2-hydroxyglutarate as a biomarker for chronic hypoxia
The present invention provides biomarkers for sensitive, specific, accurate and quantitative diagnosis and assessment of chronic hypoxia. In particular, the present invention provides 2-hydroxyglutarate as a biomarker that is differentially produced in chronic hypoxia. Furthermore, embodiments of the invention are able to differentiate between chronic and acute hypoxia. Assays for levels of 2-hydroxyglutarate may be used alone or in conjunction with additional biomarkers of hypoxia to increase the precision of analysis. In particular embodiments of the invention, the level of 2-hydroxyglutarate and at least one second biomarker may be assayed to generate a hypoxic profile that can be compared to a reference or control profile, thereby diagnosing a subject as normoxic, chronically hypoxic, or acutely hypoxic.
1. A method of treating a subject with low blood oxygen content as indicated by in vitro or in vivo atmospheric oxygen tension of approximately 0.5%, the method comprising a step of:
measuring a level of 2-hydroxyglutarate produced by wild-type IDH2 in a sample from the subject, wherein the level of 2-hydroxyglutarate is elevated at least two-fold in the sample compared to a control level derived from a population of normoxic subjects, wherein the subject does not have a neomorphic gain-of-function mutation in IDH1, does not have a neomorphic gain-of-function mutation in IDH2, and does not have a loss-of-function mutation in 2-hydroxyglutarate dehydrogenase; and
administering a treatment comprising supplemental oxygen therapy to the subject.
2. The method of claim 1 , wherein the level of 2-hydroxyglutarate is elevated at least three-fold.
3. The method of claim 1 , further comprising a step of measuring the level of 2-hydroxyglutarate in a similar sample from the subject after the step of administering.
4. The method of claim 3 , wherein the treatment reduces the level of 2-hydroxyglutarate by at least one-fold compared to pretreatment levels.
5. The method of claim 3 , wherein the treatment reduces the level of 2-hydroxyglutarate by at least two-fold compared to pretreatment levels.
6. The method of claim 1 , wherein the level of 2-hydroxyglutarate is measured by gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry or enzymatic assay.
7. The method of claim 1 , wherein the sample is a blood, plasma, serum, or urine sample.