Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children.
adiposity
aldehyde dehydrogenase 1 family member l1
genome-wide association
glycine decarboxylase
heritability
inflammation
insulin sensitivity
metabolic diseases
serine hydroxymethyltransferase
Journal
The American journal of clinical nutrition
ISSN: 1938-3207
Titre abrégé: Am J Clin Nutr
Pays: United States
ID NLM: 0376027
Informations de publication
Date de publication:
04 08 2022
04 08 2022
Historique:
received:
20
09
2021
revised:
15
02
2022
accepted:
21
04
2022
pubmed:
24
4
2022
medline:
6
8
2022
entrez:
23
4
2022
Statut:
ppublish
Résumé
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. 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. 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. 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. Our study suggests that ALDH1L1 and GLDC SNPs influence the serine-to-glycine ratio and metabolic disease risk.
Sections du résumé
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.
Identifiants
pubmed: 35460232
pii: S0002-9165(22)00054-5
doi: 10.1093/ajcn/nqac091
pmc: PMC9348975
doi:
Substances chimiques
Serine
452VLY9402
Glycine Dehydrogenase (Decarboxylating)
EC 1.4.4.2
Oxidoreductases Acting on CH-NH Group Donors
EC 1.5.-
formyltetrahydrofolate dehydrogenase
EC 1.5.1.6
Glycine
TE7660XO1C
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
500-510Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK080457
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH059490
Pays : United States
Organisme : NIMH NIH HHS
ID : RF1 MH123163
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK126666
Pays : United States
Organisme : NIH HHS
ID : P51 OD011133
Pays : United States
Organisme : NIH HHS
ID : S10 OD023696
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.
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