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Within the last decade, it was realized that during and after long-duration spaceflight, some astronauts experience ophthalmic abnormalities including refractive changes, optic disc edema, globe flattening, choroidal folds, and cotton wool spots. Much research has been initiated and conducted, but little evidence is available to differentiate affected crewmembers.The first published data to distinguish between affected and nonaffected crewmembers identified biochemical differences in affected astronauts: one-carbon pathway metabolite concentrations were higher in these individuals than in nonaffected astronauts, even before flight. These data led to findings that genetics and B-vitamin status were predictors of the incidence of the ophthalmic abnormalities. A multihit hypothesis was developed, with genetics and B-vitamin status as two of several important elements that all contribute to endothelial dysfunction and ultimately to ophthalmic changes after flight. One of these contributing factors – response to carbon dioxide exposure – was recently documented to be affected by the same one-carbon pathway genetics.This line of research may help identify which astronauts are at risk of these ophthalmic changes, and allow targeted treatment. This research may have implications for clinical populations, including patients with polycystic ovary syndrome, that have similar biochemical, endocrine, and genetic characteristics, and it may shed light on why links between cardiovascular disease and the metabolites homocysteine and folate have been elusive and confounded.