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Pirro G Hysi, Tim Spector, Christopher J Hammond; Circulating O-methylascorbate is associated with population IOP variation: a metabolomics and GWAS study. Invest. Ophthalmol. Vis. Sci. 2018;59(9):777.
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Intraocular pressure (IOP) is an important risk factor for primary open angle glaucoma (POAG). Genome-wide association studies (GWAS) have found many genetic markers associated with both, but intermediate processes and mechanisms leading up to elevated IOP and POAG are still not well understood. The purpose of this study is to find associations between circulating blood metabolites and IOP in the general population.
IOP measurements from 1785 unrelated subjects from the TwinsUK cohort were compared to the inverse-normal transformed values of 317 plasma metabolites, obtained using mass-spectrometry profiling (Metabolon). A random forest analysis was used to rank the metabolites according to the strength of their contribution to observed IOP measurements in the sample. Linear models were used to confirm associations.Results were validated by comparing genetic effects over metabolites and IOP, in the KORA and the UK Biobank cohorts respectively. Three effect mediation detecting methods (ivw, median-based and MR-Egger regressions) were used for the comparisons. All analyses were penalized, robust and random-effect.
The most important metabolite explaining IOP variation in TwinsUK was M32910 (O-methylascorbate, a Vitamin C derivative). It also significantly associated with IOP in linear models (p=4.76x10-06). Significant GWAS associations with this metabolite are located inside or near genes involved in drug metabolism (COMT), regulation transcription (KLF12), protein activation (PPPC5), endoplasmic reticulum function (SIL1) and lipid and energy metabolism (FDFT1).Tests comparing effect sizes of SNPs significantly associated with M32910 in the KORA population, with their effect sizes over IOP in the UK Biobank data, consistently suggested that this metabolite has an inverse causal relationship with IOP (penalized robust Egger test’s β=-0.639, SE=0.35, p=3.33x10-06).
The results of our multi-omics analyses of independent datasets suggest that variation in plasma metabolite levels are associated with IOP variation in the general population. They are consistent with previous reports implicating systemic oxidative stress in POAG etiology. Although our results support a causative directionality, more work is needed in the future to establish the place of different genetic, environmental and metabolic actors in the complex map of interactions associated with IOP.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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