Rs37369

rs37369 is a SNP located in the coding region of the alanine-glyoxylate aminotransferase-2 (AGXT2) gene within chromosome 5 at position 35,072,872. This polymorphism constitues a nonsynonymous valine-to-isoleucine (V140I) substitution in the AGXT2 protein. rs37369 has been proposed by one study to be the causative SNP of hyper-beta-aminoisobutyric aciduria.

Beta-aminoisobutyric acid (BAIB) is the end product of pyrimidine metabolism. Hyper-BAIB is an autosomal recessive phenotype that is distinguished by high urinary excretion levels of beta-aminoisobutyric acid. Elevated levels of BAIB have been suggested to contribute to neurological and developmental problems, as BAIB is a structural analog of gamma-aminobutyric acid and glycine--two major inhibitory neurotransmitters in the central nervous system. The Online Mendelian Inheritance in Man (OMIM) database states that hyper-beta-aminoisobutyric aciduria is likely the most common Mendelian metabolic variant in man.

In a 2011 study, rs37369 was found to have a strong association with hyper-beta-aminoisobutyric aciduria. In this study, 59 urine metabolite concentrations and 1,661 ratios between metabolite concentrations were tested for associations in 645,249 autosomal SNPs in 862 male German individuals. After correcting for multiple testing, rs37369 was found to have a significant association (p-value = 3.17 x 10^-75). The study further confirmed this result by replicating it twice more with 992 German samples of both sexes, and 870 German female samples. Resulting in p-values of 3.3 x 10^-52 and 1.3 x 10^-56, respectively. In all, these three independent replicates had a joint p-value of 2.1 x 10^-182.

The AGXT2 gene, where the coding rs37369 SNP resides, encodes a mitochondrial aminotransferase expressed primarily in the kidney that catalyzes the reactions of BAIB with pyruvate to form 2-methyl-3-oxopropanoate and alanine. High excretion of BAIB is thought to result from an impairment in BAIB catabolism due to a deficiency in the activity of the AGXT2 enzyme. The association of rs37369 with BAIB matches the enzymatic function of AGXT2. Given the strength of the association (2.1 x 10^-182), and the fact that rs37369 codes for a nonsynonymous substitution (V140I), it has been posed as the causal SNP of hyper-beta-aminoisobutyric aciduria, although this hypothesis has not yet been experimentally verified.