Metabolomic Profiling Reveals Sex Specific Associations with Chronic Obstructive Pulmonary Disease and Emphysema.

Lucas A Gillenwater,Russell P Bowler,Nichole Reisdorph,Victor E Ortega,Dawn L Demeo,Wassim W Labaki,Jerry A Krishnan,Wanda O’Neal,Katherine A Pratte,Irina Petrache,Katerina J Kechris

doi:10.3390/metabo11030161

Abstract

Susceptibility and progression of lung disease, as well as response to treatment, often differ by sex, yet the metabolic mechanisms driving these sex-specific differences are still poorly understood. Women with chronic obstructive pulmonary disease (COPD) have less emphysema and more small airway disease on average than men, though these differences become less pronounced with more severe airflow limitation. While small studies of targeted metabolites have identified compounds differing by sex and COPD status, the sex-specific effect of COPD on systemic metabolism has yet to be interrogated. Significant sex differences were observed in 9 of the 11 modules identified in COPDGene. Sex-specific associations by COPD status and emphysema were observed in 3 modules for each phenotype. Sex stratified individual metabolite associations with COPD demonstrated male-specific associations in sphingomyelins and female-specific associations in acyl carnitines and phosphatidylethanolamines. There was high preservation of module assignments in SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) and similar female-specific shift in acyl carnitines. Several COPD associated metabolites differed by sex. Acyl carnitines and sphingomyelins demonstrate sex-specific abundances and may represent important metabolic signatures of sex differences in COPD. Accurately characterizing the sex-specific molecular differences in COPD is vital for personalized diagnostics and therapeutics.

Highlights

Susceptibility to and progression of lung disease, as well as response to treatment, often differ by sex, but molecular pathways underlying these differences are poorly understood [1,2]
Similar sex-specific differences were observed for smoking pack-years and chronic obstructive pulmonary disease (COPD) cases in SPIROMICS
The COPDGene subjects were older, contained a smaller percentage of African American subjects, had a lower percentage of current smokers, had less smoke exposure measured by cigarette pack-years, and less percent emphysema compared to SPIROMICS subjects (Supplementary Table S1)

Summary

Introduction

Susceptibility to and progression of lung disease, as well as response to treatment, often differ by sex, but molecular pathways underlying these differences are poorly understood [1,2]. There are several reasons to consider analyzing the metabolome of COPD separately in men and women, including sex differences in age of onset of severe COPD [5,6,7], prevalence of airway disease and emphysema [8,9], and COPD-related comorbidities [10]. Several classes of metabolites, including sphingomyelins and branched chain amino acids, have been associated with COPD phenotypes [14,15,16,17]. These studies were often small, used targeted metabolomics, and did not elucidate the sex-specific differences for COPD and emphysema

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Conclusion