研究成人血浆肌醇状态的遗传决定因素。

Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans.

机构信息

Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.

Genetics and Environment Interaction Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

出版信息

J Nutr. 2022 Nov;152(11):2333-2342. doi: 10.1093/jn/nxac204. Epub 2022 Sep 2.

DOI:10.1093/jn/nxac204

PMID:36774100

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9644178/

Abstract

BACKGROUND

Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, whereas supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome, and congenital anomalies. Inositol status can be influenced by diet, synthesis, transport, utilization, and catabolism.

OBJECTIVES

We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites.

METHODS

GC-MS was used to determine plasma MI concentration of >2000 healthy, young adults (aged 18-28 y) from the Trinity Student Study. Genotyping data were used to test association of plasma MI with single nucleotide polymorphisms (SNPs) in candidate genes, encoding inositol transporters and synthesizing enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with d-chiro-inositol (DCI), glucose, and other metabolites by Spearman rank correlation.

RESULTS

Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 μM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11 (solute carrier family 5 member 11), encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (P < 5 × 10). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (P < 1 × 10), 3 of which were located within or close to genes: MTDH (metadherin), LAPTM4B (lysosomal protein transmembrane 4 β), and ZP2 (zona pellucida 2). We found significant positive correlation of plasma MI concentration with concentration of dci and several other biochemicals including glucose, methionine, betaine, sarcosine, and tryptophan.

CONCLUSIONS

Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11, which is worthy of further investigation.

摘要

背景

肌醇（MI）被整合到多种生物分子中，包括磷酸肌醇和肌醇磷酸盐。肌醇可用性或代谢的紊乱与各种疾病有关，包括神经疾病和癌症，而补充 MI 在抑郁症、多囊卵巢综合征和先天性异常等疾病中有治疗潜力。肌醇状态可受饮食、合成、运输、利用和分解代谢的影响。

目的

我们旨在研究循环 MI 状态的潜在遗传调控，并评估 MI 浓度与其他代谢物的相关性。

方法

使用气相色谱-质谱法（GC-MS）测定来自三一学生研究的 2000 多名健康年轻成年人（年龄 18-28 岁）的血浆 MI 浓度。基因分型数据用于测试候选基因编码的肌醇转运体和合成酶的血浆 MI 与单核苷酸多态性（SNP）之间的关联，并进行全基因组关联分析。我们通过 Spearman 秩相关评估了血浆 MI 与 d-手性肌醇（DCI）、葡萄糖和其他代谢物之间的潜在相关性。

结果

男性和女性的血浆 MI 平均值之间存在微小但显著的差异（分别为 28.5 和 26.9 μM）。候选基因分析显示，与血浆 MI 有几个具有统计学意义的关联，其中最显著的是 SLC5A11（溶质载体家族 5 成员 11），编码一种钠离子偶联肌醇转运体，也称为 SMIT2（钠离子依赖肌醇转运体 2）。然而，这些关联在经过多重检验校正后并未成立。随后对全基因组与血浆 MI 的关联进行检测，并未发现具有全基因组意义的关联（P < 5×10）。然而，有 8 个 SNP 超过了与血浆 MI 浓度相关的提示性显著关联的阈值（P < 1×10），其中 3 个 SNP 位于或靠近基因：MTDH（metadherin）、LAPTM4B（lysosomal protein transmembrane 4 β）和 ZP2（zona pellucida 2）。我们发现血浆 MI 浓度与 dci 浓度和其他几种生化物质呈显著正相关，包括葡萄糖、蛋氨酸、甜菜碱、肌氨酸和色氨酸。