Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans.

Feb 13, 2023

Experts: Eleanor Weston,Faith Pangilinan,Simon Eaton,Michael Orford,Kit-Yi Leung,Andrew J Copp,James L Mills,Anne M Molloy,Lawrence C Brody,Nicholas DE Greene

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.
We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites.
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.
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.
Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11, which is worthy of further investigation.

Copyright © 2022 American Society for Nutrition.

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ABOUT THE EXPERTS

Eleanor Weston,Faith Pangilinan,Simon Eaton,Michael Orford,Kit-Yi Leung,Andrew J Copp,James L Mills,Anne M Molloy,Lawrence C Brody,Nicholas DE Greene

Eleanor Weston

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

Faith Pangilinan

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

Simon Eaton

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

Michael Orford

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

Kit-Yi Leung

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

Andrew J Copp

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

James L Mills

Epidemiology Branch, Division of Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Anne M Molloy

Department of Clinical Medicine, School of Medicine, Trinity College, Dublin, Ireland.

Lawrence C Brody

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

Nicholas DE Greene

Developmental Biology and Cancer Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. Electronic address: n.greene@ucl.ac.uk.