Polymorphic variants of genes related to arginine metabolism and the risk of orofacial clefts.
OBJECTIVE
Maternal mid-pregnancy low levels of symmetric dimethylarginine and newborn low levels of citrulline are suspected to be risk factors for orofacial clefts. This study was undertaken to investigate the involvement of polymorphic variants of genes related to arginine metabolism in the susceptibility of clefting.


METHODS
PCR-RFLP and HRM analyses were used to analyze single nucleotide polymorphisms (SNPs) of ASS1, ASL, and SLC25A13 in 172 children with non-syndromic cleft lip with or without cleft palate (CL/P) and 188 controls without congenital anomalies. The differences in allele and genotype frequencies between cases and controls were determined using standard Chi-square and Fisher exact tests. The odds ratio (OR) and associated 95% confidence intervals (95% CI) for individuals with CL/P versus controls were also calculated. Associations between the investigated polymorphisms and the risk of being born with an orofacial cleft were tested using the nonparametric and genetic model-free Multifactor Dimensionality Reduction (MDR) approach.


RESULTS
Analysis of five SNPs of the ASS1 gene revealed that the G allele of rs7860909 is associated with increased CL/P risk. Compared to individuals with the AA genotype, the G allele carriers had an OR of 1.768 (95% CI: 1.133-2.759; p=0.012). For the remaining SNPs of all analysed genes, there was no overall evidence for cleft association considering the allele and genotype distribution. However, gene-by-gene interaction analysis conducted using the MDR approach revealed a significant interactive genetic effect of ASS1 (rs666174) and SLC25A13 (rs10252573) on the occurrence of clefting (p=0.002).


CONCLUSIONS
Our results demonstrate moderate evidence for the association of polymorphic variants of genes related to arginine metabolism with abnormal palatogenesis.
Hozyasz
Kamil K
KK
Department of Paediatrics, Institute of Mother and Child, Warsaw, Poland. khozyasz@verco.com.pl
Mostowska
Adrianna
A
Wojcicki
Piotr
P
Lianeri
Margarita
M
Jagodzinski
Pawel P
PP
D000293:Adolescent; D000483:Alleles; D001123:Argininosuccinate Lyase / Q000235:genetics*; D001124:Argininosuccinate Synthase / Q000235:genetics; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip / Q000201:enzymology / Q000235:genetics*; D002972:Cleft Palate / Q000201:enzymology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D018709:Statistics, Nonparametric
D033681:Mitochondrial Membrane Transport Proteins; C119629:SLC25A13 protein, human; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase