title: Weak association of glyoxalase 1 (GLO1) variants with autism spectrum disorder.
abstract: The prevalence of the autism spectrum disorder (ASD) was recently estimated to 1 in 88 children by the CDC MMWR. In up to 25 % of the cases, the genetic cause can be identified. Past studies identified increased level of advanced glycation end products (AGE) in the brain samples of ASD patients. The methylglyoxal (MG) is one of the main precursors for AGE formation. Humans developed effective mechanism of the MG metabolism involving two enzymes glyoxalase 1 (GLO1) and hydroxyacylglutathione hydrolase (HAGH). Our aim was to analyse genetic variants of GLO1 and HAGH in population of 143 paediatric participants with ASD. We detected 7 genetic variants in GLO1 and 16 variants in HAGH using high-resolution melting (HRM) analysis. A novel association between variant rs1049346 and ASD [OR (allele C)] = 1.5; 95 % CI = 1.1-2.2 and p < 0.05) was identified, and weak association between ASD and variant rs2736654 [OR (allele A)] = 2.2; 95 % CI = 0.99-4.9; p = 0.045) was confirmed. Additionally, a novel genetic variant (GLO1 c.484G > A, p.Ala161Thr) with predicted potentially damaging effect on the activity of the glyoxalase 1 that may contribute to the aetiology of ASD was identified in one participant with ASD. No association between genetic variants of the HAGH gene and ASD was found. Increased level of MG and, consequently, AGEs can induce oxidative stress, mitochondrial dysfunction and inflammation all of which have been implicated to act in the aetiology of the ASD. Our results indicate potential importance of MG metabolism in ASD. However, these results must be interpreted with caution until a causative relation is demonstrated.
authors.affiliation: Department of Endocrinology, Diabetes and Metabolic Diseases, UMC Ljubljana, University Children's Hospital, Bohoričeva ulica 20, 1000, Ljubljana, Slovenia.
authors.forename: Jernej
authors.initials: J
authors.lastname: Kovač
authors.forename: Katarina Trebušak
authors.initials: KT
authors.lastname: Podkrajšek
authors.forename: Marta Macedoni
authors.initials: MM
authors.lastname: Lukšič
authors.forename: Tadej
authors.initials: T
authors.lastname: Battelino
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics*; D008297:Male; D011765:Pyruvaldehyde / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000235:genetics*; D055815:Young Adult; D000099301:Hydroxyacylglutathione Hydrolase
chemical_list: D007791:Lactoylglutathione Lyase; D011765:Pyruvaldehyde; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase