ALDH1L1 和 GLDC 中的遗传变异影响西班牙裔儿童的丝氨酸-甘氨酸比率。
Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children.
机构信息
Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA.
Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, USA.
出版信息
Am J Clin Nutr. 2022 Aug 4;116(2):500-510. doi: 10.1093/ajcn/nqac091.
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 the 10-formyltetrahydrofolate dehydrogenase enzyme in serine-to-glycine conversion.
OBJECTIVES
We sought to determine the genomic influence on the 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 the serine-glycine ratio in Sequential Oligogenic Linkage Analysis Routines while accounting for relationships among family members.
RESULTS
All 3 parameters were significantly heritable (h2 = 0.22-0.78; P < 0.004). The strongest associations for the serine-glycine ratio were with single nucleotide polymorphisms (SNPs) in aldehyde dehydrogenase 1 family member L1 (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 associations between the serine-glycine ratio and rs2886059 (β = 0.68; SE, 0.25; P = 0.006) and rs3796191 (β = 0.25; SE, 0.08; P = 0.003) and between glycine and rs3796191 (β = -0.08; SE, 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 the serine-glycine ratio with metabolic disease risk factors, including adiposity, insulin sensitivity, and inflammation-related phenotypes [estimate of genetic correlation = -0.37 to 0.35 (P < 0.03); estimate of phenotypic correlation = -0.19 to 0.13 (P < 0.006)]. The significant genetic correlations indicate shared genetic effects among glycine, the serine-glycine ratio, and adiposity and insulin sensitivity phenotypes.
CONCLUSIONS
Our study suggests that ALDH1L1 and GLDC SNPs influence the serine-to-glycine ratio and metabolic disease risk.
背景
甘氨酸是一种必需的蛋白质氨基酸，参与多种代谢途径，包括嘌呤、肌酸、血红素和谷胱甘肽的生物合成。丝氨酸在丝氨酸羟甲基转移酶的催化下转化为甘氨酸，是人体内该氨基酸的主要来源。我们之前在小鼠模型中的研究表明，10-甲酰四氢叶酸脱氢酶在丝氨酸到甘氨酸的转化中起着关键作用。
目的
我们旨在确定 803 名来自 319 个 Viva La Familia 队列家庭的西班牙裔儿童的基因组对丝氨酸-甘氨酸比值的影响。
方法
我们在Sequencial Oligogenic Linkage Analysis Routines 中对血浆丝氨酸、甘氨酸和丝氨酸-甘氨酸比值进行全基因组关联分析，同时考虑家庭成员之间的关系。
结果
所有 3 个参数的遗传性均显著（h2=0.22-0.78；P<0.004）。与丝氨酸-甘氨酸比值最强相关的是醛脱氢酶 1 家族成员 L1（ALDH1L1）和甘氨酸脱羧酶（GLDC）的单核苷酸多态性（SNP），而与甘氨酸最强相关的是 GLDC（P<3.5×10-8；效应大小，0.03-0.07）。丝氨酸未发现显著关联。我们还对 ALDH1L1 外显子 SNP 进行了靶向遗传分析，发现丝氨酸-甘氨酸比值与 rs2886059（β=0.68；SE，0.25；P=0.006）和 rs3796191（β=0.25；SE，0.08；P=0.003）之间以及甘氨酸与 rs3796191（β=-0.08；SE，0.02；P=0.0004）之间存在显著关联。这些外显子 SNP 还与代谢疾病风险因素（主要是肥胖测量值）进一步相关（P<0.006）。甘氨酸和丝氨酸-甘氨酸比值与代谢疾病风险因素（包括肥胖、胰岛素敏感性和炎症相关表型）之间存在显著的遗传和表型相关性[遗传相关性估计值=-0.37 至 0.35（P<0.03）；表型相关性估计值=-0.19 至 0.13（P<0.006）]。这些显著的遗传相关性表明，甘氨酸、丝氨酸-甘氨酸比值和肥胖、胰岛素敏感性表型之间存在共同的遗传效应。
结论
我们的研究表明，ALDH1L1 和 GLDC SNP 影响丝氨酸到甘氨酸的比值和代谢疾病风险。
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