9p21

The 9p21 locus on chromosome 9 is a critical genetic region associated with coronary artery disease (CAD), myocardial infarction (MI), and various cancers. 

This region encompasses several tumor suppressor genes, including CDKN2A, CDKN2B, and MTAP, which are involved in cell cycle regulation and tumor suppression. 

Variants in these genes have been linked to an increased risk of cancers such as breast cancer, esophageal squamous cell carcinoma (ESCC), endometrial cancer, renal cell carcinoma, colorectal cancer, thyroid cancer, gastric cardia adenocarcinoma, and osteosarcoma. 

The non-coding RNA ANRIL, also located in this region, regulates CDKN2A and CDKN2B expression and influences vascular and inflammatory responses. 

Genetic alterations in 9p21 can lead to the loss of function of these critical genes, contributing to cancer progression and poor response to treatment. Understanding the role of 9p21 in health and disease can aid in developing targeted therapies and improving diagnostic and prognostic tools.

What is 9p21? [11.] 

The 9p21 locus on chromosome 9 is a critical genetic region associated with coronary artery disease (CAD) and myocardial infarction (MI). Discovered through multiple genome-wide association studies in 2007, it remains the most replicated locus for these conditions. 

9p21 also has some associations with cancer and tumorigenesis. 

Genes Located within 9p21 and Their Functions

While many genes are located on the 9p21 locus, some of the more well-researched genes include:

CDKN2A and CDKN2B [9.] 

CDKN2A and CDKN2B are genes that encode cyclin-dependent kinase inhibitors involved in cell cycle regulation. Variants in this region have been linked to several diseases, including CAD, type 2 diabetes, and certain cancers. [9.] 

Canonical pathway modeling identified the cell cycle G1 phase progression pathway as being significantly influenced by the 9p21.3 risk allele. This pathway, regulated by CDKN2A and CDKN2B, is critical for cell proliferation and may promote cardiac hypertrophy and vascular remodeling, increasing CAD risk.

The CDKN2A and CDKN2B genes produce proteins that inhibit cell cycle progression from G1 to S phase by blocking cyclin-dependent kinases 4 and 6.

The non-coding RNA ANRIL, transcribed from the same locus, regulates CDKN2A and CDKN2B expression through epigenetic mechanisms. Variants at 9p21.3 can alter ANRIL expression and splicing, affecting CDKN2A and CDKN2B levels.

The risk allele is associated with decreased CDKN2B expression in heart tissue, potentially leading to increased cell cycle progression and proliferation. This can contribute to adverse cardiac and vascular changes linked to CAD.

Activation of the G1 phase progression pathway in individuals with the 9p21.3 risk allele may lead to a proliferative phenotype, contributing to cardiac hypertrophy and vascular remodeling.

The risk allele also influences genes involved in inflammatory responses, further promoting atherosclerosis and CAD development.

CDKN2A is also a well-known tumor suppressing gene, and alterations in its function are associated with increased risk of tumor growth and a poorer response to cancer treatments. [12.] 

ANRIL, aka rs1333049 C/G [6., 10.] 

ANRIL (Antisense Noncoding RNA in the INK4 Locus) is a long noncoding RNA (lncRNA) transcribed from the chromosome 9p21 region. This locus is strongly associated with coronary artery disease (CAD) and other vascular disorders. 

It plays a critical role in gene regulation within the atherogenic network, impacting atherosclerosis development and progression.

Dysregulation of the CDKN2A and CDKN2B genes, influenced by ANRIL, promotes pathological vascular proliferation and atherosclerosis.

Linear ANRIL isoforms are associated with increased atherosclerosis risk, while circular isoforms generally exhibit protective effects. The balance between these isoforms significantly influences atherosclerotic plaque formation and stability. [10.] 

ANRIL is implicated in inflammatory responses, enhancing the expression of pro-inflammatory genes and contributing to endothelial dysfunction, which is a key factor in atherosclerosis.

ANRIL influences vascular smooth muscle cell (VSMC) proliferation and apoptosis, crucial processes in atherosclerotic plaque development. 

Linear ANRIL tends to promote cell proliferation, while circular ANRIL forms are linked to anti-proliferative and protective effects.

Essentially, ANRIL's expression and isoform balance have potential as biomarkers for diagnosing and predicting CAD risk. Therapeutic strategies targeting ANRIL could involve inhibiting its linear forms or enhancing circular isoforms to mitigate atherosclerosis progression.

MTAP [14.] 

The MTAP enzyme is coded by the MTAP gene on locus 9p21.  MTAP (5'-Methylthioadenosine phosphorylase) is a crucial enzyme in the methionine salvage pathway and acts as a tumor suppressor. 

It is frequently downregulated in various cancers, particularly breast cancer (BC), where its gene is located at chromosome 9p21—a region often deleted in BC. Low MTAP expression is significantly correlated with poor survival and increased recurrence in BC patients. [14.] 

Mechanistically, the downregulation of MTAP leads to increased polyamine levels by activating ornithine decarboxylase (ODC), which in turn promotes tumor growth, migration, invasion, angiogenesis, and metastasis. MTAP's suppression of tumorigenic abilities is evident as its overexpression inhibits these malignant behaviors, while its knockdown enhances them.

Additionally, MTAP knockdown enhances angiogenesis by upregulating MMP2 and VEGFD expression, further contributing to tumor progression.

Beyond BC, MTAP downregulation is observed in other cancers such as leukemia, lymphoma, lung cancer, pancreatic cancer, melanoma, and myxofibrosarcoma. 

These cancers often exhibit either homozygous deletion or promoter methylation of the MTAP gene. 

9p21 in Health and Disease

9p21 Associations with Cardiovascular Health and Disease

9p21 is a well-known gene locus associated with cardiovascular disease, specifically with coronary artery disease (CAD) and myocardial infarction (MI).

The risk allele at 9p21 is common, with an allele frequency of nearly 50%, and increases CAD and MI risk by 20-30% per copy. [11.] 

Approximately 21% of the population is homozygous for this variant, which increases their risk of MI by 1.64 times, and 2.02 times for early-onset cases. [3., 4.] 

Multiple genome-wide association studies (GWAS) have confirmed its association with CAD as well as other cardiovascular diseases such as carotid artery plaque, stroke, aneurysms, peripheral artery disease, heart failure, and cardiovascular mortality, across various populations. [4.] 

9p21 is also associated with carotid atherosclerosis, particularly with plaque formation rather than intima-media thickness. [4.] 

Unlike traditional cardiovascular risk factors, the effect of 9p21 on CAD and MI is not mediated by blood pressure, cholesterol levels, body mass index, or smoking behavior. [3., 11.]

The 9p21 region is devoid of protein-coding genes but includes the noncoding RNA gene ANRIL, which may play a causal role in atherosclerosis. [3., 11.] 

The locus also intersects with regions linked to type 2 diabetes, although the exact mechanisms remain distinct. Research indicates that 9p21 influences vascular structure and the development of atherosclerosis, rather than the acute events of plaque rupture or thrombosis. [11.] 

Overview of Conditions Associated with Alterations in 9p21

Coronary Artery Disease (CAD)

Variants in the 9p21 region are strongly associated with increased risk of CAD. The mechanism is thought to involve promotion of atheroma development, and risk is independent of traditional cardiovascular risk factors. [3., 11.] 

Myocardial Infarction (MI) [6., 10., 11.]

Specific SNPs like rs1333049 are associated with increased MI risk.

Type 2 Diabetes [7.] 

SNPs at the 9p21 locus are also associated with type 2 diabetes (T2D) and insulin resistance (IR), suggesting a possible shared genetic predisposition for both CVD and diabetes.

Specific variants in the 9p21 region linked to diabetes risk include the ANRIL risk allele rs1333049 and rs10757274.   

Various Cancers [5., 12.] 

Various forms of cancer have been associated with loss or alterations in function of genes on the 9p21 locus, including: 

• Breast Cancer

• Esophageal squamous cell carcinoma (ESCC)

• Endometrial cancer (EC), renal cell carcinoma

• Colorectal cancer (CRC), colorectal adenoma (CA)

• Thyroid cancer

• Gastric cardia adenocarcinoma (GCA)

• Osteosarcoma (OS).

These associations likely relate to the role of CDKN2A and CDKN2B in cell cycle regulation, and may also be associated with loss of MTAP function, another tumor suppressor gene.

Ischemic Stroke [1.] 

Some variants in 9p21 may be associated with increased stroke risk.

Aortic Aneurysm [13.] 

The presence of abdominal aortic aneurysms have been linked to 9p21 variants, but not the growth of those aneurysms. 

Periodontal Disease [2.]

Some studies have found associations between 9p21 variants and periodontal disease risk, including aggressive forms of periodontal disease.

Genetic testing can be done in many ways to identify individuals with specific chromosomal or SNP abnormalities.  Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Laboratory Testing for 9p21

Laboratory testing for 9p21 abnormalities plays a crucial role in diagnosing genetic disorders and assessing disease risk.  There are many methods used for laboratory testing of 9p21.

Overview of Testing Methods

Genetic testing involves various methodologies to analyze DNA and chromosomes for medical and research purposes. Here are the primary types:

Polymerase Chain Reaction (PCR): this technique amplifies small DNA samples to detect or measure specific genes or regions. It's widely used for identifying genetic variants associated with diseases.

DNA Sequencing:

Sanger Sequencing: once the standard for clinical DNA sequencing, this method involves marking DNA nucleotides with fluorescent dyes to read sequences. It's precise but limited to short DNA sections and one sample at a time.

Next-Generation Sequencing (NGS): this includes whole exome and whole genome sequencing, capable of analyzing millions of DNA fragments simultaneously. It's used for comprehensive genetic screening to identify mutations across all protein-coding regions (exome) or the entire genetic makeup (genome).

Cytogenetics:

Karyotyping: this traditional method examines the number and structure of chromosomes under a microscope, identifying abnormalities like extra chromosomes or translocations that can lead to diseases such as Down syndrome or chronic myelogenous leukemia.

Fluorescence In Situ Hybridization (FISH): FISH uses fluorescent probes to illuminate specific gene segments on chromosomes, useful for identifying gene amplifications or deletions.

Microarrays: this technology assesses DNA for duplications, deletions, or large identical DNA stretches using fluorescently labeled DNA samples hybridized on a chip, providing detailed chromosomal information.

Gene Expression Profiling: this test measures which genes are active in cells, using RNA from a tissue sample to determine gene activity. It's particularly used in cancer to guide treatment decisions based on the genes expressed by a tumor.

Each of these technologies plays a crucial role in diagnosing genetic disorders, guiding treatment decisions, and advancing our understanding of genetic diseases.

Sample Types

Samples typically include blood, saliva, or tissue samples containing DNA.  Sample collection can be as simple as performing a cheek swab or collecting saliva.

Interpretation of Test Results

Interpreting test results for 9p21 abnormalities requires expertise and an understanding of genetic principles. A positive result indicating a deletion or duplication in the 9p21 region may suggest an increased risk of certain genetic disorders or predisposition to specific health conditions. 

However, the clinical significance of these findings can vary depending on factors such as the size and location of the genetic alteration, as well as the presence of other genetic or environmental factors. 

Genetic counseling is often recommended to help patients and their families understand the implications of test results and make informed decisions regarding healthcare management and treatment options.

FAQ: Understanding 9p21

9p21 is a region on the short arm of chromosome 9 that has been linked to an increased risk of heart disease and other health conditions. This FAQ section addresses common questions about the 9p21 region, its significance, and how to determine if you carry the 9p21 heart attack gene.

What is 9p21?

9p21 is a region located on the short arm (p) of chromosome 9 at position 21. This specific genomic region has been identified as having a significant association with various health conditions, particularly cardiovascular diseases, including an increased risk of heart attacks.

What is the 9p21 Gene?

The 9p21 region does not refer to a single gene but rather a genomic region that contains multiple genes and regulatory elements. 

Key genes within this region include CDKN2A and CDKN2B, which are involved in cell cycle regulation. Variations within this region are linked to an increased risk of coronary artery disease and other cardiovascular conditions.

What is the 9p21 Heart Attack Gene?

The term "9p21 heart attack gene" refers to various genetic variations within the 9p21 region that are associated with an increased risk of heart attacks. 

These variations can influence the function of genes involved in cardiovascular health, leading to a higher likelihood of developing coronary artery disease and experiencing heart attacks.

How do Genetic Variations in the 9p21 Region Affect Heart Disease Risk?

Genetic variations in the 9p21 region can affect the expression and function of nearby genes, such as CDKN2A and CDKN2B. 

These genes play roles in regulating cell growth and inflammation, processes that are critical in the development of atherosclerosis, which can lead to coronary artery disease and heart attacks.

Where Can I Find Out if I Have the Heart Attack Gene 9p21?

To find out if you carry the genetic variations associated with an increased risk of heart attacks in the 9p21 region, you can:

• Consult a healthcare provider: they can refer you to a genetic counselor or specialist.

• Undergo genetic testing: this can be done through clinical laboratories or direct-to-consumer genetic testing services that include cardiovascular risk panels.

• Participate in research studies: some studies offer genetic testing as part of their research into cardiovascular health.

How is Genetic Testing for 9p21 Variations Conducted?

Genetic testing for 9p21 variations involves collecting a DNA sample, usually through a blood draw or a saliva or cheek swab. The sample is then analyzed in a laboratory to identify the presence of specific genetic variants associated with increased heart disease risk.

What are the Implications of Having the 9p21 Heart Attack Gene?

If you carry the genetic variations in the 9p21 region associated with an increased risk of heart attacks, it does not guarantee that you will develop heart disease. 

However, it indicates a higher risk. Understanding your genetic risk can help you and your healthcare provider make informed decisions about lifestyle changes, preventive measures, and monitoring for cardiovascular health.

Can Lifestyle Changes Reduce the Risk Associated with 9p21 Genetic Variations?

Yes, lifestyle changes can help reduce the overall risk of heart disease, even if you carry the 9p21 genetic variations. Recommendations include:

• Eating a heart-healthy diet: eat a diet rich in fruits, vegetables, whole grains, and lean proteins.

• Regular exercise: engage in physical activity most days of the week.

• Avoiding smoking: quit smoking and avoid exposure to secondhand smoke.

• Managing stress: incorporate stress-reducing techniques such as meditation and relaxation exercises.

• Regular health check-ups: monitor blood pressure, cholesterol levels, and other cardiovascular risk factors.

When Should I Consult a Healthcare Provider about 9p21 Genetic Testing?

You should consult a healthcare provider if you have a family history of heart disease, are concerned about your cardiovascular risk, or are considering genetic testing for 9p21 variations. A healthcare provider or genetic counselor can provide personalized advice and help you understand the potential benefits and limitations of genetic testing.

How Can I Stay Informed about Research and Developments Related to 9p21?

Stay informed by following scientific publications, attending relevant medical conferences, and monitoring updates from research institutions and health organizations. Journals focused on cardiology, genetics, and public health often publish the latest findings on 9p21 and cardiovascular risk research.

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