title: Association of common variants in PAH and LAT1 with non-syndromic cleft lip with or without cleft palate (NSCL/P) in the Polish population.
abstract: BACKGROUND
  Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common structural malformation with a complex and multifactorial aetiology. Associations of abnormalities in phenylalanine metabolism and orofacial clefts have been suggested.
  
  
  METHODS
  Eight single nucleotide polymorphisms (SNPs) of genes encoding phenylalanine hydroxylase (PAH) and large neutral l-amino acid transporter type 1 (LAT1), as well as the PAH mutation that is most common in the Polish population (rs5030858; R408W), were investigated in 263 patients with NSCL/P and 270 matched controls using high resolution melting curve analysis (HRM).
  
  
  RESULTS
  We found that two polymorphic variants of PAH appear to be risk factors for NSCL/P. The odds ratio (OR) for individuals with the rs7485331 A allele (AC or AA) compared to CC homozygotes was 0.616 (95% confidence interval [CI]=0.437-0.868; p=0.005) and this association remains statistically significant after multiple testing correction. The PAH rs12425434, previously associated with schizophrenia, was borderline associated with orofacial clefts. Moreover, haplotype analysis of polymorphisms in the PAH gene revealed a 4-marker combination that was significantly associated with NSCL/P. The global p-value for a haplotype comprised of SNPs rs74385331, rs12425434, rs1722392, and the mutation rs5030858 was 0.032, but this association did not survive multiple testing correction.
  
  
  CONCLUSIONS
  This study suggests the involvement of the PAH gene in the aetiology of NSCL/P in the tested population. Further replication will be required in separate cohorts to confirm the consistency of the observed association.
authors.affiliation: Department of Paediatrics, Institute of Mother and Child, Warsaw, Poland. Electronic address: 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; Department of Plastic Surgery, Specialist Medical Center, Polanica Zdroj, 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 Paediatrics, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wołkowicz
authors.affiliation: Department of Jaw Orthopaedics, Medical University of Lublin, Lublin, Poland.
authors.forename: Izabella
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: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip / Q000201:enzymology / Q000235:genetics*; D002972:Cleft Palate / Q000201:enzymology / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D027283:Large Neutral Amino Acid-Transporter 1; D010651:Phenylalanine Hydroxylase
keywords: Cleft lip and palate; LAT1; PAH; Phenylalanine