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Milam A Brantley, Mary Virginia Harper, Shuzhao Li, Christopher B Estopinal, Isaac M Chocron, Sophia Banton, Rachel M Roberson, Emily A Wade, Dean P Jones, David C Samuels; Metabolic pathways are altered in mitochondrial haplogroups that affect severity of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5201.
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© ARVO (1962-2015); The Authors (2016-present)
To identify metabolic pathways that are altered in patients from mitochondrial haplogroups H and Uk, which have previously been demonstrated to be risk and protective factors, respectively, for proliferative diabetic retinopathy (PDR) among patients with diabetic retinopathy (DR).
Caucasian DR patients (44 with non-proliferative diabetic retinopathy [NPDR] and 57 with PDR) were genotyped using a Sequenom pool of 22 mitochondrial SNPs, and haplogroups were determined with HaploGrep. Untargeted metabolomic analysis using C18 liquid chromatography-Fourier-transform mass spectrometry (LC-FTMS) was performed on frozen plasma samples from the 101 patients. Data were collected from mass/charge ratio (m/z) 85-2000 on a Thermo LTQ-Velos Orbitrap mass spectrometer, and metabolic features were extracted using an adaptive processing software package with xMSanalyzer. Haplogroup H patients were compared to non-H patients, and haplogroup Uk patients to non-Uk patients. For each comparison, the top 500 metabolite features (p value cutoff of approximately 0.001) were used as input for pathway analysis in mummichog, a software program designed for high-resolution metabolomics data. The influence of haplogroups H and Uk on metabolite levels were examined using linear regression models that included age, gender, HgbA1c, and interaction between haplogroup and HgbA1c as covariates.
For the haplogroup H vs. non-H comparison, the TCA cycle (p=0.0079), and the Vitamin B3 (p=0.015) and Vitamin A (p=0.016) pathways significantly differed between the groups. Comparing haplogroup Uk vs. non-Uk, twelve pathways significantly differed, including the sphingolipid pathway (p=0.0023), the TCA cycle (p=0.0092), the carnitine shuttle (p=0.023), and the Vitamin E (p=0.026) and Vitamin A (p=0.029) pathways.
Multiple pathways plausibly related to mitochondrial function based on mitochondrial site of action or relationship to mitochondrially-produced reactive oxygen species have altered funtion in H and Uk haplogroups in patients with DR. These results suggest that metabolic changes related to specific mitochondrial haplogroups may influence diabetic retinopathy severity.
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