Genetic polymorphisms of Glycine N-acyltransferase (GLYAT) in a French Caucasian population

Abstract

In humans, the glycine N-acyltransferase enzyme (GLYAT) is thought to be important in the detoxification of endogenous and xenobiotic compounds which contain a carboxylic acid group, such as benzoic, isovaleric, or acetylsalicylic acids. The aim of this work was to report a comprehensive investigation of GLYAT genetic polymorphisms in DNA samples from 55 subjects of French Caucasian origin, using polymerase chain reaction-single-strand conformation polymorphism and sequencing strategies. Seven different polymorphisms of the GLYAT gene were identified, including two polymorphisms in the 5' flanking region of the gene (g.-8457C>T and g.-8010A>G), two polymorphisms in intron 5 (g.13931A>G and g.13944C>T) and three missense mutations in exon 2 (g.49T>A; p.Ser17Thr), exon 5 (g.13886A>G; p.Asn156Ser) and exon 6 (g.14435C>T; p.Arg199Cys). In addition to the wild-type allele GLYAT*1 (2.7%), four novel alleles were identified: GLYAT*2A (75.5%), *2B (4.5%), *3 (16.4%) and *4 (0.9%), and five different genotypes. Localisation of the p.Ser17Thr and p.Arg199Cys missense mutations in predicted secondary structures suggest that these variants might have a potential role on the GLYAT protein activity. These results could be helpful in investigating the potential association of GLYAT variants with an incidence of reduced efficiency in xenobiotic carboxylic acids detoxification in humans.

Conservation of the coding regions of the glycine N-acyltransferase gene further suggests that glycine conjugation is an essential detoxification pathway

“…Rare genetic polymorphisms that have previously been shown to negatively influence GLYAT enzyme activity (van der Sluis et al, 2013) were detected at very low frequencies and most occur only as heterozygotes and in a single population group (Table 5). The present study also supports the previous suggestion that the S 156 haplotype should be considered to be the "wild-type" human GLYAT (Lino Cardenas et al, 2010), as this haplotype has the highest allele frequency in all populations studied as well as the highest relative enzyme activity (van der Sluis et al, 2013).…”

“…The R131H variant was identified as a homozygote in one East Asian individual and previously (Yamamoto et al, 2009) as a heterozygote in one individual out of 95 Japanese individuals. The R199C variant was detected once in a heterozygous East Asian individual's genome and was also previously observed in one heterozygote out of 55 French Caucasian individuals (Lino Cardenas et al, 2010).…”

“…It seems that, within each population group (EUR, AFR, AMR, ASN, SA and Khoisan), the S 156 haplotype was the ancestral haplotype. The S 156 haplotype is also the non-synonymous SNP with the highest allele frequency and highest relative enzyme activity (Lino Cardenas et al, 2010;van der Sluis et al, 2013). The haplotype diversity is however not population specific as sequences from different populations did not group together.…”

“…Within the GLYAT gene there are 1424 known single nucleotide polymorphisms (SNPs) (www.ensembl.org, July 2015, ENST00000344743), of which 99 are non-synonymous. Only two studies, on small cohorts of Japanese and French Caucasian individuals, have reported on novel genetic polymorphisms and allele frequencies of SNPs in the GLYAT gene (Lino Cardenas et al, 2010;Yamamoto et al, 2009). In both these studies the N156S variant was the dominant allele, with frequencies of 85% and 97% in the Japanese and French Caucasian populations, respectively.…”

Enzymatic Characterization and Elucidation of the Catalytic Mechanism of a Recombinant Bovine GlycineN-Acyltransferase

“…Six nonsynonymous single-nucleotide polymorphisms have been identified in the open reading frame of the human GLYAT gene. However, it is not yet understood whether, or how, these variations influence enzyme function (Yamamoto et al, 2009;Lino Cardenas et al, 2010).…”