Medical genetics is a constantly growing and quickly evolving field. When I was in school, we were taught about rare and severe genetically-inherited diseases, but genetic testing was reserved for the extreme cases and was costly for the patient. Nowadays, patients can even test themselves and often interpret their own results.
In my work as a staff physician for a laboratory that specializes in genetic testing, I frequently speak with practitioners who feel it’s an uphill battle to keep up or catch up with the enormous amount of research produced on a daily basis.
Mutations in DNA are the basis for many diseases, from cancer to genetic disorders like hemophilia. However, mutations in DNA are also a driving force behind evolution, and are responsible for genetic variation, both good and bad, within a population. Basically, mutations are part of what make us different from one another.
Not all mutations are created the same way. There can be parts of a chromosome that translocate, or certain genes can be deleted or copied. Large portions of DNA within a gene can be damaged, or there can be a change in a single nucleotide known as a single nucleotide polymorphism (SNP).
SNPs are of particular interest in the medical genetics field because the change made to the gene is often less severe and, even if it results in a decrease in enzyme function, it is usually not enough to stop the organism from reproducing thereby passing the new trait to offspring. Most medical genetic testing of interest is SNP testing, where single changes to the DNA sequence in certain genes can have strong effects on the health of an individual.
The body of knowledge surrounding SNPs and their clinical relevancy is ever growing. Genome Wide Association studies are an approach that involves rapidly scanning genetic markers, such as the gene folate metabolism, across complete sets of DNA, of many people to find genetic variations associated with a particular disease. As more alleles are found to be associated with disease, the more the field of medical genetic testing grows.
When looking to use a genetic test, start with an example of a gene with a risk allele that has been shown to be associated with certain disease manifestations.
The catechol-O-methyltransferase (COMT) gene codes for the essential COMT enzyme, which is involved in the inactivation of catecholamines, such as dopamine, epinephrine, and norepinephrine, according to a 1996 article by Herbert Lachman. It is also described as a key enzyme in the inactivation of catechol estrogens, taking forms of estrogen that are cancer promoting and metabolizing them to 2-methoxyestradiol, which is known to be protective against tumor formation in an 2010 article by Daniela Mier.
Alterations to the rate of this enzyme can have widespread effects in the body. There are three distinct genotypes for this enzyme:
- Intermediate valine/methionine
Look at what these SNP changes do to the amino acid sequence of the protein encodes for the gene. SNPs often cause a change or substitution in an amino acid within the polypeptide chain. In the example of COMT, the gene product or polypeptide sequence can have either a valine or a methionine in a specific position within the chain. This variation can either increase or decrease the COMT enzyme activity, according to Herbert Lachman and Richard Weisnshilboum in a series of articles published in 1996 and 1999, respectively. In every gene there is a “wild type”—if you remember back to your genetics class that means the allele that is most commonly found in the population. For the COMT gene this is valine type.
Changes in the COMT enzyme affect the body, and practitioners should test for it because of its pivotal role in the reduction of neurotransmitters as well as estrogen. This enzyme has far reaching effects on human health. Certain alleles can convey an increase, decrease, or intermediate activity for the COMT enzyme resulting in high, low, or balanced dopamine levels in the brain, which can have an effect on the development of many mood disorders.
In an 2003 article written by Jon-Kar Zubieta, research showed that low dopamine levels, as seen with patients who are homozygous for the valine allele, have been linked to depression. Research conducted by Piotr Janicki in 2013 showed a greater resiliency to stress, and higher pain tolerance. High dopamine levels, which are found in patients that have two copies of the methionine alleles, result in lower resiliency to stress, and lowered pain tolerance, said Janicki.
COMT is also involved in the metabolism of estrogen. During the metabolism of estrogen, intermediates are formed called 2-OHE2 and 4-OHE2. In a 2003 article written by Nehal Lakhani, research showed that catechol estrogens simultaneously stimulate cell proliferation and gene expression via the estrogen receptor, as well as cause DNA damage through their oxidation products. Changes in the level of COMT catalytic activity have been shown in a meta-analysis conducted by Daniel Mier in 2010 to be associated with significant differences in catechol estrogen and methoxy estrogen levels and, thereby, may contribute to individual differences in estrogen associated with breast cancer risk.
The COMT gene is a great example of how the use of medical genetics can be a valuable tool, not only because it helps the practitioner to understand genetic causes of a patient’s symptom picture, but to help formulate a targeted treatment plan. If you have a patient with mental health symptoms and you find that their genotype puts them at risk of having an imbalance in neurotransmitters, then that gives you a great place to start developing a list of recommendations. Through practice and application, medical genetics can become straightforward, easy to use, and help enhance individualized patient care.
- Lachman H et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6:243-250.
- Weinshilboum R et al. Methylation Pharmacogenetics: Catechol-O methyltransferase, Thiopurine Methyltransferase, and Histamine N-Methyltransferase. Annu. Rev. Pharmacol. Toxicol. 1999; 39:19-52.
- Mannisto P and S Kaakkola. Catechol-O-methyltransferase (COMT): Biochemistry, Molecular Biology, Pharmacology, and Clinical Efficacy of the New Selective COMT Inhibitors. Pharm Rev. 1999; 51(4):594-622.
- Dawling S et al. Catechol-O-Methyltransferase (COMT)-mediated Metabolism of Catechol Estrogens: Comparison of Wild-Type and Variant COMT Isoforms. Cancer Res. 2001; 61:6716-6722.
- Janicki PK. Pharmacogenetics of Pain Management. Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. Edited by TR Deers. American Academy of Pain Medicine. 2013.
- Zubieta JK et al. COMT val158met Genotype Affects mu-opioid Neurotransmitter Responses to a Pain Stressor. Science. 2003; 299(5610):1240-1243.
- Mier D et al. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Molecular Psychiatry. 2010; 15:918-927.
- Lakhani NJ et al. 2-methoxyestradiol, a Promising Anticancer Agent. Pharmacotherapy. 2003; 23:165-172.
- Crooke P et al. Estrogen, Enzyme Variants and Breast Cancer: A Risk Model. Cancer Epidemiol Biomarkers Prev 2006;15(9).