang D., (2017) Two Single Nucleotide

Polymorphisms (rs2431697 and rs2910164) of miR-146a Are Associated with Risk of

Coronary Artery Disease.

https://www.researchgate.net/publication/316852453_Two_Single_Nucleotide_Polymor

phisms_rs2431697_and_rs2910164_of_miR-

146a_Are_Associated_with_Risk_of_Coronary_Artery_Disease
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