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RESEARCH PRODUCT

Sex-Specific Differences in the Control of Serum Concentrations of Glycine in Subjects with Metabolic Syndrome and Mendelian Randomization Analysis for Obesity

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OBJECTIVES: Glycine is a novel circulating marker for metabolic diseases associated with lower type-2 diabetes and protection against obesity in some studies. Circulating glycine levels are genetically determined under the control of several loci. The locus most strongly associated is the carbamoyl-phosphate synthase I (CPS1). Interestingly, some sex-specific genome-wide association studies (GWAS) showed differences in the effect of the main single nucleotide polymorphisms (SNPs) in this locus on glycine levels (significant sex * CPS1 interactions). However, the potential mechanisms explaining this sex-heterogeneity are unknown. Therefore, our aims were: 1) to analyze whether the sex * CPS1 interaction for serum glycine is present in subjects from a Mediterranean population, and 2) to test, in another population, the glycine sex-specific associations with obesity, using a Mendelian randomization approach. METHODS: We studied 426 subjects (aged 55–75 y) with metabolic syndrome from the PREDIMED Plus-Valencia Study. Serum glycine was determined by NMR spectroscopy. We screened the CPS1 gene for SNP associations. In another Mediterranean population (PREDIMED-Valencia participants, n = 1009) we analyzed the sex-specific associations between the genetically determined glycine (CPS1-SNP) and obesity, using Mendelian randomization. RESULTS: In the PREDIMED Plus-Valencia subjects, serum glycine levels were higher in women than in men (280 vs 240 micromol/L, respectively; P = 1.4 × 1E15). The CPS1-rs7684 (3’-UTR) SNPs was strongly associated with glycine levels in women but not in men (P for sex * CPS1 interaction = 0.004), replicating previous findings. The minor allele was associated with lower serum glycine. In the Mendelian randomization study in the population with unmeasured glycine levels, the CPS1-rs7684 SNPs presented a sex-specific interaction for obesity (P < 0.05). Women with the minor allele (lower glycine levels) were more likely to be obese than homozygous women for the major allele (P < 0.05). No associations were detected in men. CONCLUSIONS: We replicated the sex * CPS1 interaction in determining glycine levels and also detected sex * CPS1 interactions for obesity risk. FUNDING SOURCES: Generalitat Valenciana (PROMETEO2017/017, APOSTD/2019/136), Fundació La Marató de TV3 (538/U/2016), and CIBEROBN.