Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk

Guanosine triphosphate cyclohydrolase 1 (GCH 1) 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 GCH 1 gene, leading mostly to a dominant negative enzyme. However, recent evidence suggests a clinical genetics of GCH 1 beyound these hereditary loss-of-function diseases. That is, a non-coding GCH 1 haplotype has been associated with reduced pain hypersensitivity and with altered vascular endothelial function. Moreover, the presence of the noncoding c 243>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 GCH 1 genetics that is so far known to be related to unfavorable changes of endothelial function and a reduced risk for chronic pain.