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Elevated homocysteine (Hcy) levels are a risk factor for vascular diseases. Recently, increases in ultraviolet radiation (UVR) have been linked to decreased Hcy levels. This relationship may be mediated by the status of UVR-responsive vitamins, vitamin D and folate, and/or genetic variants influencing their levels; however, this has yet to be examined. Therefore, the independent and interactive influences of environmental UVR, vitamin D and folate levels and related genetic variants on Hcy levels were examined in an elderly Australian cohort ( n = 619). Red blood cell folate, 25-hydroxyvitamin D (25(OH)D), and plasma Hcy levels were determined, and genotyping for 21 folate and vitamin D-related variants was performed. Erythemal dose rate accumulated over six-weeks (6W-EDR) and four-months (4M-EDR) prior to clinics were calculated as a measure of environmental UVR. Multivariate analyses found interactions between 6W-EDR and 25(OH)D levels (p interaction = 0.002), and 4M-EDR and MTHFD1 -rs2236225 (p interaction = 0.006) in predicting Hcy levels. The association between 6W-EDR and Hcy levels was found only in subjects within lower 25(OH)D quartiles (&lt;33.26 ng/mL), with the association between 4M-EDR and Hcy occurring only in subjects carrying the MTHFD1 -rs2236225 variant. 4M-EDR, 6W-EDR, and MTHFD1 -rs2236225 were also independent predictors of Hcy. Findings highlight nutrient-environment and gene-environment interactions that could influence the risk of Hcy-related outcomes.

Independent and Interactive Influences of Environmental UVR, Vitamin D Levels, and Folate Variant MTHFD1-rs2236225 on Homocysteine Levels