title: Nucleotide Variants of the BH4 Biosynthesis Pathway Gene GCH1 and the Risk of Orofacial Clefts.
abstract: A deficiency of GTP cyclohydrolase, encoded by the GCH1 gene, results in two neurological diseases: hyperphenylalaninaemia type HPABH4B and DOPA-responsive dystonia. Genes involved in neurotransmitter metabolism and motor systems may contribute to palatogenesis. The purpose of the study was to analyse polymorphic variants of the GCH1 gene as risk factors for non-syndromic cleft lip with or without cleft palate (NSCL/P). Genotyping of nine polymorphisms was conducted in a group of 281 NSCL/P patients and 574 controls. The GCH1 variant rs17128077 was associated with a 1.7-fold higher risk for NSCL/P (95 %CI = 1.224-2.325; p = 0.001). We also found a significant correlation between the rs8004018 and rs17128050 variants and an increased risk of oral clefts (p trend = 0.003 and 0.004, respectively). The best evidence of the global haplotype association was observed for rs17128050 and rs8004018 (p corr = 0.0152). This study demonstrates that the risk of NSCL/P is associated with variants of the GCH1 gene related to BH4 metabolism and provides some evidence of the relationships between morphological/functional shifts in the central nervous system and orofacial clefts.
authors.affiliation: Department of Paediatrics, Institute of Mother and Child, 17a Kasprzaka Str., 01-211, Warsaw, Poland. khozyasz@verco.com.pl.
authors.forename: Kamil K
authors.initials: KK
authors.lastname: Hozyasz
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Adrianna
authors.initials: A
authors.lastname: Mostowska
authors.affiliation: University Clinic of Medical Academy, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Wójcicki
authors.affiliation: Department of Jaw Orthopaedics, Medical University of Lublin, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Lasota
authors.affiliation: Department of Orthodontics, Institute of Dentistry, The Medical University of Warsaw, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zadurska
authors.affiliation: Department of Jaw Orthopaedics, Medical University of Lublin, Lublin, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Dunin-Wilczyńska
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Paweł P
authors.initials: PP
authors.lastname: Jagodziński
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D002971:Cleft Lip / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006136:GTP Cyclohydrolase / Q000096:biosynthesis / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D001708:Biopterins; D006136:GTP Cyclohydrolase; C003402:sapropterin
keywords: GCH1; Individual variability; NSCL/P; Neurotransmitters; Segawa’s disease