Louck Lauren E, Klatt Kevin C, Wallace Taylor C, Ma Jiantao, Chung Mei
Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA.
Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA.
Nutrients. 2025 Aug 14;17(16):2630. doi: 10.3390/nu17162630.
Genetic variation has been thought to alter the human dietary requirement for choline and subsequent circulating levels of its metabolites betaine and dimethylglycine (DMG). The aim of this genome-wide association study (GWAS) was to identify single nucleotide polymorphisms (SNPs) associated with serum choline, betaine, and dimethylglycine (DMG) as well as choline-to-betaine and betaine-to-DMG ratios. Data from the Collaborative Study of Genes, Nutrients and Metabolites (CSGNM; = 2402) were used to model individual associations of choline, betaine, and DMG circulating metabolites and their ratios with 680,975 SNPs, using linear regression. Models were unadjusted (model 1), adjusted for age and sex (model 2), and further adjusted for selected principal components (model 3) and B, B, B, and holotranscobalamin (model 4). Statistical significance was set at < 5.0 × 10. Affected SNPs in the dbSNP (database of Single Nucleotide Polymorphisms) were then identified. GWAS revealed both intuitive and novel results, including the recently described SLC25A48, several intronic variants in the gene encoding LYPLAL1, and a pair of SNPs present in the intronic region of PID1 related to serum choline. SNPs related to betaine and DMG included SLCA12, BHMT, DMGDH, and additional SLC family transporters that require further validation. While exploratory, GWAS of the choline-to-betaine and betaine-to-DMG ratios revealed common targets with direct links to choline and one-carbon metabolism. These results suggest that metabolic handling of choline has genetic determinants not formerly recognized in the scientific literature. Replication is needed in larger cohorts due to low statistical power.
人们一直认为基因变异会改变人体对胆碱的饮食需求以及随后其代谢产物甜菜碱和二甲基甘氨酸（DMG）的循环水平。这项全基因组关联研究（GWAS）的目的是识别与血清胆碱、甜菜碱、二甲基甘氨酸（DMG）以及胆碱与甜菜碱的比例和甜菜碱与DMG的比例相关的单核苷酸多态性（SNP）。基因、营养素和代谢产物合作研究（CSGNM；n = 2402）的数据用于通过线性回归模拟胆碱、甜菜碱和DMG循环代谢产物及其比例与680,975个SNP的个体关联。模型未进行调整（模型1），对年龄和性别进行了调整（模型2），并进一步对选定的主成分（模型3）以及维生素B12、甲钴胺、腺苷钴胺和全转钴胺素（模型4）进行了调整。统计学显著性设定为P < 5.0×10⁻⁸。然后在单核苷酸多态性数据库（dbSNP）中识别受影响的SNP。GWAS揭示了直观和新颖的结果，包括最近描述的SLC25A48、编码LYPLAL1的基因中的几个内含子变异，以及与血清胆碱相关的PID1内含子区域中存在的一对SNP。与甜菜碱和DMG相关的SNP包括SLCA12、BHMT、DMGDH以及其他需要进一步验证的SLC家族转运蛋白。虽然具有探索性，但胆碱与甜菜碱的比例和甜菜碱与DMG的比例的GWAS揭示了与胆碱和一碳代谢有直接联系的共同靶点。这些结果表明，胆碱的代谢处理具有科学文献中以前未认识到的遗传决定因素。由于统计功效较低，需要在更大的队列中进行重复研究。
