Background: Glycine is a proteogenic amino acid that is required for numerous metabolic pathways, including purine, creatine, heme and glutathione biosynthesis. Glycine formation from serine, catalyzed by serine hydroxy methyltransferase, is the major source of this amino acid in humans. Our previous studies in a mouse model have shown a crucial role for the10-formyltetrahydrofolate dehydrogenase (ALDH1L1) enzyme in serine to glycine conversion.
Objectives: To determine the genomic influence on serine-glycine ratio in 803 Hispanic children from 319 families of the Viva La Familia cohort.
Methods: We performed a genome-wide association analysis for plasma serine, glycine, and serine-glycine ratio in SOLAR while accounting for non-independence among family members.
Results: All three parameters were significantly heritable [h2 = 0.22-0.78, P < 0.004]. The strongest associations for serine-glycine ratio were with single nucleotide polymorphisms (SNPs) in ALDH1L1 and glycine decarboxylase (GLDC) and for glycine with GLDC [P < 3.5 × 10-8, effect sizes: 0.03-0.07]. No significant associations were found for serine. We also conducted a targeted genetic analysis with ALDH1L1 exonic SNPs and found significant association between serine-glycine ratio and rs2886059 [β (SE) = 0.68 (0.25), P = 0.006] and rs3796191 [β (SE) = 0.25 (0.08), P = 0.003], and glycine and rs3796191 [β (SE) = -0.08 (0.02), P = 0.0004]. These exonic SNPs were further associated with metabolic disease risk factors, mainly adiposity measures [P < 0.006]. Significant genetic and phenotypic correlations were found for glycine and serine-glycine ratio with metabolic disease risk factors including adiposity, insulin sensitivity and inflammation-related phenotypes [ρg = -0.37 to 0.35, P < 0.03, ρp = -0.19 to 0.13, P < 0.006]. The significant genetic correlations indicate shared genetic effects among glycine, serine-glycine ratio, and adiposity and insulin sensitivity phenotypes.
Conclusions: Our study suggests that ALDH1L1 and GLDC SNPs influence serine to glycine ratio and metabolic disease risk.
Krupenko, S. A., Cole, S. A., Hou, R., Haack, K., Laston, S., Mehta, N. R., Comuzzie, A. G., Butte, N. F., & Voruganti, V. S. (2022). Genetic variants in ALDH1L1 and GLDC influence serine to glycine ratio in Hispanic children. The American journal of clinical nutrition, nqac091. Advance online publication. https://doi.org/10.1093/ajcn/nqac091
The American journal of clinical nutrition
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