DNA

New Marker Additions to GPL-SNP1000 DNA Sequencing Profile

BY: MATTHEW PRATT-HYATT, PHD

The number one goal for The Great Plains Laboratory is to provide the best quality results to our clients.  Our GPL-SNP1000 DNA Sequencing Profile has proven to be a great tool in helping provide personalized healthcare to our clients.  The nine pathways we analyze include: methylation, mental health, oxalate metabolism, drug and environmental metabolism/detoxification, gluten sensitivity, cholesterol metabolism, autism risk genes, and transporter gene.  These are crucial biological pathways, which are at the root of many chronic health conditions.  We are now announcing the addition of nine new markers to our already incredibly comprehensive genetic test:

Dopamine Beta Hydroxylase (DBH)
This is an enzyme that catalyzes the oxidation hydroxylation of dopamine to norepinephrine.  DBH can be inhibited by phenolic compounds including those produced by Clostridium species as well as certain organophosphate herbicides and pesticides.  There are two SNPs that can cause decreased activity of DBH.  These are rs2007153 and rs2283123.  These polymorphisms can lead to an increase in dopamine levels and a deficiency in norepinephrine.  Mental health disorders can result because of the imbalance of dopamine and norepinephrine.  Common symptoms can include depression and anxiety.

Paroxonase 1 (PON1)
This is an important enzyme in the metabolism and elimination of many organophosphorus insecticides (PMID: 13032041) and is located mainly in the liver.  PON1 is important in the reduction of atherosclerosis because of its involvement in the protection of high and low density lipoproteins from oxidation.  Individuals with polymorphisms to PON1 are more susceptible to heart disease (PMID: 8675673).  There are two known polymorphisms that can decrease the activity of PON1 and make the individual more susceptible to pesticide exposure, which are Q192R (rs662) and L55M (rs854560).

Hemochromatosis Protein (HFE)
The hemochromatosis gene HFE (high iron) codes for the HFE protein.   This protein is important for regulating the uptake of circulating iron.  This is done by regulating the interaction between transferrin receptor with transferrin.  SNPs to this gene can cause hemochromatosis, a disorder in which the body loads excess iron, which is autosomal recessive.  This means the patient normally needs two bad copies of the gene in order to exhibit symptoms.  There are three SNPs that can lead to hemochromatosis, rs1800562, rs1800730, and rs1799945.  Patients that are homozygous positive for this SNP should have their iron level measured. 

Vitamin K Epoxide Reductase Complex Subunit 1(VKORC1)
This is an enzyme that is necessary for the reduction of vitamin K 2,3-epoxide to its active form, which is important for clotting.  This enzyme is the primary target for the drug warfarin (Coumadin).  The three SNPs that are associated with warfarin sensitivity are rs9923231 (VKORC1*2), rs9934438, and rs8050894.  These polymorphisms can be used in conjuncture with the genotype of Cyp2C9 in order to accurately dose warfarin.

Tryptophan Hydroxylase 2 (TPH2)
This enzyme catalyzes the first and rate-limiting step in the biosynthesis of serotonin. Mutations to this enzyme have been associated with numerous psychiatric diseases including depression, OCD, bipolar disorder, and suicidal behavior.

Major Histocompatibility Complex DQA1 and DQA8
Patients with SNPs to HLA DQA1 and DQA8 have a higher risk of celiac disease.   The HLA-DQA1 and DQA8 are human leukocyte antigen serotype (also called major histocompatibility complex II). The role of this peptide is to present proteins on the surface of cells for identification purposes. This particular serotype presents proteins belonging to a foreign invader on the cells the macrophages, B cells, and dendritic cells in order to activate the helper T cells of the immune system. Proper presentation is critical for immune system activation against pathogens and may possibly be a mediator of autoimmunity.

UDP Glucosyltransferase 1A1 and 1A8 (UGT1A1 and UGT1A8)
These enzymes are important members of the glucuronidation phase II detoxification pathway.  These enzymes catalyze the addition of a glycosyl group from a nucleotide sugar to a small hydrophobic molecule.  The addition of glycosyl groups results in these molecules becoming more water-soluble and easier to excrete. Some of the target molecules for these enzymes include bilirubin, drugs, hormones, and steroids.

The Importance of Genetic Testing for Mental Health

Two weeks ago I talked about how we are starting to move into the age of personalized medicine.  Our goal at The Great Plains Laboratory is to determine what factors lead to chronic illnesses and what treatments may help.  Previously I discussed how the Organic Acids Test (OAT) and the GPL-SNP1000 DNA Sequencing Profile work well together to determine both the risk for and causes of many chronic illnesses and how useful these two tests are in helping practitioners develop individualized treatments.  Last week I specifically discussed the DNA methylation pathway, of the GPL-SNP1000.  This week I am going to go over the mental health pathway of the this same test.  I will talk about what genes are most important, some specific polymorphisms to be aware of, how the OAT can help diagnosis these disorders, and what treatments seem to work best. 

The two most important genes in this pathway are MAO-A (monoamine oxidase A) and COMT (catechol-o-methyltransferase) (Please see Figure 1). Both enzymes are required for metabolizing neurotransmitters critical to mental health. Mutations to either one can have serious consequences relating to how we think, feel, and interpret the world around us.

Figure 1

MAO-A
Monoamine oxidase A is important for the metabolism (breakdown) of biogenic amines such as the neurotransmitters dopamine, norepinephrine, and serotonin (figure 2).  Mutations to this gene have also been linked to depression, borderline personality disorder, and bipolar disorder. 

 

Figure 2

 

There are two different types of polymorphisms involved with MAO-A.  The first type, which is characterized by rs6323 , causes an increase in activity of the enzyme. Rapid metabolism resulting from this mutation causes depletion in the neurotransmitter. This depletion is directly related to the extent of the enzyme activity which can be determined on the Organic Acid test (OAT) by measuring the production of Homovanillic acid (HVA) and Vanillylmandelic acid (VMA) which are the end products of dopamine and epinephrine metabolism (see figure 1).  Patients who are rapid metabolizers will show an increase of HVA of VMA (Figure 3).  Such patients will have a depletion of these neurotransmitters which leads to multiple neurological diseases including depression. Treatment for these polymorphisms includes supporting the methylation pathway which helps to promote the cofactor required for neurotransmitter synthesis and providing neurotransmitter precursors such as tyrosine, B6 and 5-HTP.

Figure 3

A second type of polymorphism to MAO-A is one that decreases activity (rs72554632,  Gln296X), whichcauses a premature stop codon in the gene..  This polymorphismwill lead to a buildup of neurotransmitters, which can lead to the development of Brunner syndrome.  Brunner syndrome is characterized by a decrease of mental capabilities, increased impulsivity, mood swings, and sleep disorders. These individuals will have a decrease of HVA and VMA metabolites on the OAT. Without the benefit of genetic testing, these results could lead a practitioner to treat with neurotransmitter precursors. Increasing neurotransmitters for individuals with this type of mutation would actually exacerbate the condition. Treatments include decreasing the amine containing foods such as fish, cheese, and fruit, taking progesterone to increase MAO; taking inositol(which reduces 5HT2A serotonin receptor), taking riboflavin (increases MAO activity), or taking ginkgo, which has been shown to decrease aggressiveness in MAO-A deficient patients.

COMT
Catechol-O-methltransferase (COMT) is present in the body in two different forms.  The short form is called soluble catechol-O-methyltransferase (S-COMT).  The longer form is called membrane-bound catechol-O-methyltransferase (MB-COMT).   MB-COMT is mainly present in the nerves of the brain, while S-COMT is located in the liver, kidney, and blood.  In the brain, MB-COMT is responsible for degrading neurotransmitters called catecholamines, which include dopamine, epinephrine, and norepinephrine. Therefore the membrane bound form is believed to have a greater affect on mental health, though both forms may be implicated in disease since both are capable of metabolizing catecholamines.

GPL-SNP1000 analyzes six different SNPs for COMT.   Of these, the most extensively studied is a mutation to rs4680 (Val158Met). Despite the many studies available about this mutation, the scientific community is still at odds about the degree to which this mutation causes disease. What is known is that individuals with this mutation have lower activity of the enzyme.  Mutations to COMT will lead to dopamine and epinephrine not being broken down properly, which can be detected by a decrease in the HVA metabolite in the Organic Acids Test.

Figure 4

Interestingly, some individuals may benefit from increased dopamine while others may benefit from less. Dopamine functions differently depending on the area of the brain it is produced in and there are likely other mutation to this gene may also influence its function and expression. These interactions are still being investigated and are why GPL is looking beyond the most common mutation to help inform results.  Conditions associated with these mutations include OCD, depression, and schizophrenia.  Symptomatic patients may benefit from treatment aimed at promoting the enzyme function so that dopamine and epinephrine can be metabolized. This is a SAM dependant enzyme and methylation support can be helpful in patients with this mutation.

APOE
Apolipoprotein E (APOE) combines with lipids in the body to form lipoproteins.  Lipoproteins are responsible for packaging cholesterol and other lipids and carrying them through the bloodstream.  Like so many genes in the human body, this is not its only function. The ApoE protein is involved with more than was originally thought. In this case, it has a role in immune expression, cognitive function, and telomere regulation.  There are four different gene versions of APOE called e1 (the double mutant), e2 (rs7412), e3, and e4 (rs429358).  The most common version is e3, the most detrimental is e4

 Mutations to APOE can lead to an increased risk of developing Alzheimer’s disease. People who inherit even one copy of the APOE e4 allele have an increased risk of developing the disease. Certain mutations to this protein impair the ability of the body to phosphorylate NMDA (glutamate) receptors causing a reduction in activity (Glutamate receptors have been implicated in a number of neuropsychiatric disorders including depression, biopolar disorder, schizophrenia, and Autism (PMID: 12404584, 21315104). While this gene is being extensively studied for its role in Alzheimer’s disease, vulnerable patients may also be predisposed to other psychiatric disorders. (PMID: 25751510, 15557508). Patients with certain ApoE mutations may develop cognitive symptoms well before onset of Alzheimer’s disease (http://psycnet.apa.org/journals/neu/16/2/254/).  Patients with these polymorphisms should look for early signs of the development of Alzheimer’s disease.  Treatment with estrogen has demonstrated some encouraging results.

DAOA
The D-amino acid oxidase activator (DAOA) protein (also known as G72) is a 153 amino acid protein that localizes in the brain, spinal cord, and testis.  This protein is located in the endoplasmic reticulum and the mitochondria cellular compartments.   DAOA is a modulator of D-amino acid oxidase (DAO) activity.  If DAO is hyper activated it can result in a decrease in the D-serine level and hypo function of the NMDA receptor.  Overexpression of DAOA has been found in schizophrenics and those suffering from bipolar disorder.  Mutations to DAOA have been linked to a higher incidence of schizophrenia and bipolar disorder. 

It is important to remember that our genes influence our mental health and well being but do not necessarily determine the eventual outcome. There are countless factors that play an equal role in how we perceive the world including diet and lifestyle.   I believe that understanding the most common mutations and their function is very helpful in diagnosing, treating, and preventing different neurological disorders.  Using the GPL-SNP1000 test in combination with the OAT can further help determine the extent to which our genes are being expressed metabolically. The combination of these two tests can help bring about the best chance to achieve emotional health and physical well being.

Email gplblog@gpl4u.com if you have any questions about this blog post.