Metabolome-Wide Association Study of Primary Open Angle Glaucoma

Burgess, L. Goodwin; Uppal, Karan; Walker, Douglas I.; Roberson, Rachel M.; Tran, ViLinh; Parks, Megan; Wade, Emily A.; May, Alexandra T.; Umfress, Allison C.; Jarrell, Kelli L.; Stanley, Brooklyn; Kuchtey, John; Kuchtey, Rachel W.; Jones, Dean P.; Brantley, Milam A.

doi:10.1167/iovs.15-16702

Cited by 67 publications

(79 citation statements)

References 44 publications

(52 reference statements)

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“…Utilizing HRM and using two different columns allowed for better metabolite separation; we detected and quantified on average 6,500 and 10,500 unique features per column (AE and C18) in urine and plasma, respectively. The number of detected features in the plasma here is slightly lower than reported data for human plasma analyzed similarly (Burgess et al, 2015;Frediani et al, 2014;Patel et al, 2015). However, compared with other untargeted metabolomics applied to both plasma and urine in rodents or humans (Chen et al, 2012;Feng et al, 2016;Ohta et al, 2009;Wikoff et al, 2009), our HRM method is more robust.…”

Section: Discussioncontrasting

confidence: 49%

Metabolomics of fescue toxicosis in grazing beef steers

Mote

Hill

Uppal

et al. 2017

Food and Chemical Toxicology

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Fescue toxicosis (FT) results from consumption of tall fescue (Lolium arundinaceum) infected with an endophyte (Epichloë coenophiala) that produces ergot alkaloids (EA), which are considered key etiological agents of FT. Decreased weight gains, hormonal imbalance, circulating cholesterol disruption, and decreased volatile fatty acid absorption suggest toxic (E+) fescue-induced metabolic perturbations. Employing untargeted high-resolution metabolomics (HRM) to analyze E+ grazing-induced plasma and urine metabolome changes, fescue-naïve Angus steers were placed on E+ or non-toxic (Max-Q) fescue pastures and plasma and urine were sampled before, 1, 2, 14, and 28 days after pasture assignment. Plasma and urine catecholamines and urinary EA concentrations were also measured. In E+ steers, urinary EA appeared early and peaked at 14 days. 13,090 urinary and 20,908 plasma HRM features were detected; the most significant effects were observed earlier (2 days) in the urine and later (≥14 days) in the plasma. Alongside EA metabolite detection, tryptophan and lipid metabolism disruption were among the main consequences of E+ consumption. The E+ grazing-associated metabolic pathways and signatures described herein may accelerate development of novel early FT detection and treatment strategies.

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Section: Discussioncontrasting

confidence: 49%

Metabolomics of fescue toxicosis in grazing beef steers

Mote

Hill

Uppal

et al. 2017

Food and Chemical Toxicology

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“…In ophthalmology, metabolomics has been used to study various eye diseases including glaucoma [10][11][12][13][14][15][16] , age-related macular degeneration [17][18][19] , diabetic retinopathy [20][21][22] , keratoconus [23] , refractive error [24,25] , retinal detachment [26] , uveitis [27,28] , dry eye [29,30] , and other ocular surface diseases [31] . Analyses have been performed on tear fluid [23,[29][30][31][32] , aqueous humor [24,25,33,34] , vitreous humor [20,26,27,35,36] , cornea [37][38][39] , conjunctiva [40] , and lens [41,42] samples.…”

Section: Metabolomics In Ophthalmologymentioning

confidence: 99%

“…Moreover, substantial heterogeneity exists among patients. The incidence differs considerably between races, and the clinical manifestation and progression profiles are variable [11] . Genetic mutations and common genetic variants have been linked to several types of glaucoma, but these factors can only explain a small portion of all cases [45] .…”

Section: Metabolomics In Glaucomamentioning

confidence: 99%

“…Indeed, a blood-plasma comparison between primary open-angle glaucoma patients and healthy controls using mass spectrometry found significant differences in specific metabolic processes involving palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors. These observations might be linked to mitochondrial dysfunction and energy metabolism changes [11] . This study was the first attempt to perform a metabolome-wide analysis of glaucoma patients.…”

Section: Metabolomics In Glaucomamentioning

confidence: 99%

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Clinical Metabolomics and Glaucoma

Breda

Himmelreich²,

Ghesquière³

et al. 2017

Ophthalmic Res

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Glaucoma is one of the leading causes of irreversible blindness worldwide. However, there are no biomarkers that accurately help clinicians perform an early diagnosis or detect patients with a high risk of progression. Metabolomics is the study of all metabolites in an organism, and it has the potential to provide a biomarker. This review summarizes the findings of metabolomics in glaucoma patients and explains why this field is promising for new research. We identified published studies that focused on metabolomics and ophthalmology. After providing an overview of metabolomics in ophthalmology, we focused on human glaucoma studies. Five studies have been conducted in glaucoma patients and all compared patients to healthy controls. Using mass spectrometry, significant differences were found in blood plasma in the metabolic pathways that involve palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors. For nuclear magnetic resonance spectroscopy, a high glutamine-glutamate/creatine ratio was found in the vitreous and lateral geniculate body; no differences were detected in the optic radiations, and a lower N-acetylaspartate/choline ratio was observed in the geniculocalcarine and striate areas. Metabolomics can move glaucoma care towards a personalized approach and provide new knowledge concerning the pathophysiology of glaucoma, which can lead to new therapeutic options.

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“…In this study, we used a metabolome-wide association study (MWAS) 30 , 36 , 37 to identify dose-dependent metabolic changes in TCE-exposed workers and unexposed controls, using a well-characterized, worker population 17 , 19 . Direct TCE and endogenous metabolites were characterized, and pathway analysis was used to identify biological response to TCE exposure.…”

Section: Introductionmentioning

confidence: 99%

High-resolution metabolomics of occupational exposure to trichloroethylene

et al. 2016

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Background: Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin’s lymphoma and kidney and liver cancer; however, TCE’s mode of action for development of these diseases in humans is not well understood. Methods: Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers [full shift exposure range of 0.4 to 230 parts-per-million of air (ppma)] and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population. Results: Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (β = 0.13, P-value = 3.6 × 10−5), glutamine (β = 0.08, P-value = 0.0013), cystine (β = 0.75, P-value = 0.0022), methylthioadenosine (β = −1.6, P-value = 0.0043), taurine (β = −2.4, P-value = 0.0011) and chenodeoxycholic acid (β = −1.3, P-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological endpoints supported known disease associations. Conclusions: High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology.

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Metabolome-Wide Association Study of Primary Open Angle Glaucoma

Cited by 67 publications

References 44 publications

Metabolomics of fescue toxicosis in grazing beef steers

Metabolomics of fescue toxicosis in grazing beef steers

Clinical Metabolomics and Glaucoma

High-resolution metabolomics of occupational exposure to trichloroethylene

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