How do DNA and the environment work together to cause diseases?

Have you ever wondered how all human beings share remarkably similar genetic makeup (99.9% identical) yet every one of us is at different risks for diseases? The human genome is the blueprint for how we are, as it provides the necessary instructions for growth and functions. Genes contain the information needed to produce amino acids–– the building blocks for biological beings. These amino acids influence everything from our physical attributes to our susceptibility to diseases [1].  As such, an individual’s genes and environment are the main determinants when accounting for how prone we are to certain diseases. Indeed, the environment and our genetics play a profound role, further contributing to the phenotypic differences within the human population: especially our vulnerability to diseases such as Alzheimer’s [2]. 

Alzheimer’s disease is a progressive disorder in which its presence is influenced by a complex interplay of genetics and the environment. The brain experiences atrophy, resulting in the loss of brain cells, subsequently causing dementia–– the degeneration of cognitive functions such as memory, thinking, and behavior. Therefore, completing familiar tasks become increasingly difficult [3].

One of the main factors that contribute to Alzheimer’s stems from genetic variations. Researchers have identified more than 80 genes that are associated with this disorder. The apolipoprotein E (APOE) gene, which delivers cholesterol and other fats into the bloodstream, has three common variants: APOE ε2, APOE ε3, and APOE ε4 [3]. The presence of APOE ε2 and ε3 does not escalate the chances of Alzheimer’s in an individual. However, the presence of APOE ε4 is associated with an increased risk of developing Alzheimer’s. Not only do APOE ε4 genes heighten the risk for developing Alzheimer’s, individuals who exhibit this allele tend to develop earlier-onset Alzheimer’s, meaning that symptoms of Alzheimer’s may be prevalent as early as age 65. With these three major alleles, each person inherits two copies of the APOE gene, one from each parent. Therefore, we have six possible combinations of the two alleles: ε2/ ε2, ε2/ε3, ε3/ ε3, ε2/ ε4, and ε4/ε4. Every one of the combinations significantly influence one’s likelihood of succumbing to the disease, with certain combinations carrying a higher risk than others [4, 5]. 

Found on chromosome 19, the APOE genes are surrounded by neighboring genes to make a neighborhood of genes called gene clusters.  With more than 30 single nucleotide variants (SNPS) or genetic variations in the bases of DNA found in the APOE gene cluster, the APOE gene is considered to be a strong determinant for Alzheimer’s. Together, these genes within the cluster cooperate to carry out tasks involving delivering cholesterol through the bloodstream to cells, inflammation, metabolism, viral resistance, and reproduction. Functions they carry out make the APOE gene cluster associated with problems such as hyperlipidemia (high cholesterol), arteriosclerosis (buildup of fats on the artery wall), hypertension (high blood pressure, 140/90mmHg>, normal is 90/60mmHg to 120/80mmHg), obesity, and longevity [5, 6, 7, 8, 9, 10]. In a study done on mice [5], exposure to particulate matter (nPM) in the air, a consequence of air pollution, was found to induce alterations in gene activity during the process of transcribing DNA to RNA molecules. Since mice and humans have evolutionary similarities in the APOE cluster, the study suggests that similar transcriptional responses to air pollution may occur in humans as well.  The exposure of nPM leads to changes in the transcriptional responses of genes within the APOE cluster, significantly affecting how the genes function, therefore causing susceptibility to Alzheimer’s. When transcription of a gene is disrupted, the ribosomes produce the wrongful proteins [11]. It must be mentioned that the expression of APOE clusters varies depending on the tissue in which they are found. These tissue-specific expressions can be tied back to their functions; therefore, we can see expression in organs such as the brain and lungs.  After much exposure to nPM, the study has found that APOE clusters in mouse brain tissues exhibit transcriptional responses, illustrating that their normal expression levels were interrupted. These tissue-specific expressions of APOE clusters suggest that different organs may respond differently to environmental stressors such as nPM particles. In particular, the brain and lungs, being vital organs that may be severely affected by air pollution more than any other organs, are susceptible to changes in APOE cluster expressions due to their roles in overseeing bodily functions. Therefore, the expressions of the APOE cluster and its functions are inhibited by air pollution, which contributes to the interplay of genetics and the environment to induce Alzheimer’s [5].

written by: Peyton Chen 

REFERENCE LIST

1. Henninger, J. (2012, October 2). The 99 Percent… of the Human Genome. Science in the News. https://sitn.hms.harvard.edu/flash/2012/issue127a/ 

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2. Virolainen, S. J., VonHandorf, A., Viel, K. C. M. F., Weirauch, M. T., & Kottyan, L. C. (2022). Gene–environment interactions and their impact on human health. Genes & Immunity, 24(1). https://doi.org/10.1038/s41435-022-00192-6 

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3. Mayo Clinic. (2023, August 30). Alzheimer’s disease - symptoms and causes. Mayo Clinic; Mayo Foundation for Medical Education and Research (MFMER). https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447

4. Alzheimer’s Disease Genetics Fact Sheet. (n.d.). National Institute on Aging. https://www.nia.nih.gov/health/genetics-and-family-history/alzheimers-disease-genetics-fact-sheet#:~:text=One%20well%2Dknown%20gene%20that

5. Haghani, A., Thorwald, M., Morgan, T. E., & Finch, C. E. (2020) via Pubmed. The APOEgene cluster responds to air pollution factors in mice with coordinated expression of genes that differs by age in humans. Alzheimer’s & Dementia, 17(2), 175–190. https://doi.org/10.1002/alz.12230 

6. Lipoprotein (a) Blood Test: MedlinePlus Medical Test. (n.d.). Medlineplus.gov. https://medlineplus.gov/lab-tests/lipoprotein-a-blood-test/#:~:text=Lipoproteins%20are%20particles%20made%20of 

7. Mayo Clinic. (2022, July 1). Arteriosclerosis / Atherosclerosis - Symptoms and Causes. Mayo Clinic; Mayo Clinic Staff. https://www.mayoclinic.org/diseases-conditions/arteriosclerosis-atherosclerosis/symptoms-causes/syc-20350569

8. What Is Hyperlipidemia? Symptoms and Treatment | UPMC. (n.d.). UPMC Heart and Vascular Institute. https://www.upmc.com/services/heart-vascular/conditions-treatments/hyperlipidemia#:~:text=Hyperlipidemia%20defines%20an%20elevated%20level
   
   
9. ‌NHS. (2022, December 12). What is Blood Pressure? https://www.nhs.uk/common-health-questions/lifestyle/what-is-blood-pressure/ 
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11. Possible Explanation for Human Diseases Caused by Defective Ribosomes | College of Natural Sciences. (n.d.). Cns.utexas.edu. https://cns.utexas.edu/news/research/possible-explanation-human-diseases-caused-defective-ribosomes#:~:text=The%20researchers%20found%20that%20the 

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