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From SNPedia

Magnitude 3
Repute Bad
Summary Two copies of GCH1 variant associated with lower levels of tetrahydrobiopterin
Criteria Gs224/criteria

You have two copies of a GCH1 variant associated with lower levels of tetrahydrobiopterin (BH4) and total biopterins. BH4 is used in the production of several neurotransmitters, including serotonin and dopamine. While many people carry this with no obvious ill effects, it does seem noteworthy.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699614/ reports median plasma BH4 levels in patients with this genotype were reduced by approximately 80%. Several potentially serious health issues could result from an 80% reduction in BH4 levels.

There may not be enough BH4 to convert phenylalanine to tyrosine. Therefore, phenylalanine can build up in body tissue and cause health issues (like high blood pressure).

But, now there may not be enough tyrosine, which is needed to create dopamine. And so then there may not be enough dopamine, which can possibly lead to symptoms SIMILAR to conditions like Fibromyalgia and Parkinson’s (but not actually Parkinson’s). People who have low levels of tyrosine, and therefore low levels of dopamine, sometimes take a supplement called L-tyrosine, which may help the body to produce enough dopamine to alleviate symptoms and feel better. Instead of L-tyrosine, a doctor may instead prescription Levadopa to restore dopamine levels. http://www.livestrong.com/article/25194-symptoms-low-dopamine-levels

There may also not be enough BH4 to help convert tryptophan-hydroxylase to serotonin. And so then there may not be enough serotonin, which can possibly lead to symptoms of anxiety, depression, headaches, insomnia and Fibromyalgia. People who have low levels of serotonin sometimes take a time-release supplement of 5-HTP (5-Hydroxytryptophan). There are lots of warnings on the internet that 5-HTP should NEVER be taken with an SSRI antidepressant. Also, in some cases, SSRI medications can reduce dopamine levels, which can exasperate the symptoms of low-dopamine with gs224, anyway.

Additional studies about this haplotype:

  • Offspring carrying two copies of this haplotype (i.e. gs224) have a three fold increased for being born with neural tube defects, and mothers carrying two copies also have roughly a three fold higher risk of having an offspring with a neural tube defect, based on http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704723/
  • Several publications report that carrying two copies of this haplotype associates with higher pain thresholds (in other words, less pain is felt when a nerve is injured).

Additional reading:

GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. The haplotype rs10483639(C)-rs3783641(A)-rs8007267(T) is associated with lower levels of tetrahydrobiopterin.[PMID 18598896]

"GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus" http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108587#pone-0108587-g004

"Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk" http://www.geneqol-consortium.org/wp-content/uploads/sites/9/2013/07/Doehring_GCH1-and-pain_Mutat-Res-2008.pdf

"Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies" http://www.zora.uzh.ch/56963/1/Blau_MolGenMetab_Diagnosis,_classification,_and_genetics_2011.pdf

The GCH1 gene provides instructions for making an enzyme called GTP cyclohydrolase. The following paper has a lot of information about how a deficiency in BH4 from a GCH1 mutation can ultimately affect the production of serotonin and dopamine.

"Inherited Disorders Affecting Dopamine and Serotonin: Critical Neurotransmitters Derived from Aromatic Amino Acids" http://jn.nutrition.org/content/137/6/1568S.full.pdf

Here is a link to an excellent analysis of gs224, authored by one of the "GCH1discussions" Yahoo Group members: http://groups.yahoo.com/neo/groups/GCH1discussions/conversations/messages/454