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2016 ; 14
(1
): 133
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Urine metabolome profiling of immune-mediated inflammatory diseases
#MMPMID27609333
Alonso A
; Julià A
; Vinaixa M
; Domènech E
; Fernández-Nebro A
; Cañete JD
; Ferrándiz C
; Tornero J
; Gisbert JP
; Nos P
; Casbas AG
; Puig L
; González-Álvaro I
; Pinto-Tasende JA
; Blanco R
; Rodríguez MA
; Beltran A
; Correig X
; Marsal S
BMC Med
2016[Sep]; 14
(1
): 133
PMID27609333
show ga
BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are a group of complex
and prevalent diseases where disease diagnostic and activity monitoring is highly
challenging. The determination of the metabolite profiles of biological samples
is becoming a powerful approach to identify new biomarkers of clinical utility.
In order to identify new metabolite biomarkers of diagnosis and disease activity,
we have performed the first large-scale profiling of the urine metabolome of the
six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis,
systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. METHODS:
Using nuclear magnetic resonance, we analyzed the urine metabolome in a discovery
cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups
were recruited representing extreme disease activity (very high vs. very low).
Metabolite association analysis with disease diagnosis and disease activity was
performed using multivariate linear regression in order to control for the
effects of clinical, epidemiological, or technical variability. After multiple
test correction, the most significant metabolite biomarkers were validated in an
independent cohort of 1200 patients and 200 controls. RESULTS: In the discovery
cohort, we identified 28 significant associations between urine metabolite levels
and disease diagnosis and three significant metabolite associations with disease
activity (P FDR?0.05). Using the validation cohort, we validated 26 of the
diagnostic associations and all three metabolite associations with disease
activity (P FDR?0.05). Combining all diagnostic biomarkers using multivariate
classifiers we obtained a good disease prediction accuracy in all IMIDs and
particularly high in inflammatory bowel diseases. Several of the associated
metabolites were found to be commonly altered in multiple IMIDs, some of which
can be considered as hub biomarkers. The analysis of the metabolic reactions
connecting the IMID-associated metabolites showed an over-representation of
citric acid cycle, phenylalanine, and glycine-serine metabolism pathways.
CONCLUSIONS: This study shows that urine is a source of biomarkers of clinical
utility in IMIDs. We have found that IMIDs show similar metabolic changes,
particularly between clinically similar diseases and we have found, for the first
time, the presence of hub metabolites. These findings represent an important step
in the development of more efficient and less invasive diagnostic and disease
monitoring methods in IMIDs.