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

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

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.

Keywords: COPD; emphysema; lung; network analysis; sex differences; weighted gene co-expression network analysis (WGCNA).

Conflict of interest statement

D.L.D. has received support from the National Institutes of Health, Bayer, Novartis, the Alpha-1 Foundation and a BWH First in Women Precision Medicine Award. W.W.L. reports grants from NIH, non-financial support from Pulmonx and personal fees from Konica Minolta.

Figures

Figure 1
Figure 1
WGCNA results. (A,B). Hierarchical clustering tree (dendrogram) of genes based on human brain co-expression network for COPDGene (A) and SPIROMICS (B). Each “leaf” (short vertical line) corresponds to one gene. The color rows below the dendrogram indicate module membership. (C) Module Preservation between cohorts. Each row of the table corresponds to one SPIROMICS module (labeled by color as well as text), and each column corresponds to one COPDGene module. Numbers in the table indicate metabolite counts in the intersection of the corresponding modules. Coloring of the table encodes−log(p), with p being the Fisher’s exact test p-value for the overlap of the two modules. The darker the red color, the more significant the overlap is. D-E. Heat maps showing association between module eigenvalue and clinical variables in the COPDGene (D) and SPIROMICS (E) cohorts for all subjects, males, and females. Module metabolite assignments are based on the full cohort of profiles. Modules with a negative association were assigned shades of purple and those with a positive association were assigned shades of green based on the 10 log10 FDR or nominal p value for COPDGene and SPIROMICS, respectively.
Figure 2
Figure 2
Preservation of female set-specific modules and male set-specific modules in Figure 2. Preservation of female set-specific modules and male set-specific modules in COPDGene. Each row of the table corresponds to one male set-specific module (labeled by color as well as text), and each column corresponds to one female set-specific module. Numbers in the table indicate metabolite counts in the intersection of the corresponding modules. Coloring of the table encodes−log(p), with p being the Fisher’s exact test p-value for the overlap of the two modules. The stronger the red color, the more significant the overlap is.
Figure 3
Figure 3
Scatter plot of sex specific betas for COPD models in COPDGene. The x-axis represents the beta estimates in the female stratum while the y-axis represents the beta estimates in the male stratum. Point shape corresponds with module assignment. Points are colored by significance in specific strata.
Figure 4
Figure 4
Barplot of beta estimates most divergent by sex. Metabolites along x-axis represent the 10 metabolites with the most sex-divergent beta estimates for COPD models. The red bars represent females, while the blue bars are for males. Only ceramide (d18:1/17:0, d17:1/18:0)* reached significance in males.
Figure 5
Figure 5
Scatter plot of sex specific betas in percent emphysema. The x-axis represents the beta estimates in the female stratum while the y-axis represents the beta estimates in the male stratum. Point shape corresponds with module assignment. Points are colored by significance in specific strata.

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