Integration of targeted metabolomics and transcriptomics identifies deregulation of phosphatidylcholine metabolism in Huntington's disease peripheral blood samples.

Anastasios Mastrokolias,Cornelia Prehn,Rene Pool,Willeke Van Roon-Mom,Kristina M Hettne,Jerzy Adamski,Roos C Van Der Mast,Eleni Mina,Gertjan Van Ommen,Erik Van Duijn,Peter A C ‘T Hoen

doi:10.1007/s11306-016-1084-8

Abstract

IntroductionMetabolic changes have been frequently associated with Huntington’s disease (HD). At the same time peripheral blood represents a minimally invasive sampling avenue with little distress to Huntington’s disease patients especially when brain or other tissue samples are difficult to collect.ObjectivesWe investigated the levels of 163 metabolites in HD patient and control serum samples in order to identify disease related changes. Additionally, we integrated the metabolomics data with our previously published next generation sequencing-based gene expression data from the same patients in order to interconnect the metabolomics changes with transcriptional alterations.MethodsThis analysis was performed using targeted metabolomics and flow injection electrospray ionization tandem mass spectrometry in 133 serum samples from 97 Huntington’s disease patients (29 pre-symptomatic and 68 symptomatic) and 36 controls.ResultsBy comparing HD mutation carriers with controls we identified 3 metabolites significantly changed in HD (serine and threonine and one phosphatidylcholine—PC ae C36:0) and an additional 8 phosphatidylcholines (PC aa C38:6, PC aa C36:0, PC ae C38:0, PC aa C38:0, PC ae C38:6, PC ae C42:0, PC aa C36:5 and PC ae C36:0) that exhibited a significant association with disease severity. Using workflow based exploitation of pathway databases and by integrating our metabolomics data with our gene expression data from the same patients we identified 4 deregulated phosphatidylcholine metabolism related genes (ALDH1B1, MBOAT1, MTRR and PLB1) that showed significant association with the changes in metabolite concentrations.ConclusionOur results support the notion that phosphatidylcholine metabolism is deregulated in HD blood and that these metabolite alterations are associated with specific gene expression changes.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-016-1084-8) contains supplementary material, which is available to authorized users.

Highlights

IntroductionAt the same time peripheral blood represents a minimally invasive sampling avenue with little distress to Huntington’s disease patients especially when brain or other tissue samples are difficult to collect
Metabolic changes have been frequently associated with Huntington’s disease (HD)
We identified 3 metabolites significantly changed in the HD mutation carriers versus controls analysis and 8 metabolites significantly changed in the 4 disease stage group analysis that associated with disease progression

Summary

Introduction

At the same time peripheral blood represents a minimally invasive sampling avenue with little distress to Huntington’s disease patients especially when brain or other tissue samples are difficult to collect. Recent studies show that lowering mutant huntingtin protein levels using RNAi is a promising therapeutic approach that is close to clinical trials (Yu et al 2012; Evers et al 2011). This highlights/prompts the need for biomarkers that track disease progression and measure clinical trial therapeutic effectiveness

Objectives

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Conclusion