Clinical and metabolic phenotypes of Oxford Biobank subjects with variations in human flavin-containing monooxygenase 5 (FMO5).

INTRODUCTION: Knockout of the Fmo5 gene in mice led to a lean, slow-ageing phenotype characterised by the presence of 2,3-butanediol isomers in their urine and plasma. Oral treatment of wildtype mice with 2,3-butanediol led to a low cholesterol, low epididymal fat phenotype. OBJECTIVES: Determine if significant, heterozygous coding variations in human FMO5 would give rise to similar clinical and metabolic phenotypes in humans, as in C57BL/6J mice with knockout of the Fmo5 gene and in particular, increased excretion of 2,3-butanediol. METHODS: Recruitment of 12 female, Oxford Biobank volunteers with heterozygous coding variations in FMO5, associated with changed clinical traits, and 12 age- and gender-matched controls. Analysis of the key NMR-based, urine and plasma, metabolic phenotypes of these volunteers to determine if there were any statistically significant differences. RESULTS: Some clinical parameters of the female volunteers with heterozygous coding variations in FMO5 were altered in a direction consistent with our hypothesis viz; lower insulin levels and lower waist circumference, but no consistent elevation of urinary 2,3-butanediol was found in the subjects with heterozygous coding variations in FMO5. CONCLUSION: Heterozygous coding variations in human FMO5 appeared to have some impact on the clinical phenotype of the females in this study but the natural variation in the levels of 2,3-butanediol was higher than any inter-group differences between women with heterozygous coding variations in human FMO5 and the women in the control group with wildtype FMO5.