Investigating Genetic Determinants of Plasma Inositol Status in Adult Humans

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, while supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome and congenital anomalies. Inositol status may be influenced by diet, synthesis, transport, utilisation 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 Gas chromatography mass spectrometry was used to determine plasma MI concentration of more than 2,000 healthy, young adults (aged 18–28 years) from the Trinity Student Study. Genotyping data was used to test association of plasma MI with SNPs in candidate genes, encoding inositol transporters and synthesising enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with D-chiro inositol, glucose and other metabolites by Spearman's 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, 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 × 10–8). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (p < 1 × 10–5), 3 of which were located within or close to genes: MTDH, LAPTM4B and ZP2. We found significant positive correlation of plasma MI concentration with concentration of D-chiro-inositol and several other biochemicals including glucose, methionine, betaine, sarcosine and tryptophan. Conclusion Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11 which is worthy of further investigation.

Association of embryonic inositol status with susceptibility to neural tube defects, metabolite profile, and maternal inositol intake

“…The potential for a genetic component in the regulation of circulating MI was investigated in a genome‐wide association study in healthy young adults. This study revealed a nominally significant association of plasma MI with SLC5A11 , encoding a sodium‐coupled inositol transporter (SMIT2), and suggestive association with three other genes 22 . However, lack of association of genome‐wide significance suggested that plasma MI is strongly influenced by non‐genetic factors such as diet.…”

“…For example, among mice maintained on the standard diet in this study, the mean plasma MI of approximately 69 μM was approximately double the mean value of 28 μM that we observed in a population of young healthy adults. 22 In considering MI deficiency as a potential risk factor for NTDs, serum MI concentration has been determined among mothers and their infants with spina bifida. Although, a relatively small-scale study, there was a non-significant difference in mean values between NTDs and controls but the lowest decile of maternal MI values was significantly associated with having a child with spina bifida.…”

“…The supernatants were transferred to fresh tubes, dried via lyophilization, and stored at −20°C. Derivatization of samples and GC–MS were performed as described previously 22 . GC was performed using a Rxi‐5Sil MS fused silica (5% diphenyl/95% dimethylpolysiloxane), 30 m × 0.25 mm I.D, 0.25 μm film thickness column (RESTEK), which enables separation of inositol enantiomers ( myo , d ‐chiro , allo , muco , and scyllo ) on the basis of retention time.…”

“…Derivatization of samples and GC-MS were performed as described previously. 22 GC was performed using a Rxi-5Sil MS fused silica (5% diphenyl/95% dimethylpolysiloxane), 30 m × 0.25 mm I.D, 0.25 μm film thickness column (RESTEK), which enables separation of inositol enantiomers (myo, d-chiro, allo, muco, and scyllo) on the basis of retention time. Selected ion monitoring (SIM) was used for analysis of inositol enantiomers (M/Z 372.5-373.5) and the myoinositol-d 6 (378.5-379.5) internal standard.…”

“…This study revealed a nominally significant association of plasma MI with SLC5A11, encoding a sodium-coupled inositol transporter (SMIT2), and suggestive association with three other genes. 22 However, lack of association of genome-wide significance suggested that plasma MI is strongly influenced by non-genetic factors such as diet.…”