Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk.
Guanosine triphosphate cyclohydrolase 1 (GCH1) is the first enzyme in the tetrahydrobiopterin (BH4) biosynthesis, an important co-factor for the formation of nitric oxide, biogenic amines and serotonin. Hereditary diseases such as DOPA-responsive dystonia and atypical phenylketonuria are known to be caused by coding or splice-site mutations in the GCH1 gene, leading mostly to a dominant negative enzyme. However, recent evidence suggests a clinical genetics of GCH1 beyond these hereditary loss-of-function diseases. That is, a non-coding GCH1 haplotype has been associated with reduced pain hypersensitivity and with altered vascular endothelial function. Moreover, the presence of the non-coding c.*243C>T variant in the 3'-untranslated region (3'-UTR) of the GCH1 gene has been associated with mildly increased heart rate and blood pressure. Here, we show that carriers of the pain-protective GCH1 haplotype also carry the c.*243C>T variant and vice versa. We thus demonstrate that apart from the coding or splice-site variants causing DOPA-responsive dystonia and atypical phenylketonuria, there is a common clinically relevant GCH1 genetics that is so far known to be related to unfavorable changes of endothelial function and a reduced risk for chronic pain.
pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany.
Alexandra
A
Doehring
Charalambos
C
Antoniades
Keith M
KM
Channon
Irmgard
I
Tegeder
Jörn
J
Lötsch
D020413:3' Untranslated Regions; D002318:Cardiovascular Diseases / Q000235:genetics*; D004730:Endothelium, Vascular / Q000503:physiopathology; D006136:GTP Cyclohydrolase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D010146:Pain / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk
D020413:3' Untranslated Regions; D006136:GTP Cyclohydrolase