LC-MS metabolomics of psoriasis patients reveals disease ... · Muhammad Anas Kamleha*, Stuart G....

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Supplementary Material

LC-MS metabolomics of psoriasis patients reveals disease severity-dependent increases in

circulating amino acids that are ameliorated by anti-TNFα treatment

Muhammad Anas Kamleha*, Stuart G. Snowdena*, Dmitry Gaprovb, Gavin J. Blackburnc,

David G. Watsonc, Ning Xud, Mona Ståhled**, Craig E. Wheelocka**

aDepartment of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II,

Karolinska Institutet, SE-17177, Stockholm, Sweden.

bNIH West Coast Metabolomics Center, University of California, Davis, CA, USA

cStrathclyde Institute of Pharmacy and Biomedical Science, 161 Cathedral Street, Glasgow,

United Kingdom.

dDermatology Unit, Department of Medicine, Karolinska Institutet 171 76 , Stockholm,

Sweden

*Contributed equally to the manuscript

**Corresponding authors

Craig Wheelock: [email protected]

Mona Ståhle: [email protected]

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Materials and Methods

Sample preparation for HILIC metabolomics

Samples were removed from storage (-80oC) and thawed on ice. 50µl of EDTA plasma was

used for extraction and plasma protein was precipitated using a 4 volumes ratio of HPLC

grade acetonitrile (Rathburn Chemicals). Samples were vortexed for 5 s, left to stand on ice

for 10 min then centrifuged (Eppendorf Centrifuge 5430 R) at 15000 rcf for 10 min at 4oC.

The supernatant (150 µl) was transferred to a clean Eppendorf tube and stored in -20oC until

the day of analysis. A HILIC quality control (HQC) was prepared by pooling aliquots of 20µl

of each sample from each sample set. On analysis day a 50 µl aliquot of the HILIC extract

was transferred to a Chromacol clear high recovery chromatography glass vials with a

sealed insert (03-FISV Thermo Fischer) and capped with a pre-slit PFTE caps (03-FISV

Thermo Fischer 9-SC(B)-ST1X). Plasma was replaced by HPLC grade water (Milli-Q,

Millipore) to prepare a HILIC extraction blank.

Sample preparation for reversed-phase (RP) metabolomics

Samples were removed from storage (-80oC) and thawed on ice. 50µl of EDTA plasma was

used for extraction and plasma protein was precipitated using a 3 volumes ratio of cold (-

20⁰C) HPLC grade methanol (Rathburn Chemicals). Samples were vortexed for 5 s, left to

stand at -20oC for 2h, then centrifuged (Eppendorf Centrifuge 5430 R) at 15000 rcf for 12

min at 4oC. The supernatant was transferred to a clean Eppendorf tube and stored in -80oC

until the day of analysis. A reversed-phase quality control (RPQC) was produced by pooling

aliquots of 10µ of each sample for each sample set. On analysis day, an aliquot of 20µl of

the RP extract was diluted 1:1 with HPLC grade water (Milli-Q, Millipore) and transferred to a

Chromacol clear high recovery chromatography glass vials with a sealed insert (03-FISV

Thermo Fischer) and capped with a pre-slit PFTE caps (03-FISV Thermo Fischer 9-SC(B)-

ST1X). Plasma was replaced by HPLC grade water (Milli-Q, Millipore) to prepare a RP

extraction blank.

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HILIC metabolomic analysis

Clinical samples, HQC, HILIC extraction blanks and external identification standard mixtures

were analyzed on a Thermo Ultimate 3000 UHPLC and Thermo Q-Exactive Orbitrap mass

spectrometer. 10µl of sample was injected on a Merck-Sequant ZIC-HILIC column (150 ×

4.6 mm, 5µm particle size) fitted with a Merck Sequant ZIC-HILIC guard column (20 × 2.1

mm). A 40min gradient (0.3ml/min flow rate, 23oC column oven) using 0.1% formic acid in

HPLC water (mobile phase A) (Milli-Q, Millipore) and 0.1% formic acid in HPLC acetonitrile

(mobile phase B) (Rathburn Chemicals) was applied. The gradient started at 80% B

reducing to 20% B after 30 min, the system was immediately returned to initial conditions

followed by a 10 min column re-equilibration. Mass spectrometry data was acquired (full

scan mode) in both positive and negative ionization modes (an independent run for each

polarity), using a mass range of 75 and 1000 m/z with a resolution of 140000 at 400 m/z. In

positive mode the spray voltage was 4.0 kV with a capillary temperature of 350oC, a sheath

gas flow of 30 and an auxiliary gas flow of 10 (arbitrary units by vendor). In negative mode,

the spray voltage was 3.6 kV with a capillary temperature of 350oC, a sheath gas flow of 30

and an auxiliary gas flow of 12 (arbitrary units by vendor). The HILIC chromatographic

method was adopted from the work of Zhang et al.(1). A set of six clinical samples (2 healthy

controls, 2 mild and 2 severe psoriasis) was bracketed by two injections of the HQC

material. Samples from each group were randomized across each batch to prevent potential

confounding signal drift.

Reversed-phase metabolomic analysis

Clinical samples, RPQC and extraction blanks were analyzed on a Thermo ultimate 3000

HPLC and Thermo Q-Exactive Orbitrap mass spectrometer. 20µl of samples was injected on

a Thermo Accucore aQ RP C18 column (150 × 2.1 mm, 2.7µm particle size). A 27 min

gradient was used with a flow rate of0.65ml/min, a column temperature of 40oC, 0.1% formic

acid in HPLC water (Milli-Q, Millipore) as mobile phase A and 0.1% formic acid in HPLC

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acetonitrile (Rathburn Chemicals) as mobile phase B. The gradient started with a 3 min

isocratic flow 0.1% B, followed by a linear increase to 99.9% B at 19 min, then a 3 min

isocratic flow and a rapid restoration of starting conditions and column re-equilibration for 5

min. The flow was split post-column 1:1 (source:waste) using an adjustable flow splitter

(Scantec Lab, AB, Gothenburg). Mass spectrometry data were acquired (full scan mode) in

both positive and negative ionization modes, an independent run for each polarity, using a

mass range of 130-900 with 70,000 mass resolution at 400 m/z. In positive mode the spray

voltage was 4.0 kV with a capillary temperature of 350oC, a sheath gas flow of 30 and an

auxiliary gas flow of 10 (arbitrary units by vendor). In negative mode the spray voltage was

3.6 kV, with a capillary temperature of 350oC, a sheath gas flow of 40 and an auxiliary gas

flow of 12 (arbitrary units by vendor). A set of six clinical samples (2 healthy controls, 2 mild

and 2 severe psoriasis) was bracketed by two injections of the HQC material. Samples from

each group were randomized across each batch to prevent potential confounding signal drift.

Safety considerations:

No toxic materials were used in the metabolomics analyses. Chemical reference standards

of toxic nature were handled according to the safety guidelines and the COSSH (Control of

Substances Hazardous to Health) forms provided by the manufacturer.

Data Processing

MSconvert was used to convert and centroid the raw files to mzXML(2). All chromatograms

were evaluated using the open source software package XCMS(3) performed under the

package R. The mzXML files were organized in the working directory by sample class. Peak

picking was performed using the centwave method, allowing the de-convolution of closely

eluting or partially overlapping peaks(4). The peak width range parameter was set to [3-25

seconds] for RP and [10-50] seconds for HILIC. The coefficient of variance (CV) of the HILIC

internal standard cocktail was <35% and for reversed-phase <15%. All CVs of the discussed

metabolites were <30%, except for cystathionine and cytidine (exploratory and validation)

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and cysteine and proline (validation cohort only). The median CV for the identified

metabolites was 14.8% and 16.0% for the exploratory and validation cohorts, respectively.

Metabolite annotation and pathway mapping

Metabolic features from the XCMS output were matched to an in-house accurate

mass/retention time (AMRT) library of reference standard mixtures for a confident annotation

of metabolites. Metabolites were annotated by matching the accurate mass in HILIC (+/-

0.0005Da) and in reversed-phase (+/- 0.004Da) and retention time (+/- 30 s in HILIC and +/-

10 s in reversed-phase) of analyte peaks to those of chemical reference standards (Table

S2). Metabolites of interest were also subjected to fragmentation analysis in a high collision

dissociation cell (HCD) with normalized collision energy (NCE) of 25eV.The fragmentation

spectra were compared to those of reference standards for further identification confidence.

Annotated metabolites of interest were mapped to known metabolic pathways using KEGG’s

pathway mapping tool(5).

Putative Metabolite Annotation Method

Metabolite suggestions for significant metabolite peaks were identified by initially querying

the m/z’s using the Human Metabolome Database’s MS search functionality (

http://www.hmdb.ca/spectra/spectra/ms/search) with the “molecular weight tolerance” set to

0.001Da for HILIC peaks and 0.005Da for reversed phase peaks. If these suggestions failed

to yield an annotation, a broader search was performed in both the Kyoto Encylopedia of

Genes and Genomes (KEGG) and Lipid Maps databases using the “putative ionisation

product” interface of the annotation tool MZedDB

(http://maltese.dbs.aber.ac.uk:8888/hrmet/search/addsearch0.php) using a mass accuracy

of 20ppm for HILIC and 50ppm for reversed phase.

Once metabolite suggestions had been generated, annotation was performed in two

steps. Where possible, the first step was to try to determine the molecular formula of the

underlying metabolite matching the isotope ratio observed for the annotated peak, and the

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expected isotope ratios for the suggested metabolites. The second step aimed to narrow the

metabolite suggestions to a single metabolite annotation. For HILIC and reversed phase

peaks, published literature and metabolite databases were interrogated, to see whether

metabolite suggestions have been reported in blood or other human biofluids, and if the

suggested metabolite ID was plausible within the given biological context. For HILIC data the

second annotation step also included the calculation of predicted retention times of

metabolites based on their partition coefficient (LogP) to determine approximate retention

time (6). The predicted retention times were calculated by plotting the LogP against the

measured retention time of the identification standards (Table S2). The LogP values of

suggested metabolites were then interpolated against the trend line to give an approximate

retention time.

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Supplemental Table 1. Analytical internal standards used for HILIC and Reversed-Phase

mode metabolomic analysis.

Internal Standards Molecular Formula

HILIC

Fluorocinnamic acid C9H7FO2

Fluorocytosine C4H4FN3O

Fluorodeoxyuridine C9H11FN2O5

Fluoronicotinic acid C6H4FNO2

Reversed-Phase

Chloroquine C18H26ClN3

CHAPS C32H58N2O7S

N-(4-fluorophenyl)maleamic acid C10H8FNO3

8-Fluoro-4-hydroxy-2-

(trifluoromethyl)quinoline

C10H5F4NO

CUDA C19H36N2O3

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Supplemental Table 2. HILIC mode and Reversed-Phase identification chemical reference

standards.

HILIC RP

1-(4-Hydroxyphenyl)-2-aminoethanol 1,2-Didecanoyl PC

1,10-Phenanthroline 1,2-Dioleoyl-rac-glycerol

1,7-DimethylXanthine 1,2-Dioleoyl-sn-glycerol

1H-Imidazole-4-ethanamine 1,2-dipalmitoyl-sn-glycero-3-PC

1-Phenylethylamine 10,17-hydroxy-docosahexaenoic acid

2-Hydroxybutanoic acid 11(12)-epoxy-eicosatrienoic acid

2-Indolecarboxylicacid 11,12-dihydroxy-eicosatrienoic acid

2-Methyl-3-oxopropanoyl-CoA 11B-Prostaglandin F2a

2-Oxoglutarate 11-hydroxy-docosahexaenoic acid

2-phenyl Imidazole 11-hydroxy-eicosapentaenoate

2-Phenylglycine 11-hydroxyeicosatetraenoic acid

2-Thiouracil 12(13)-Epoxyoctadecenoic acid

3-Hydroxybutanoate 12,13-Dihydroxyoctadecenoate

3-Phenylpropionylglycine 12,13-Epoxy-octadecadienoate

4-Aminobutanoate 12-hydroxy-heptadecatrienoic acid

4-Coumarate 12-hydroxy-eicosapentaenoate

4-Hydroxyphenylacetaldoxime 12-hydroxyeicosatetraenoic acid

4-hydroxyphenylacetate 12-keto-eicosatetraenoic acid

4-Nitrobenzoate 13-hydrox-octadecatrienoic acid

5-Aminolevulinate 13-hydroxy-octadecadienoate

5-Hydroxyindoleacetate 13-oxo-octadecadienoate

5-methoxytryptophan 14(15)-epoxy-eicosatrienoic acid

5-Methylthioadenosine 14(15)-epoxy-eicosatetraenoic Acid

5-Oxoproline 14,15-dihydroxy-eicosatrienoic acid

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6-Hydroxydopamine 14,15-dihydroxy-eicosatetraenoate

6-Phospho-D-gluconate 14-hydroxy-docosahexaenoic acid

Acetlyglycine 15-deoxy-delta-12,14-Prostaglandin J2

Acetylbenzoate 15-hydroxy-eicosapentaenoate

AcetylCholine 15-hydroxyeicosatetraenoic acid

Acetyl-CoA 15-hydroxyicosatrienoic acid

Acetyl-cysteine 15-keto-eicosatetraenoic acid

Acetylglycine 16(17)-docosapentaenoic acid

Acetyl-leucine 17(18)-epoxy-eicosatetraenoic Acid

Adenine 17,18-dihydroxy-eicosatetraenoate

Adenosine 17-hydroxy-docosahexaenoic acid

Alanyl-Glycine 17-Resolvin D1

Allantoin 18-hydroxy-eicosapentaenoate

Alloxanthine 19(20)-docosapentaenoic acid

Aminocaproate 19,20-dihydroxy-docosapentaenoic acid

Aminovalerate 1-Arachidonyl glycerol

AMP

1-Hexadecyl Lysophosphatidic Acid (sodium

salt)

Amphetamine 1-Linoleoyl glycerol

Antipyrine

1-Octadecyl Lysophosphatidic Acid (sodium

salt)

Arachidonic acid 1-oleoyl glycerol

Ascorbate 1-Oleoyl Lysophosphatidic Acid (sodium salt)

Asparagine 1-Stearoyl-2-Arachidonoyl PC

Aspirin 20-CO2H-Leukotriene B4

ATP 20-hydroxyeicosatetraenoic acid

Azelaic acid 20-OH-Leukotriene B4

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Benzenesulfonate 25-hydroxy Vitamin D2

Benzoate 25-hydroxy Vitamin D3

beta,7alpha,12alpha-Trihydroxy-5alpha-

cholan-24-oic Acid 2-Arachidonyl glycerol

Beta-Alanine 2-cis Eicosenoic Acid

beta-alanine-methyl-ester 2-Linoleoyl glycerol

Betaine 2-oleoyl glycerol

beta-L-fucose 2-trans Eicosenoic Acid

Biopterin 5(6)-epoxy-eicosatrienoic acid

Biotin 5,15-dihydroxyeicosatetraenoic acid

Caffeate 5,6-dihydroxy-eicosatrienoic acid

Caffeine 5,6-dihydroxyeicosatetraenoic acid

Carnitine 5-hydroxy-eicosapentaenoate

Cis-4-Hydroxy-D-Proline 5-hydroxyeicosatetraenoic acid

Cis-Aconitate 5-hydroxyicosatrienoic acid

Citraconate 5-keto-eicosatetraenoic acid

Citramalate 5α-hydroxy-6-keto Cholesterol

Citrate 5α-hydroxy-6-keto Cholesterol

Citrulline 6-keto-Prostaglandin F2a

CMP 8(9)-epoxy-eicosatrienoic acid

creatine 8,15-dihydroxyeicosatetraenoic acid

Creatinine 8,9-dihydroxy-eicosatrienoic acid

Cystathionine 8-hydroxy-docosahexaenoic acid

Cytidine 8-hydroxy-eicosapentaenoate

Cytosine 8-hydroxyeicosatetraenoic acid

dADP 8-hydroxyicosatrienoic acid

dAMP 8-iso-Prostaglandin E2

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Deoxyribose 9(10)-Epoxyoctadecenoic acid

D-Fructose 9,10,13-Trihydroxyoctadecenoate

D-Galactono-1,4-lactone 9,10-Dihydroxyoctadecenoate

D-Galactose 9,12,13-Trihydroxyoctadecenoate

D-Galacturonate 9-HODE cholesteryl ester

D-Gluconic acid 9-hydrox-octadecatrienoic acid

D-Glucosamine 9-hydroxy-eicosapentaenoate

D-Glucosamine 9-hydroxyeicosatetraenoic acid

D-Glucosamine 6-Phosphate 9-hydroxy-octadecadienoate

D-Glucose 9-keto-octadecatrienoic acid

D-Glucose 6-phosphate 9-Octadecenamide

D-Glucuronate 9-oxo-octadecadienoate

Diethylmalonate Arachglycine

Dihydrobiopterin Arachidonic Acid

Dihydroxyphenylacetate Arachidonoyl PAF C-16

Dimethyl 2-oxoglutarate Arachidonoylethanolamine

Dimethylarginine Arachidoyl glycine

Dimethylglycine Archidonyl-glycerol

D-Isoascorbic acid Atorvastatin

DL-3-aminobutyrate Calcitriol

D-Mannose Ceramide (C12:0)

Dopamine Ceramide (C14:0)

D-Sorbitol Ceramide (C16:0)

D-Xylose Ceramide (C18:0)

Ectoine Ceramide (C18:1)

Ethanolamine phosphate Ceramide (C20:0)

Fluorescein Ceramide (C22:0)

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Folate Ceramide (C24:0)

Fumarate Ceramide (C24:1)

GABA Ceramide-1-Phosphate (C16:0)

Galactarate Ceramide-1-Phosphate (C18:1)

Galactoronate Ceramide-1-Phosphate (C24:0)

Gallate Chenodeoxycholic Acid

Glutathione Coenzyme Q10

Glutethimide Delta-Prostaglandin J2

Glycerol Dihydroceramide (C16:0)

Glycine Dihydroceramide (C16:0)

Glycine-C13 Dihydroceramide (C24:0)

Glycocholic acid Docosahexaenoic Acid

Glycolate Docosahexaenoyl Ethanolamide

Gly-Glycine Eicosapentaenoic Acid

Glyoxal Elaidic Acid

GMP Epoxy-keto-octadecenoic Acid

GTP Estradiol

Guanidine Estriol

Guanine Estrone

Guanosine Glucosylceramide (C12:0)

Hippurate Glucosylceramide (C16:0)

Homogentisate Glucosylceramide (C18:0)

Homogentisate Glucosylceramide (C18:1)

Homoserine lactone Glucosylceramide (C24:1)

Hydroxybenzoate Hesperetin

Hypoxanthine KOdiA-PC

Imidazole-4-acetate Lactoceramide (C12:0)

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IMP Lactoceramide (C16:0)

Indole-3-acetate Lactoceramide (C24:0)

Inosine Lactoceramide (C24:1)

Isocitrate Leukotriene B3

Isonicotinic acid Leukotriene B4

Itaconate Leukotriene B5

Kynurenine Leukotriene E4

Lactate Linolenic Acid

L-Adrenaline Linoleoyl ethanolamide

L-Alanine Lipoxin A4

L-Arabinose Lipoxin A5

L-Arginine Lipoxin B4

L-Aspartate Lyso-PAF C-16

L-Cysteine Lyso-PAF C-18 -d4

L-Cysteine-N15 Lyso-PC

L-Cystine Myricetin

L-Glutamate N-Arachidonoyl Taurine

L-Glutamine N-archidonyl-glycine

L-Histidine N-Methyltryptamine

L-Homocysteine N-Nervonoyl Taurine

L-Homoserine N-Oleoyl-L-Serine

Linoleic acid N-Palmitoyl Taurine

Linolenic Acid N-Stearoyl Taurine

Lipoate Oleic Acid

L-isoleucine Oleoylethanolamine

L-Kynurenine PAF C-18

L-Leucine PAF C-18-d4

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L-Lysine Palmitoleic Acid

L-Metanephrine Palmitoyl Serotonin

L-Methionine Palmitoylethanolamide

L-Noradrenaline PGPC

L-Ornithine POV-PC

L-Phenylalanine Prostaglandin B2

L-Proline Prostaglandin D1

L-Serine Prostaglandin D2

L-Threonine Prostaglandin D3

L-Tryptophan Prostaglandin E1

L-Tyrosine Prostaglandin E2

L-Valine Prostaglandin E3

Malate Prostaglandin F2a

Maleic acid Resolvin D1

Malonate Resolvin D2

Malonyl-CoA Resolvin E1

Maltose Retinoic Acid

Mannitol Simvastatin

Mehtylmalonate Sphinganine

Melatonin Sphinganine (d18:0)

Mesaconate Sphinganine-1-Phosphate

Methoxytryptophan Sphinganine-1-Phosphate (d18:0)

Methylcysteine Sphingomyelin (C12:0)

Methylglyoxal Sphingomyelin (C16:0)

Methylhippurate Sphingomyelin (C18:0)

Methylmalonate Sphingomyelin (C18:1)

Methylpicolinate Sphingomyelin (C24:0)

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Methylsalicylate Sphingomyelin (C24:1)

Methylxanthine Sphingosine

N(pi)-Methyl-L-histidine Sphingosine (d18:1)

N6-(L-1,3-Dicarboxypropyl)-L-lysine Sphingosine (d20:1)

N6-Acetyl-L-Lysine Sphingosine-1-Phosphate

N-Acetyl-D-Galactosamine Sphingosine-1-Phosphate (d18:1)

N-Acetyl-D-Glucosamine Thromboxane B2

N-Acetyl-D-glucosamine 6-phosphate trans-Leukotriene B4

N-Acetyl-L-aspartate Vitamin D2

N-Acetyl-L-glutamate Vitamin D3

NAD+

NADP+

NADPH

N-Formyl-L-methionine

Nicotinamide

Nicotinate

O-Acetylcarnitine

O-Acetyl-L-serine

Oxalate

Oxaloacetate

Pantothenate

PE(18:1(11Z)/18:1(11Z))

Phenylephrine

Phenyllactate

Phosphocreatine

Phosphoenolpyruvate

Phthalate

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Picolinic acid

Pipecolate

Putrescine

Pyridoxal

Pyridoxamine

Pyruvate

Retinoic Acid

Riboflavin

Ribose

S-Adenosyl-L-homocysteine

S-Adenosyl-L-methionine

Salicylate

Sarcosine

Sebacic Acid

Sepiapterin

serotonin

Spermidine

Spermine

Succinate

Sucrose

Taurine

taurocholate

Taurocholate

Theobromine

Theophylline

Thymidine

Thymine

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trans-4-Hydroxy-L-proline

Triethanolamine

UDP-N-acetyl-D-glucosamine

UMP

Uracil

Urate

Uridine

Xanthine

Xanthosine

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Supplemental Table 3. Summary of metabolic perturbations associated with psoriasis disease severity for the exploratory cohort.

Control vs. Mild Control vs. Severe Mild vs. Severe

FCa padjb qc Fdd padj

b qc FCd padjb qc

5-oxoproline 1.0 9.94E-01 7.47E-01 2.0 1.68E-02 7.06E-03 2.0 2.72E-02 1.29E-02

9-Octadecenamide 1.0 9.94E-01 7.61E-01 1.0 1.00E+00 4.32E-01 1.0 9.99E-01 5.16E-01

Acetyl-cysteine 1.2 7.29E-01 5.36E-01 0.9 7.03E-01 2.95E-01 0.7 1.96E-01 1.03E-01

Acetylgalactosamine 0.8 7.37E-01 5.65E-01 1.6 1.76E-01 7.76E-02 1.9 2.92E-02 1.75E-02

Acetylglucosamine 1.2 3.80E-01 2.95E-01 2.4 9.12E-03 3.90E-03 2.0 2.78E-02 1.45E-02

Acetyl-glycine 0.7 5.20E-01 3.91E-01 0.9 9.80E-01 3.79E-01 1.3 5.59E-01 3.05E-01

Acetylleucine 0.8 1.74E-01 1.36E-01 1.0 1.00E+00 4.27E-01 1.3 4.41E-01 2.28E-01

Adenine 0.0 7.29E-01 5.44E-01 0.0 4.66E-01 2.08E-01 1.1 4.53E-01 2.36E-01

Adenosine 1.3 5.20E-01 4.02E-01 2.8 3.47E-01 1.49E-01 2.1 4.95E-01 2.62E-01

Alanine 0.8 7.29E-01 5.39E-01 1.3 3.47E-01 1.42E-01 1.7 1.96E-01 1.04E-01

Alanyl-Glycine 0.3 7.37E-01 5.74E-01 1.0 1.00E+00 4.32E-01 4.1 4.41E-01 2.22E-01

Allantoin 1.0 9.94E-01 7.75E-01 1.7 8.73E-02 3.83E-02 1.7 1.17E-01 5.83E-02

AMP 1.0 1.00E+00 7.82E-01 1.8 2.84E-01 1.17E-01 1.8 2.44E-01 1.27E-01

Arginine 1.8 2.24E-01 1.75E-01 2.5 2.53E-02 1.06E-02 1.4 4.53E-01 2.34E-01

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Asparagine 1.3 3.80E-01 2.97E-01 2.2 2.60E-03 1.14E-03 1.7 2.78E-02 1.45E-02

Aspartate 2.4 1.42E-01 1.11E-01 2.4 1.02E-02 4.48E-03 1.0 9.99E-01 5.17E-01

Azelaic acid 0.3 5.90E-01 4.68E-01 1.0 1.00E+00 4.36E-01 3.7 3.52E-01 1.88E-01

Benzoate 1.1 9.39E-01 7.11E-01 1.1 9.84E-01 3.86E-01 1.0 9.99E-01 5.13E-01

Betaine 1.2 1.42E-01 1.11E-01 1.2 3.52E-01 1.55E-01 1.0 9.62E-01 4.95E-01

Biotin 0.6 9.39E-01 7.12E-01 2.8 5.07E-01 2.27E-01 4.5 4.57E-01 2.42E-01

Caffeine 1.0 9.94E-01 7.73E-01 1.1 1.00E+00 4.06E-01 1.0 9.99E-01 5.19E-01

Carnitine 1.4 5.20E-01 3.72E-01 2.1 9.28E-02 4.08E-02 1.5 3.61E-01 1.93E-01

Chenodeoxycholic Acid 1.1 9.39E-01 7.12E-01 0.8 3.06E-01 1.29E-01 0.7 2.80E-01 1.47E-01

Citrulline 1.2 3.48E-01 2.42E-01 2.3 5.47E-04 2.38E-04 2.0 1.59E-02 6.89E-03

Creatinine 1.2 5.20E-01 3.93E-01 1.4 7.09E-02 3.06E-02 1.2 2.69E-01 1.41E-01

Cystathionine 0.9 7.37E-01 5.72E-01 0.8 1.32E-02 5.81E-03 0.9 3.71E-01 1.98E-01

Cystine 1.4 3.80E-01 2.85E-01 2.8 5.43E-03 2.30E-03 2.0 2.78E-02 1.49E-02

Cytidine 1.2 5.77E-01 4.44E-01 2.2 4.75E-03 1.71E-03 1.5 1.99E-02 9.02E-03

Cytosine 0.3 5.20E-01 4.07E-01 0.9 1.00E+00 4.24E-01 3.2 4.41E-01 2.26E-01

Dimethylglycine 0.9 7.86E-01 6.19E-01 1.2 5.64E-01 2.48E-01 1.3 4.17E-01 2.12E-01

Docosahexaenoic Acid 1.0 9.94E-01 7.75E-01 0.8 2.10E-01 9.02E-02 0.8 4.57E-01 2.45E-01

20

Dopamine 1.0 7.86E-01 6.15E-01 0.8 8.19E-02 3.58E-02 0.8 3.18E-01 1.67E-01

GABA 0.9 9.30E-01 6.86E-01 2.1 1.76E-01 7.59E-02 2.4 1.87E-01 9.56E-02

GlcCer (C16:0) 1.2 5.20E-01 4.05E-01 1.5 5.70E-02 2.51E-02 1.2 3.33E-01 1.76E-01

Glutamic acid 1.0 9.94E-01 7.74E-01 3.0 1.77E-02 7.80E-03 3.0 2.78E-02 1.40E-02

Glutamine 1.3 2.24E-01 1.70E-01 2.0 2.32E-03 9.87E-04 1.6 2.72E-02 1.33E-02

Glycerol 0.8 5.65E-01 4.52E-01 0.7 3.47E-01 1.51E-01 1.0 9.62E-01 4.90E-01

Glycine 1.2 5.20E-01 4.04E-01 2.1 1.32E-02 5.65E-03 1.8 6.17E-02 3.18E-02

Glycocholic acid 1.1 9.94E-01 7.61E-01 2.8 1.76E-01 7.62E-02 2.6 2.57E-01 1.34E-01

Glycolate 0.8 5.20E-01 3.86E-01 0.8 3.47E-01 1.46E-01 1.0 9.57E-01 4.82E-01

Guanine 1.0 9.88E-01 7.27E-01 1.1 7.03E-01 2.97E-01 1.1 8.83E-01 4.50E-01

Hippurate 1.0 9.94E-01 7.77E-01 1.3 4.66E-01 2.07E-01 1.3 5.59E-01 3.07E-01

Histidine 1.2 3.80E-01 2.94E-01 1.9 1.55E-03 6.77E-04 1.6 2.72E-02 1.30E-02

Hydroxybenzoate 2.0 8.56E-01 6.54E-01 6.8 3.47E-01 1.51E-01 3.4 5.06E-01 2.71E-01

Hydroxyproline 1.3 5.20E-01 3.71E-01 2.9 2.88E-02 1.27E-02 2.3 8.63E-02 4.61E-02

Hypoxanthine 0.7 5.20E-01 3.97E-01 0.8 3.47E-01 1.45E-01 1.1 9.62E-01 4.91E-01

Indole-3-acetate 1.1 9.94E-01 7.49E-01 1.1 8.19E-01 3.33E-01 1.0 9.99E-01 5.08E-01

Inosine 0.7 8.03E-01 6.32E-01 0.5 2.67E-01 1.10E-01 0.6 4.56E-01 2.38E-01

21

Isoleucine 1.3 1.42E-01 1.11E-01 1.9 2.53E-02 1.09E-02 1.5 1.32E-01 7.09E-02

Itaconate 0.7 3.80E-01 2.86E-01 1.0 1.00E+00 4.21E-01 1.5 4.41E-01 2.29E-01

Kynurenine 1.0 9.39E-01 7.02E-01 1.3 8.19E-02 3.52E-02 1.3 7.86E-02 4.16E-02

Lecuine 1.1 5.20E-01 3.88E-01 1.6 2.98E-01 1.25E-01 1.4 7.55E-01 3.98E-01

Linolenic Acid 0.9 8.03E-01 6.28E-01 1.0 1.00E+00 4.02E-01 1.2 5.97E-01 3.33E-01

Lysine 1.5 3.50E-01 2.51E-01 2.8 9.71E-03 4.21E-03 1.9 7.86E-02 4.05E-02

Malate 1.0 9.94E-01 7.75E-01 2.1 2.67E-01 1.10E-01 2.1 3.18E-01 1.67E-01

Mannitol 2.1 7.37E-01 5.75E-01 2.6 1.59E-01 6.67E-02 1.2 8.91E-01 4.58E-01

Methionine 1.3 1.42E-01 1.11E-01 2.1 1.97E-02 8.67E-03 1.6 1.32E-01 6.97E-02

Methoxytryptophan 1.0 9.94E-01 7.35E-01 2.3 3.47E-01 1.50E-01 2.2 4.41E-01 2.28E-01

Methylcysteine 1.1 9.36E-01 6.90E-01 0.8 3.47E-01 1.50E-01 0.7 3.47E-01 1.85E-01

Methylhippurate 1.0 9.94E-01 7.71E-01 1.4 2.84E-01 1.19E-01 1.4 3.21E-01 1.70E-01

Methylmalonate 1.0 9.94E-01 7.78E-01 1.0 1.00E+00 4.30E-01 1.0 9.99E-01 5.23E-01

Methylpicolinate 0.8 5.36E-01 4.24E-01 0.7 1.26E-01 5.32E-02 0.9 4.57E-01 2.44E-01

Methylsalicylate 0.9 9.94E-01 7.32E-01 0.7 2.84E-01 1.16E-01 0.7 4.57E-01 2.41E-01

Nicotinamide 0.8 5.97E-01 4.77E-01 0.7 1.26E-01 5.42E-02 0.8 3.47E-01 1.84E-01

N-Oleoyl-L-Serine 1.1 9.51E-01 7.17E-01 1.6 4.46E-01 1.94E-01 1.4 5.83E-01 3.19E-01

22

Ornithine 1.4 5.20E-01 3.77E-01 3.4 9.12E-03 3.79E-03 2.5 2.78E-02 1.48E-02

Palmitoleic Acid 1.1 8.69E-01 6.61E-01 1.3 1.71E-01 7.12E-02 1.2 5.36E-01 2.89E-01

Pantothenate 1.2 7.86E-01 6.03E-01 1.6 5.54E-02 2.38E-02 1.3 4.75E-01 2.55E-01

PGPC 1.7 7.86E-01 6.12E-01 3.2 5.00E-01 2.22E-01 1.8 7.55E-01 3.95E-01

Phenylalanine 1.0 9.94E-01 7.70E-01 1.3 2.64E-02 1.15E-02 1.3 3.59E-02 1.92E-02

Pipecolate 0.8 7.37E-01 5.77E-01 0.7 3.80E-01 1.68E-01 0.9 8.75E-01 4.45E-01

POV-P 0.8 5.20E-01 4.01E-01 0.8 1.33E-01 5.77E-02 0.9 5.91E-01 3.27E-01

Proline 1.3 3.09E-01 2.20E-01 1.8 1.75E-02 7.50E-03 1.9 1.29E-01 6.36E-02

Riboflavin 1.4 7.37E-01 5.71E-01 2.1 2.10E-01 9.05E-02 1.5 5.11E-01 2.76E-01

Ribose 0.7 5.65E-01 4.50E-01 1.5 3.47E-01 1.42E-01 2.0 1.32E-01 6.97E-02

Salicylate 2.0 8.56E-01 6.54E-01 6.8 3.47E-01 1.51E-01 3.4 4.32E-01 3.82E-01

Sebacic acid 0.9 7.80E-01 5.95E-01 0.8 3.58E-01 1.58E-01 0.9 8.00E-01 4.20E-01

Serine 1.2 5.20E-01 3.86E-01 2.0 6.30E-03 2.76E-03 1.7 2.78E-02 1.48E-02

Sphingomyelin (C16:0) 1.1 9.39E-01 7.06E-01 1.3 3.06E-01 1.30E-01 1.2 5.48E-01 2.96E-01




23

Sphingosine-1-phosphate 1.0 9.39E-01 7.08E-01 1.2 4.39E-02 1.90E-02 1.3 1.97E-02 1.05E-02

Succinate 1.0 9.94E-01 7.78E-01 1.0 1.00E+00 4.30E-01 1.0 9.99E-01 5.23E-01

Taurine 1.2 4.79E-01 3.34E-01 1.9 3.59E-04 1.58E-04 1.6 1.62E-02 8.67E-03

Threonine 1.4 1.42E-01 1.11E-01 2.7 5.47E-04 2.41E-04 1.9 1.62E-02 8.12E-03

Thymine 0.6 9.30E-01 6.85E-01 1.1 1.00E+00 4.19E-01 1.7 7.55E-01 4.00E-01

Tryptophan 1.0 9.94E-01 7.49E-01 1.1 3.58E-01 1.57E-01 1.1 4.71E-01 2.51E-01

Tyrosine 1.4 5.20E-01 3.74E-01 1.8 2.88E-02 1.25E-02 1.3 4.41E-01 2.23E-01

Uracil 1.0 9.94E-01 7.70E-01 0.9 9.84E-01 3.85E-01 0.8 8.91E-01 4.59E-01

Uridine 0.8 1.42E-01 1.11E-01 0.9 3.47E-01 1.48E-01 1.1 7.55E-01 3.91E-01

Valine 1.2 1.42E-01 1.11E-01 1.2 3.52E-01 1.55E-01 1.0 9.62E-01 4.95E-01

Vitamin D3 1.1 9.39E-01 7.07E-01 1.3 2.24E-01 9.62E-02 1.2 5.06E-01 2.71E-01

Xanthine 0.8 3.77E-01 2.67E-01 1.0 1.00E+00 3.97E-01 1.3 3.00E-01 1.56E-01

a Fold change relative to control

b FDR adjusted p-value from t-test

c Direct estimate of FDR as a q-value

d Fold change relative to mild

24

Supplemental Table 4. Summary of metabolic perturbations associated with psoriasis disease severity for the validation cohort.

Control vs. Mild Control vs. Severe Mild vs. Severe Severe vs. Treated

FCa padjb qc FCa padj

b qc FCd padjb qc FCe padj

b qc

1,2-Didecanoyl PC 0.3 5.84E-01 4.14E-01 0.1 1.67E-01 7.86E-02 0.5 3.52E-01 1.98E-01 1.3 7.85E-01 6.44E-01

5-hydroxy-6-keto

Cholesterol 1.4 6.95E-01 5.23E-01 0.5 2.07E-01 9.59E-02 0.3 1.46E-01 8.11E-02 0.5 6.00E-01 4.92E-01

5-methoxytryptophan 1.3 6.57E-01 4.78E-01 1.2 5.31E-01 2.45E-01 0.9 8.34E-01 4.44E-01 0.9 7.44E-01 6.11E-01

9-Octadecenamide 1.0 8.99E-01 6.89E-01 0.9 1.58E-01 7.42E-02 0.8 3.23E-01 1.72E-01 1.0 7.85E-01 6.44E-01

Acetlyglycine 0.8 6.95E-01 5.12E-01 0.8 3.81E-01 1.75E-01 1.0 9.55E-01 5.43E-01 1.2 7.05E-01 5.78E-01

Acetylbenzoate 1.0 8.98E-01 6.71E-01 0.9 5.86E-01 2.72E-01 1.0 8.77E-01 4.81E-01 1.1 7.85E-01 6.44E-01

Acetylgalactosamine 1.7 3.43E-01 2.52E-01 1.5 4.37E-02 2.03E-02 0.9 8.34E-01 4.45E-01 0.7 7.77E-01 6.38E-01

Acetylglucosamine 1.0 9.37E-01 7.26E-01 1.3 3.83E-03 1.81E-03 1.3 2.60E-02 1.48E-02 1.1 1.76E-01 1.45E-01

Acetylglycine 1.0 1.00E+0 7.51E-01 1.0 9.99E-01 4.33E-01 1.0 9.42E-01 5.23E-01 1.0 1.00E+00 8.20E-01

Acetyl-leucine 1.0 8.99E-01 6.82E-01 1.1 5.31E-01 2.48E-01 1.2 3.73E-01 2.12E-01 1.1 8.60E-01 7.06E-01

Adenosine 1.0 9.33E-01 7.21E-01 1.0 9.38E-01 4.06E-01 0.9 8.34E-01 4.57E-01 1.0 9.36E-01 7.68E-01

Alanine 1.7 6.57E-01 4.72E-01 1.0 9.83E-01 4.25E-01 0.6 3.86E-01 2.20E-01 1.9 2.01E-01 1.65E-01

Alanyl-Glycine 2.5 6.95E-01 5.28E-01 1.0 9.09E-01 3.94E-01 0.4 5.65E-01 3.14E-01 1.0 8.67E-01 7.12E-01

25

Allantoin 0.8 5.84E-01 4.24E-01 0.8 1.35E-01 6.14E-02 1.0 9.30E-01 5.03E-01 1.0 9.36E-01 7.68E-01

Aminocaproate 2.0 6.95E-01 5.29E-01 0.6 4.33E-01 2.04E-01 0.3 3.52E-01 2.00E-01 1.4 7.85E-01 6.44E-01

Aminovalerate 1.2 6.95E-01 5.17E-01 1.4 4.45E-02 2.10E-02 1.2 3.72E-01 2.10E-01 0.8 2.24E-01 1.83E-01

AMP 1.2 6.95E-01 5.26E-01 1.8 1.35E-01 6.38E-02 1.5 3.39E-01 1.87E-01 1.2 7.19E-01 5.90E-01

Arachidonic acid 0.9 8.57E-01 6.27E-01 1.0 9.43E-01 4.12E-01 1.0 9.47E-01 5.32E-01 0.8 6.46E-01 5.30E-01

Arginine 1.4 2.36E-01 1.79E-01 2.3 2.28E-03 1.08E-03 1.7 4.31E-02 2.39E-02 0.5 5.97E-02 4.90E-02

Asparagine 1.0 9.99E-01 7.45E-01 1.2 2.57E-01 1.19E-01 1.2 3.39E-01 1.80E-01 0.7 1.45E-01 1.19E-01

Aspartate 1.3 5.94E-01 4.42E-01 2.0 4.04E-05 1.91E-05 1.5 3.79E-02 2.09E-02 0.7 3.83E-01 3.14E-01

Azelaic acid 1.1 9.14E-01 7.09E-01 0.8 3.37E-01 1.57E-01 0.7 4.74E-01 2.59E-01 1.1 8.52E-01 6.99E-01

Betaine 1.2 6.95E-01 5.17E-01 1.4 3.03E-02 1.38E-02 1.2 3.39E-01 1.82E-01 0.8 1.98E-01 1.62E-01

Caffeine 0.9 9.37E-01 7.24E-01 1.0 1.00E+0 4.68E-01 1.1 9.30E-01 5.09E-01 1.0 1.00E+00 8.20E-01

Carnitine 1.1 6.95E-01 5.06E-01 1.1 7.80E-01 3.53E-01 0.9 8.00E-01 4.23E-01 2.6 6.00E-01 4.92E-01

Chenodeoxycholic Acid 0.9 8.99E-01 6.93E-01 1.2 4.13E-01 1.95E-01 1.3 3.49E-01 1.94E-01 1.0 7.85E-01 6.44E-01

Citrulline 1.2 5.16E-01 3.46E-01 1.9 1.52E-05 7.18E-06 1.6 4.17E-04 2.38E-04 0.6 5.02E-02 4.12E-02

Creatinine 1.1 8.99E-01 6.93E-01 1.5 3.32E-02 1.53E-02 1.4 7.16E-02 4.06E-02 0.6 4.07E-02 3.34E-02

Cystathionine 0.7 2.13E-01 1.62E-01 0.3 4.71E-06 2.22E-06 0.4 1.87E-02 9.34E-03 1.5 6.46E-01 5.30E-01

Cystine 1.1 8.57E-01 6.35E-01 1.8 2.78E-04 1.20E-04 1.7 2.93E-03 1.67E-03 0.9 5.71E-01 4.68E-01

26

Cytidine 1.4 6.95E-01 5.23E-01 2.5 4.04E-02 1.89E-02 1.8 2.01E-01 1.12E-01 0.6 4.56E-01 3.74E-01

Cytosine 0.6 5.84E-01 4.15E-01 0.6 1.74E-01 8.22E-02 0.9 8.34E-01 4.48E-01 1.8 5.47E-01 4.49E-01

Diethylmalonate 1.1 8.99E-01 6.90E-01 1.3 3.16E-01 1.42E-01 1.2 5.02E-01 2.81E-01 0.8 2.37E-01 1.94E-01

Dihydroxyphenylacetate 1.2 8.57E-01 6.40E-01 1.0 1.00E+0 4.61E-01 0.8 3.72E-01 2.09E-01 1.2 5.91E-01 4.85E-01

Dimethylarginine 1.2 6.95E-01 5.11E-01 2.2 1.32E-03 6.23E-04 1.8 2.06E-02 1.18E-02 0.7 2.01E-01 1.65E-01

Dimethylglycine 1.0 9.14E-01 7.00E-01 1.6 8.00E-03 3.77E-03 1.6 1.43E-02 6.94E-03 0.8 6.00E-01 4.92E-01

Docosahexaenoic Acid 0.8 3.43E-01 2.53E-01 0.7 1.50E-02 6.90E-03 0.9 5.70E-01 3.21E-01 1.0 1.00E+00 8.20E-01

Galactoronate 2.1 5.84E-01 4.13E-01 1.8 1.35E-01 6.01E-02 0.9 9.30E-01 5.01E-01 1.4 5.49E-01 4.50E-01

GlcCer (C16:0) 1.3 5.16E-01 3.57E-01 1.6 1.53E-02 7.23E-03 1.2 2.48E-01 1.41E-01 1.0 8.67E-01 7.12E-01

Glutamate 1.1 8.99E-01 6.85E-01 2.2 7.64E-03 3.48E-03 2.0 2.27E-02 1.29E-02 0.8 6.00E-01 4.92E-01

Glutamine 1.2 6.00E-01 4.55E-01 1.7 4.71E-04 2.22E-04 1.5 1.87E-02 9.71E-03 0.6 2.24E-02 1.84E-02

Glycerol 1.3 6.57E-01 4.78E-01 1.2 3.36E-01 1.54E-01 1.0 9.42E-01 5.22E-01 1.1 6.35E-01 5.21E-01

Glycine 1.3 5.16E-01 3.63E-01 1.7 3.79E-03 1.71E-03 1.3 1.17E-01 6.47E-02 0.5 5.50E-03 4.51E-03

Glycocholic acid 1.2 8.57E-01 6.44E-01 1.2 8.76E-01 3.83E-01 1.0 9.55E-01 5.43E-01 0.7 5.30E-01 4.35E-01

Glycolate 1.5 2.43E-02 1.84E-02 1.2 1.47E-01 6.92E-02 0.8 1.95E-01 1.06E-01 1.1 7.19E-01 5.90E-01

Gly-Glycine 0.9 6.00E-01 4.51E-01 0.9 2.57E-01 1.20E-01 1.0 9.42E-01 5.26E-01 0.9 6.00E-01 4.92E-01

Hippurate 1.4 6.95E-01 5.24E-01 0.6 3.37E-01 1.57E-01 0.4 1.95E-01 1.05E-01 1.0 9.62E-01 7.89E-01

27

Histidine 1.1 8.81E-01 6.60E-01 1.0 1.00E+0 4.70E-01 1.0 8.34E-01 4.44E-01 1.2 5.48E-01 4.50E-01

Hydroxyproline 1.2 6.95E-01 5.21E-01 1.8 1.10E-02 5.10E-03 1.5 4.50E-02 2.56E-02 0.7 1.98E-01 1.62E-01

Hypoxanthine 1.0 9.23E-01 7.15E-01 1.6 2.15E-02 9.87E-03 1.5 5.05E-02 2.88E-02 0.9 8.67E-01 7.12E-01

Inosine 1.0 1.00E+0 7.57E-01 3.8 1.40E-02 6.35E-03 3.8 2.06E-02 1.14E-02 0.5 1.25E-01 1.03E-01

Kynurenine 0.9 8.06E-01 6.04E-01 1.0 1.00E+0 4.64E-01 1.1 7.56E-01 3.99E-01 0.9 2.12E-01 1.74E-01

Leucine/Isoleucine 1.0 9.50E-01 7.31E-01 0.8 2.52E-01 1.15E-01 0.9 4.63E-01 2.52E-01 0.9 7.05E-01 5.78E-01

Linoleic acid 0.9 6.95E-01 5.27E-01 0.9 7.00E-01 3.11E-01 1.0 9.30E-01 5.09E-01 0.9 5.71E-01 4.68E-01

Linolenic Acid 0.7 2.13E-01 1.61E-01 1.0 1.00E+0 4.43E-01 1.4 3.46E-01 1.91E-01 0.8 5.85E-01 4.80E-01

Lysine 0.8 6.57E-01 4.81E-01 1.1 7.16E-01 3.20E-01 1.3 2.44E-01 1.38E-01 0.6 2.12E-01 1.74E-01

Mannitol 1.1 9.14E-01 7.10E-01 1.0 1.00E+0 4.49E-01 0.9 8.34E-01 4.60E-01 1.8 4.56E-01 3.74E-01

Mehtylmalonate 2.2 3.43E-01 2.52E-01 1.2 2.88E-01 1.32E-01 0.5 2.33E-01 1.32E-01 1.3 4.61E-01 3.78E-01

Methionine 1.5 1.75E-01 1.16E-01 1.8 2.80E-04 1.27E-04 1.3 1.18E-01 6.72E-02 0.4 2.86E-03 2.35E-03

Methylcysteine 0.9 8.81E-01 6.62E-01 1.1 7.16E-01 3.28E-01 1.1 5.03E-01 2.85E-01 1.3 6.22E-01 5.10E-01

Methylhippurate 1.1 8.99E-01 6.84E-01 1.1 7.74E-01 3.48E-01 1.0 9.58E-01 5.46E-01 1.0 8.09E-01 6.64E-01

Methylsalicylate 0.7 8.57E-01 6.43E-01 3.1 3.32E-02 1.56E-02 4.3 1.97E-02 1.06E-02 0.4 5.02E-02 4.12E-02

Methylxanthine 0.8 7.42E-01 5.64E-01 1.0 1.00E+0 4.53E-01 1.3 5.80E-01 3.31E-01 1.0 9.59E-01 7.87E-01

Nicotinamide 0.9 8.81E-01 6.61E-01 0.8 3.25E-01 1.47E-01 0.9 7.60E-01 4.07E-01 1.1 5.47E-01 4.49E-01

28

N-Nervonoyl Taurine 0.9 8.06E-01 6.01E-01 0.7 8.85E-02 4.07E-02 0.8 7.60E-01 4.05E-01 1.3 4.61E-01 3.78E-01

N-Oleoyl-L-Serine 0.8 5.23E-01 3.79E-01 1.1 7.16E-01 3.22E-01 1.3 2.03E-01 1.15E-01 1.1 7.85E-01 6.44E-01

N-Stearoyl Taurine 0.8 6.00E-01 4.51E-01 0.9 3.78E-01 1.72E-01 1.1 8.34E-01 4.59E-01 1.1 8.09E-01 6.64E-01

Oleic Acid 0.8 5.84E-01 4.31E-01 0.8 3.82E-01 1.77E-01 1.0 9.47E-01 5.35E-01 0.7 3.68E-01 3.02E-01

Ornithine 1.3 2.13E-01 1.57E-01 2.9 2.80E-04 1.31E-04 2.3 2.57E-03 1.29E-03 0.4 1.35E-02 1.11E-02

Palmitoleic Acid 0.8 4.94E-01 3.26E-01 0.8 3.26E-01 1.49E-01 1.1 8.77E-01 4.77E-01 1.1 7.54E-01 6.19E-01

PGPC 1.3 7.43E-01 5.68E-01 1.2 7.16E-01 3.26E-01 0.9 9.42E-01 5.24E-01 0.5 3.27E-01 2.69E-01

Phenylalanine 1.0 7.58E-01 5.77E-01 1.5 3.01E-04 1.42E-04 1.5 4.17E-04 2.14E-04 0.7 1.98E-01 1.62E-01

Phenyllactate 0.9 7.87E-01 5.91E-01 1.0 9.99E-01 4.35E-01 1.2 5.00E-01 2.78E-01 1.2 5.93E-01 4.87E-01

Pipecolate 1.0 9.14E-01 7.03E-01 1.0 1.00E+0 4.53E-01 0.9 8.77E-01 4.82E-01 0.9 6.78E-01 5.56E-01

POV-PC 0.7 2.43E-02 1.84E-02 0.7 2.13E-04 9.95E-05 1.0 9.42E-01 5.19E-01 1.1 7.05E-01 5.78E-01

Proline 1.5 3.43E-01 2.60E-01 1.9 2.15E-02 1.01E-02 1.2 5.19E-01 2.93E-01 0.6 1.82E-01 1.50E-01

Retinoic Acid 1.0 9.99E-01 7.47E-01 0.8 3.95E-01 1.82E-01 0.8 5.65E-01 3.17E-01 1.3 5.47E-01 4.49E-01

Ribose 1.3 6.95E-01 5.12E-01 1.1 9.38E-01 4.08E-01 0.8 5.71E-01 3.25E-01 1.4 4.56E-01 3.74E-01

Salicylate 1.5 6.95E-01 5.00E-01 1.5 2.38E-01 1.08E-01 1.0 4.92E-01 2.72E-01 1.2 4.56E-01 3.74E-01

Sebacic Acid 1.9 5.84E-01 4.34E-01 0.7 1.21E-01 5.38E-02 0.4 2.09E-01 1.19E-01 1.1 7.77E-01 6.38E-01

Serine 1.1 7.09E-01 5.43E-01 1.6 1.83E-04 8.40E-05 1.5 2.93E-03 1.60E-03 0.8 1.98E-01 1.62E-01

29

Sphingomyelin (C16:0) 1.3 5.16E-01 3.69E-01 1.9 8.21E-02 3.73E-02 1.5 3.39E-01 1.86E-01 1.4 5.49E-01 4.50E-01

Sphingomyelin (C18:0) 1.1 9.14E-01 7.08E-01 1.3 3.98E-01 1.88E-01 1.2 6.31E-01 3.53E-01 1.1 7.85E-01 6.44E-01

Sphingosine-1-phosphate 1.3 2.13E-01 1.57E-01 1.9 3.01E-04 1.41E-04 1.5 1.87E-02 9.88E-03 0.9 6.00E-01 4.92E-01

Sucrose 0.2 6.95E-01 5.09E-01 0.2 4.44E-01 2.11E-01 1.1 8.34E-01 4.54E-01 1.0 9.40E-01 7.71E-01

Taurine 0.9 6.95E-01 5.14E-01 1.5 7.90E-04 3.72E-04 1.6 7.12E-04 4.05E-04 0.8 1.82E-01 1.49E-01

Taurocholate 1.6 5.84E-01 4.35E-01 1.7 3.98E-01 1.85E-01 1.1 9.47E-01 5.35E-01 0.5 4.39E-01 3.60E-01

Threonine 1.3 1.75E-01 1.22E-01 2.6 6.36E-06 3.00E-06 2.0 8.75E-05 4.98E-05 0.3 5.28E-05 4.33E-05

Tryptophan 1.0 8.99E-01 6.88E-01 0.8 3.57E-02 1.69E-02 0.8 9.63E-02 5.38E-02 1.0 9.59E-01 7.87E-01

Tyrosine 1.1 7.42E-01 5.61E-01 0.9 3.98E-01 1.86E-01 0.8 1.98E-01 1.09E-01 0.9 7.85E-01 6.44E-01

Uridine 1.0 9.99E-01 7.47E-01 1.1 5.31E-01 2.50E-01 1.1 5.45E-01 3.05E-01 1.0 8.09E-01 6.64E-01

Valine 1.2 6.95E-01 5.17E-01 1.5 2.02E-02 9.20E-03 1.3 2.81E-01 1.56E-01 0.7 1.97E-01 1.62E-01

Xanthine 1.0 1.00E+0 7.54E-01 1.1 3.78E-01 1.72E-01 1.1 4.83E-01 2.65E-01 0.9 6.78E-01 5.56E-01

a Fold change relative to control

b FDR adjusted p-value from t-test

c Direct estimate of FDR as a q-value

d Fold change relative to mild

e Fold change relative to severe untreated

30

Supplemental Table 5. Changes in putatively identified (accurate mass) metabolomic

features in severe psoriasis relative to control patients in the exploration cohort.

m/z RTa Putative Annotation FCb padjc qd

237.0489 0.51 Cystathionine sulfoxide 0.24 1.68E-12 1.41E-12

237.0435 0.52 Benzoylmalic acid 0.26 1.48E-11 1.24E-11

195.0741 0.51 Aminohippuric acid 0.23 1.49E-10 1.65E-10

351.0150 0.52 Apigenin sulfate 0.22 2.06E-09 2.47E-09

132.0289 0.55 Iminodiacetic acid 0.33 9.15E-08 7.67E-08

305.0367 0.51 Dihydroxybenzoic acid 0.05 9.63E-08 8.07E-08

315.2540 12.94 Dihydroxy-octadecanoic acid 0.38 1.90E-07 1.59E-07

429.3254 8.03 Glyceryl lactooleate 0.27 2.78E-07 3.09E-07

243.0694 8.58 Indolylacryloylglycine 3.29 3.64E-07 3.05E-07

152.0705 15.38 Dopamine quinone 0.03 5.07E-07 2.63E-07

261.0457 0.51 Galactose 1-phosphate 0.31 5.89E-07 6.47E-07

216.0702 0.55 Alanyl-Glutamate 0.30 7.49E-07 6.28E-07

168.1018 13.79 Epinine 0.10 8.15E-07 4.24E-07

345.2103 11.46 Deoxycortisol 3.38 9.29E-07 7.78E-07

239.1060 0.49 Glycyl-Tyrosine 0.40 1.40E-06 1.52E-06

220.1608 5.49 C10H21NO4 2.23 1.57E-06 8.14E-07

31

372.2803 14.49 C24H37NO2 0.47 1.76E-06 1.94E-06

351.3298 5.57 Triglygeride 3.23 1.87E-06 9.75E-07

299.2582 12.95 Oxo-octadecanoic acid 0.38 2.82E-06 3.38E-06

146.0298 0.43 C8H3NO2 0.71 2.82E-06 3.10E-06

357.0292 0.50 Hydroxytriazolam 1.18 3.02E-06 2.53E-06

252.0654 18.81 Phenazopyridine 0.12 3.49E-06 1.82E-06

443.3339 5.63 Diacetoxypropyl stearate 0.27 3.92E-06 2.04E-06

215.0667 0.54 Methylenedioxyphenyl-

hexadienone

0.44 3.93E-06 3.30E-06

154.0110 0.46 Nitrocatechol 0.20 4.14E-06 3.47E-06

571.4606 5.77 Dihydro-dihydroxycarotene 0.36 4.96E-06 2.58E-06

171.0764 0.53 Glycylproline 0.52 5.13E-06 4.30E-06

262.0491 0.51 Phosphotyrosine 0.33 5.83E-06 6.99E-06

509.3681 5.72 Apocarotenal 0.32 6.22E-06 3.24E-06

358.0328 0.50 C10H17NO9S2 1.22 6.68E-06 5.59E-06

529.1397 0.56 Caffeoyl-feruloylquinic acid 0.09 6.79E-06 5.69E-06


511.1267 0.59 C28H24O12 1.40 1.00E-05 8.42E-06

151.0353 0.43 Phenylglyoxylic acid 0.72 1.04E-05 1.13E-05

145.0971 18.76 Amino-piperidinecarboxylic acid 0.07 1.05E-05 5.47E-06

32



226.0497 18.31 C8H7N3O5 1.29 1.81E-05 9.42E-06

174.0954 18.77 Oxoarginine 0.08 1.96E-05 1.02E-05

316.0813 18.78 Queuine 0.00 2.09E-05 1.09E-05

204.1382 5.51 Crotamiton 7.19 2.99E-05 1.55E-05

231.1702 5.57 Valyl-Isoleucine 0.28 3.07E-05 3.37E-05

253.0387 0.51 C11H10O7 0.02 3.14E-05 2.63E-05

211.0786 4.94 Sedoheptulose 2.89 3.43E-05 1.78E-05

415.2818 5.60 Ursodeoxycholic acid 6.35 3.84E-05 2.00E-05

262.0109 26.52 Malonylaminobenzoic acid 1.49 4.51E-05 2.35E-05

219.1742 5.52 Furanoeremophilane 1.56 5.56E-05 2.89E-05

190.0264 0.51 Lanthionine ketimine 0.12 5.65E-05 6.07E-05

134.0418 18.40 Carbamazepine-quinone 1.31 6.09E-05 3.17E-05

554.9020 0.49 Diphosphoglyceric acid 1.32 6.57E-05 7.88E-05

146.1004 18.76 Guanidinobutanoic acid 0.28 7.62E-05 3.96E-05

238.0520 0.51 C14H9NO3 0.03 7.84E-05 6.57E-05

162.1123 16.74 Carnitine 2.39 7.95E-05 4.13E-05

245.0443 17.71 Fucose phosphate 1.73 8.05E-05 4.19E-05

33

229.1552 5.55 Valyl-Isoleucine 0.21 8.09E-05 6.78E-05

217.0560 0.52 Bisnorbiotin 0.44 8.27E-05 8.88E-05

165.1200 17.03 C11H16O 1.73 9.90E-05 5.15E-05

217.0131 18.74 Gluconolactone 2.56 9.90E-05 5.15E-05

164.1165 16.99 Isotope of C11H16O 1.77 1.02E-04 5.33E-05

274.0707 17.72 C14H11NO5 2.86 1.10E-04 5.69E-05

204.0179 17.70 Galloylgalactaric acid 1.66 1.14E-04 5.92E-05

153.0328 0.43 Oxypurinol 0.67 1.16E-04 1.39E-04

350.2983 14.49 Stearoylethanolamide 0.46 1.19E-04 1.32E-04

306.0830 6.01 Quercetin-rutinoside 2.40 1.23E-04 1.35E-04

212.0341 18.72 Phosphocreatine 1.99 1.25E-04 6.51E-05

173.0920 15.00 C12H12O 0.18 1.40E-04 7.29E-05

201.9837 15.17 Cysteine-sulfate 10.30 1.40E-04 7.30E-05

233.0774 0.57 Aspartyl-L-threonine 1.33 1.43E-04 1.20E-04

217.0820 0.64 Methylenedioxyphenyl-

hexadienone

0.41 1.45E-04 1.59E-04

331.2479 11.30 Trihydroxy-octadecenoic acid 0.05 1.45E-04 1.61E-04

152.0707 0.69 Methylaminobenzoate 0.47 1.57E-04 1.88E-04

225.1208 20.44 C12H16O4 3.12 1.58E-04 8.21E-05

253.2526 12.94 Heptadecenal 0.31 1.58E-04 1.73E-04

34

324.2353

5.41

Glycerol-octadecenoate-

tetradecanoate-phosphate

11.61

1.77E-04

9.20E-05

230.0446 17.71 Chloro-hexamethoxyflavone 2.51 1.79E-04 9.31E-05

181.0288 0.65 Ethyl methyldithopropionate 0.52 2.13E-04 2.37E-04

300.2614 12.94 Pentadecanoylglycine 0.26 2.13E-04 2.34E-04

201.0181 17.71 Erythrose Phosphate 1.68 2.60E-04 1.35E-04

203.9795 15.18 Methylene-pyrrolidinecarboxylic

acid

23.07 2.60E-04 1.35E-04

332.2513 10.58 C18H29N5O 0.00 2.63E-04 2.93E-04

357.2358 7.72 C19H32O6 0.21 2.63E-04 2.89E-04

415.2776 7.95 Carboxy-alpha-tocotrienol 0.27 2.63E-04 3.16E-04

171.0357 11.80 C7H6O5 1.76 2.83E-04 1.47E-04

393.2503 7.95 C26H32O3 0.25 2.84E-04 3.10E-04

168.0278 11.80 Quinolinic acid 1.42 3.04E-04 1.58E-04

267.0722 0.51 Allopurinol riboside 2.18 3.10E-04 2.60E-04

379.2490 7.84 C22H34O5 0.26 3.13E-04 3.75E-04

274.2013 9.05 Heptanoylcarnitine 1.95 3.15E-04 3.38E-04

740.4640 7.83 C39H65NO12 0.24 3.24E-04 3.56E-04

741.4675 7.83 Isotope of C39H65NO12 0.22 3.24E-04 3.89E-04

35

169.0354 11.80 Isotope of Quinolinic acid 1.65 3.33E-04 1.73E-04

784.4903 7.95 Phosphatidylethanolamine 0.28 3.34E-04 3.64E-04

401.2621 7.95 Carboxy-gamma-tocotrienol 0.30 3.89E-04 4.33E-04

412.2147 12.94 C23H29N3O2S 0.33 4.29E-04 4.71E-04

295.2268 10.47 Hydroxy octadecatrienoic acid 0.16 4.65E-04 5.17E-04

352.3574 20.05 Solanidine 10.32 4.71E-04 5.14E-04

371.2374 7.83 C20H34O6 0.29 4.74E-04 5.09E-04

282.2509 12.94 Octadecenoate 0.21 4.74E-04 5.68E-04

101.0713 18.49 Nitroso-pyrrolidine 2.10 4.79E-04 2.49E-04

403.0075 0.51 Thioxanthylic acid 1.27 4.88E-04 5.43E-04

629.3146 7.46 C38H44O8 0.28 4.98E-04 5.56E-04

233.1131 16.70 Valyl-Aspartate 0.37 5.05E-04 2.63E-04

353.2299 10.58 C20H32O5 0.15 5.08E-04 5.54E-04

102.0553 17.74 Aminocyclopropanecarboxylic

acid

2.30 5.11E-04 2.66E-04

90.0918 17.66 Dimethylethanolamine 13.00 5.24E-04 2.72E-04

313.2370 5.60 Hydroxy-oxo-octadecenoic acid 0.33 5.34E-04 2.78E-04

295.2265 5.51 Epoxy-octadecadienoic acid 0.41 5.77E-04 3.01E-04

339.2510 12.94 C20H34O4 0.40 5.85E-04 6.38E-04

724.4691 7.72 Sulfogalactosylceramide 0.22 6.15E-04 6.76E-04

36

355.2822 15.78 MG(18:2) 0.63 6.16E-04 6.72E-04

191.1025 17.74 Threoninyl-Alanine 4.82 6.71E-04 3.49E-04

185.0304 11.81 Hydroxyisourate 1.50 6.75E-04 3.51E-04

445.3203 8.19 Stearyl citrate 0.43 6.87E-04 7.64E-04

723.4374 7.83 C39H62O12 0.20 6.87E-04 7.50E-04

162.0760 14.52 Acetylhomoserine 2.13 7.23E-04 3.76E-04

413.1411 8.50 Carbamoyl-threonyladenosine 3.35 9.05E-04 4.72E-04


103.0393 16.99 Acetoacetic acid 1.55 1.08E-03 5.60E-04

217.1181 17.10 Prolyl-Threonine 2.04 1.33E-03 6.93E-04

281.2475 12.95 Bovinic acid 0.69 1.45E-03 1.45E-03

658.8484 0.51 Myo-inositol hexakisphosphate 1.28 1.88E-03 1.57E-03

287.0441 5.47 Orotidine 0.79 2.36E-03 1.98E-03

498.9303 11.57 Myo-inositol tetrakisphosphate 0.32 3.17E-03 2.66E-03

132.0671 15.95 Amino-hydroxypentanoic acid 0.15 7.78E-03 6.15E-03

471.1131 4.12 Clofazimine 0.18 7.78E-03 6.15E-03

327.2222 5.58 Dihydroxy-oxooctadecenoic

acid

0.67 7.78E-03 6.15E-03

325.2065 5.58 Epoxy-eremophilene-

trimethoxyol

0.64 7.78E-03 6.15E-03

37

329.2378 5.64 Trihydroxyoctadecenoic acid 0.10 8.77E-03 6.93E-03

628.4959 5.41 Isotope of DG(22:5/15:0) 0.14 9.85E-03 7.78E-03

627.4927 5.41 DG(22:5/15:0) 0.27 1.01E-02 7.98E-03

329.0239 7.29 Fenarimol 4.69 1.01E-02 7.98E-03

401.0934 5.63 Hydroxy-tetramethoxy-

methylenedioxyflavone

3.72 1.39E-02 1.10E-02

585.1891 11.01 C30H34O12 0.44 1.71E-02 1.35E-02

331.2535 5.72 Trihydroxystearic acid 0.35 1.71E-02 1.35E-02

154.9970 6.92 Furandicarboxylic acid 1.47 1.76E-02 1.39E-02


777.6990 20.73 C49H94O6 0.51 1.94E-02 1.53E-02

200.0560 15.61 Gentiatibetine 0.12 2.14E-02 1.69E-02

259.1407 4.38 Hydroxy-methoxy-

cadinatetraenone

0.19 2.17E-02 1.72E-02

558.1695 11.04 C31H29NO9 0.43 2.24E-02 1.77E-02

189.1149 6.01 Decenal 0.40 2.24E-02 1.77E-02

181.0556 4.54 Dihydroxyhydrocinnamic acid 20.92 2.24E-02 1.77E-02

862.1630 20.72 Hexenoyl-CoA 0.46 2.24E-02 1.77E-02

856.6714 20.76 C49H96NO8P 0.69 2.40E-02 1.90E-02

315.2583 5.55 MG(15:0) 0.41 2.42E-02 1.92E-02

38

197.0086 6.93 Quindoxin 2.37 2.49E-02 1.97E-02

329.2208 5.61 Hydroxyprogesterone 0.11 2.57E-02 2.03E-02

162.0783 20.14 Dimethylaminopurine 0.16 2.60E-02 2.05E-02

311.2271 5.52 Hydroperoxyoctadecadienoic

acid

0.77 3.00E-02 2.37E-02

a Retention time in minutes

b Fold change relative to control

c FDR adjusted p-value from t-test

d Direct estimate of FDR as a q-value

39


features in severe psoriasis relative control patients in the validation cohort.


272.0957 9.49 Isotope of hydroxy ketorolac 2.23 5.34E-09 2.78E-09

271.0923 9.49 hydroxy ketorolac 1.92 7.77E-09 4.04E-09

237.0869 13.34 Formylkynurenine 0.46 9.89E-09 5.14E-09

189.0680 13.33 Cyanomethyl-hydroxy-indolone 0.48 1.08E-08 5.61E-09

178.0533 11.95 Acetyl-benzoxazolone 0.66 2.20E-08 1.14E-08

171.1128 6.97 Trimethyl-naphtalene 0.53 1.16E-08 6.01E-09

760.5760 8.00 Phosphatidylcholine 0.57 1.40E-08 7.31E-09

345.1471 13.36 Tyrosyl-Tyrosine 0.43 1.47E-08 7.66E-09

347.1582 13.35 Isotope of Tyrosyl-Tyrosine 0.61 1.58E-08 8.23E-09

341.0703 27.41 Salvianolic acid 0.63 1.72E-08 8.97E-09

145.0841 13.33 Hydroxycyclohexylcarboxylic

acid

0.32 2.28E-08 1.19E-08

892.6540 20.08 Sulfogalactosylceramide 0.74 2.90E-08 1.51E-08

158.0839 13.33 Methylcrotonylglycine 0.59 3.40E-08 1.77E-08

349.1104 14.08 Reduced Riboflavin 0.43 3.69E-08 1.92E-08

161.1303 14.65 Methyllysine 1.78 3.69E-08 1.92E-08

522.3460 10.03 LysoPC(18:1) 0.57 4.25E-08 2.21E-08

40

441.3766 10.66 C30H48O2 1.89 4.75E-08 2.47E-08

315.0710 27.40 Salicylate glucuronide 0.62 5.43E-08 2.83E-08

132.0812 13.35 Guanidinopropionic acid 0.59 5.97E-08 3.10E-08

157.0760 13.35 Indoleacetonitrile 0.63 1.64E-07 8.52E-08

147.0634 13.33 Methylglutaric acid 0.78 3.34E-07 1.74E-07

204.1383 5.51 Crotamiton 2.06 4.12E-07 2.14E-07

131.0687 13.35 Ketoleucine 0.31 4.17E-07 2.17E-07

190.0772 13.33 Glycyl-Asparagine 0.68 4.27E-07 2.23E-07

105.0526 13.91 Hydroxybutyric acid 2.50 4.37E-07 2.27E-07

334.2375 8.91 Oxotetradecanoic acid

glycerides

1.83 4.68E-07 2.43E-07

139.0169 10.55 C3H7O4P 1.58 4.70E-07 2.44E-07

160.0757 13.35 Indoleacetaldehyde 0.60 5.00E-07 2.61E-07

219.0763 13.34 Cysteinyl-Proline 0.57 5.04E-07 2.62E-07

251.0774 8.26 Methoxycanthinone 1.74 6.32E-07 3.29E-07

159.0917 13.33 Hydroxycyclohexylacetic acid 0.65 8.51E-07 4.43E-07

146.0600 13.33 Indole-carboxaldehyde 0.79 8.96E-07 4.66E-07

188.0706 13.33 Indoleacrylic acid 0.59 9.16E-07 4.76E-07

130.0654 13.35 Methylene-indolenine 0.42 1.08E-06 5.61E-07

231.1703 12.87 Isoleucyl-Valine 0.62 1.08E-06 5.63E-07

41

280.1291 14.09 Cycloclausenamide 0.43 1.19E-06 6.19E-07

189.0739 13.33 Tetrahydro-furan-diacetic acid 0.69 1.22E-06 6.34E-07

117.0576 13.34 Alpha-ketoisovaleric acid 0.65 1.27E-06 6.61E-07

298.1300 12.57 Phenethylamine glucuronide 0.42 1.38E-06 7.18E-07

160.0950 13.33 Methylbutyrylglycine 0.61 1.49E-06 7.76E-07

170.0601 13.33 Phosphodimethylethanolamine 0.69 1.70E-06 8.86E-07

115.0546 13.33 Dihydrouracil 0.79 1.76E-06 9.17E-07

428.3644 10.72 Isotope of Oleoylcarnitine 1.55 1.89E-06 9.81E-07

204.0283 13.14 Cystathionine ketimine 1.64 2.12E-06 1.11E-06

426.3576 10.71 Oleoylcarnitine 1.79 2.18E-06 1.13E-06

276.1793 11.49 Hydroxyhexanoycarnitine 2.56 2.19E-06 1.14E-06

427.3610 10.71 Isotope of Oleoylcarnitine 1.49 2.46E-06 1.28E-06

142.0652 13.33 C7H11NS 0.50 2.90E-06 1.51E-06

107.0529 7.26 Benzaldehyde 1.87 3.04E-06 1.58E-06

168.0928 12.81 Methoxytyramine 0.69 3.05E-06 1.58E-06

328.1060 13.90 Acetaminophen glucuronide 0.55 3.16E-06 1.64E-06

347.2443 11.67 C18H34O6 2.58 3.52E-06 1.83E-06

207.1038 13.33 C12H14O3 0.28 3.54E-06 1.84E-06

345.0360 27.61 C13H12O11 0.59 3.71E-06 1.93E-06

42

523.3484 10.00 C26H50O10 0.67 4.02E-06 2.09E-06


451.3610 10.69 C31H46O2 1.57 4.15E-06 2.16E-06

283.1036 9.05 Dimethoxyisoflavone 1.44 4.15E-06 2.16E-06

119.0835 15.00 Diaminobutyric acid 1.75 4.52E-06 2.35E-06

553.4057 16.34 Isotope of LyoPC(20:0) 0.63 2.60E-05 1.75E-05

552.4021 16.34 LysoPC(20:0) 0.63 2.60E-05 1.75E-05

580.4331 17.98 LysoPC(22:0) 0.55 4.16E-05 2.81E-05

155.0791 0.50 Hydroxytyrosol 1.79 5.06E-05 3.42E-05

525.3740 14.68 Isotope of LysoPC(18:0) 0.74 5.06E-05 3.42E-05

524.3709 14.69 LysoPC(18:0) 0.74 5.06E-05 3.42E-05

546.7418 14.49 LysoPC(20:3) 0.74 5.34E-05 3.61E-05


241.0426 7.77 C14H8O4 0.38 7.14E-05 4.82E-05

508.3759 15.40 LysoPC(p-18:0) 0.75 7.14E-05 4.82E-05

434.1379 9.43 Tolmetin glucuronide 0.45 7.74E-05 5.23E-05

301.1410 0.53 Promazine-sulfoxide 0.71 7.75E-05 5.24E-05

289.1383 14.77 C17H20O4 0.65 7.81E-05 5.28E-05

324.3258 19.04 C21H41NO 3.69 7.81E-05 5.28E-05

43

481.3480 14.06 C28H48O6 0.63 7.81E-05 5.28E-05


251.1809 10.60 C14H22N2O2 0.48 8.01E-05 5.41E-05

219.1420 0.56 C9H18N2O4 0.63 8.01E-05 5.41E-05

480.3446 14.06 LysoPC(16:0) 0.74 8.01E-05 5.41E-05

548.3707 14.26 LysoPC(20:2) 0.70 8.01E-05 5.41E-05

268.1882 10.60 Metoprolol 0.48 8.51E-05 5.75E-05

145.1011 16.37 Amino-piperidinecarboxylic acid 0.72 8.58E-05 5.80E-05

482.3239 14.77 LysoPC(15:0) 0.76 8.78E-05 5.93E-05

327.0952 9.07 Hydroxy-methylribityl lumazine 2.55 9.53E-05 7.53E-05

255.1336 5.42 C17H18O2 1.83 9.66E-05 6.52E-05

538.3864 15.63 LysoPE(22:0) 0.58 9.66E-05 6.52E-05

570.3528 14.26 LysoPC(22:5) 0.70 1.03E-04 6.98E-05

504.3056 14.78 LysoPE(20:3) 0.77 1.03E-04 6.98E-05

173.0383 6.25 Isopropyl-oxosuccinate 0.36 1.07E-04 8.43E-05

262.0394 16.85 Shikimic acid 2.46 1.08E-04 8.56E-05

162.0946 6.43 Tryptophanol 0.57 1.12E-04 7.57E-05

190.0537 13.30 Hydroxyindoleacetic acid 1.96 1.13E-04 8.94E-05

296.0659 0.50 Aminoimidazole ribonucleotide 0.69 1.25E-04 8.43E-05

44

167.0526 6.27 Arabinonic acid 0.58 1.26E-04 8.54E-05

197.1010 0.49 Methyl-fucose 0.67 1.26E-04 8.54E-05

219.0827 0.50 Cysteinyl-Proline 0.74 1.30E-04 8.76E-05

362.2041 8.99 Isotope of Cortisone 0.77 1.34E-04 9.08E-05

361.2007 8.99 Cortisone 0.78 1.36E-04 9.19E-05

192.0689 5.48 Hydroxyindoleacetic acid 1.88 1.36E-04 9.19E-05

303.0991 6.25 C10H16N4O7 0.44 1.37E-04 1.08E-04

189.0406 27.54 Dehydroquinate 1.79 1.39E-04 1.10E-04

135.0300 9.90 Threonic acid 1.82 1.43E-04 1.13E-04

88.0107 6.93 Galactonolactone 1.76 1.45E-04 1.15E-04

197.0451 6.87 Vanillylmandelic acid 1.65 1.45E-04 1.15E-04

180.0520 9.53 Hydroxy-methylguanine 1.58 1.54E-04 1.21E-04

245.0780 10.09 C14H14O4 0.66 1.70E-04 1.34E-04

173.0673 19.52 Demethylated antipyrine 0.43 1.85E-04 1.46E-04

840.4954 11.34 C47H71NO12 1.68 1.89E-04 1.49E-04

305.0550 9.50 Methylpinosylvic acid 3.14 1.91E-04 1.51E-04

352.0882 7.26 Acenocoumarol 1.88 1.91E-04 1.51E-04

366.1392 16.90 Desmethylazelastine 1.54 1.91E-04 1.51E-04

261.0409 27.55 Mannitol phosphate 1.96 1.91E-04 1.51E-04

45

337.0644 12.18 C19H14O6 0.47 1.92E-04 1.52E-04

233.0256 12.44 Erythrose 2.94 1.98E-04 1.56E-04

89.0230 10.54 Lactate 1.51 2.02E-04 1.60E-04

295.1918 5.54 C17H28O4 0.37 2.09E-04 1.65E-04

105.0180 7.22 Glyceric acid 1.85 2.09E-04 1.65E-04

300.0841 12.16 Thiamine 1.66 2.09E-04 1.65E-04

258.0753 12.39 Mizoribine 1.82 2.32E-04 1.83E-04

87.0074 6.93 Pyruvate 1.65 2.33E-04 1.84E-04

300.2265 5.51 Nonanoylcarnitine 0.61 2.35E-04 1.86E-04

267.1237 9.91 C14H20O5 2.26 2.78E-04 9.73E-05

307.0694 10.58 Erythroascorbic acid glucoside 3.36 2.78E-04 9.78E-05

447.2322 12.36 Neryl arabinofuranosyl-

glucoside

1.44 2.82E-04 1.01E-04

435.1306 5.41 C21H24O10 0.41 2.85E-04 1.05E-04

505.1017 5.37 Quercetin acetyl-glucoside 0.42 2.87E-04 1.07E-04

183.0290 6.62 Dihydroxymandelic acid 1.76 2.88E-04 1.08E-04

437.2671 14.97 LysoPA(18:0) 0.80 2.89E-04 1.08E-04

155.0701 9.46 Hydroxy-octadienoic acid 2.89 2.93E-04 1.13E-04

679.1914 10.78 C42H32O9 0.27 2.96E-04 1.13E-04

301.1193 10.79 C14H22O7 0.51 2.97E-04 1.16E-04

46

302.1228 10.79 Isotope of C14H22O7 0.50 2.97E-04 1.16E-04

249.1105 10.58 Ubiquinone 3.24 2.98E-04 1.17E-04

409.2358 13.68 LysoPA(16:0) 0.79 3.09E-04 1.27E-04

211.9921 0.47 Aspartyl-phosphate 0.78 3.12E-04 1.30E-04

504.0912 5.37 C23H21O13 0.40 3.13E-04 1.31E-04

396.2516 12.17 Phytosphingosine-phosphate 2.28 3.14E-04 1.32E-04

154.0608 0.50 Amino-pyrazolylpropanoic acid 0.81 3.18E-04 1.35E-04

248.0595 5.88 Sulfapyridine 2.96 3.21E-04 1.39E-04

272.9973 5.37 Glucuronic acid phosphate 0.55 3.29E-04 1.46E-04

378.0888 5.38 Lactoylglutathione 0.38 3.43E-04 1.61E-04

209.0448 6.91 Vanilpyruvic acid 1.64 3.47E-04 1.63E-04

255.1136 8.53 Carboxy-aminopropyl histidine 0.61 3.51E-04 1.69E-04

262.0444 5.37 Epinephrine sulfate 0.56 3.57E-04 1.73E-04

284.0888 4.77 Acetylcytidine 1.60 3.57E-04 1.73E-04

157.0493 5.40 Succinylacetone 1.82 3.65E-04 1.80E-04

156.0734 9.47 Tiglylglycine 3.19 3.66E-04 1.82E-04

565.0554 5.37 UDP-glucose 0.57 3.75E-04 1.86E-04

278.1590 7.27 Hydroxynortriptyline 0.60 3.77E-04 1.88E-04

489.1097 5.38 Aminoadipate adenylate 0.51 4.17E-04 1.95E-04

47


b Fold change relative to control



48


features in Etanercept-treated compared to untreated severe psoriasis patients in the

validation cohort.


211.9921 0.47 Aspartyl-phosphate 1.22 6.12E-04 4.49E-04

544.3427 13.68 LysoPC(20:3) 1.48 6.12E-04 4.49E-04

159.0252 16.88 C6H6O5 4.50 7.43E-04 6.06E-04

433.0710 4.72 Adenosylselenohomocysteine 1.86 7.48E-04 6.11E-04

475.3452 5.38 Epoxy-

trihydroxynorlanostenone

2.78 7.71E-04 6.30E-04

575.3201 10.19 C32H46O9 0.53 9.02E-04 7.40E-04

166.0711 35.64 Methylguanine 0.33 9.60E-04 7.88E-04

289.0376 4.82 C19H25N5O4 2.91 9.94E-04 8.17E-04

235.1651 15.04 C15H22O2 0.60 1.09E-03 9.01E-04

236.1685 15.04 Isotope of C15H22O2 0.60 1.12E-03 9.21E-04

214.0156 5.78 Indoxyl sulfate 0.43 1.16E-03 9.55E-04

179.0540 35.64 Keto-galactose 1.27 1.23E-03 1.01E-03

148.0967 0.72 Amino

hydroxymethylpentanoic acid

1.44 1.28E-03 7.51E-04

222.1893 17.44 C14H23NO 1.53 1.29E-03 1.06E-03

49

214.0156 9.39 Indoxyl sulfate 0.37 1.31E-03 7.73E-04

200.0243 0.57 Phosphohomoserine 1.16 1.33E-03 7.90E-04

552.3924 15.10 LysoPC(20:0) 1.52 1.35E-03 8.02E-04


301.2159 14.25 Retinoic acid 1.38 1.35E-03 8.02E-04

371.2579 5.72 Oxo-choladienoic acid 3.22 1.45E-03 1.20E-03

338.9900 0.74 Hexose-bisphosphate 1.35 1.49E-03 1.14E-03

298.1145 10.73 Methylguanosine 0.83 1.52E-03 1.26E-03

168.0232 0.67 Furoylglycine 1.24 1.54E-03 1.18E-03

401.1058 0.80 Hydroxy-(dihydroxyphenyl)-

valeric acid-glucuronide

1.31 1.54E-03 1.18E-03

409.2358 13.68 LysoPA(16:0) 1.28 1.55E-03 1.19E-03

520.3258 13.68 LysoPC(18:2) 1.32 1.61E-03 1.01E-03

195.0502 0.51 Dimethylurate 1.28 1.67E-03 1.29E-03

257.0161 0.80 Phosphonoglucono-lactone 1.20 1.67E-03 1.29E-03

217.0738 19.94 Bisnorbiotin 1.74 1.67E-03 1.39E-03

166.0120 5.37 Quinolinic acid 1.48 1.73E-03 1.33E-03

206.0699 7.27 Dihydrolipoamide 1.91 1.75E-03 1.35E-03

481.3480 14.06 Isotope of LysoPC(p-16:0) 1.36 1.75E-03 1.12E-03

480.3446 14.06 LysoPC(p-16:0) 1.36 1.75E-03 1.12E-03

50

531.3056 13.68 Cyprinol sulfate 1.16 1.77E-03 1.36E-03


550.3863 15.11 LysoPC(20:1) 1.45 1.81E-03 1.17E-03

241.0426 7.77 C14H8O4 3.74 1.85E-03 1.20E-03

570.3528 14.26 LysoPC(22:5) 1.57 1.85E-03 1.20E-03

506.3606 14.30 LysoPC(p-18:1) 1.36 1.85E-03 1.20E-03

219.1127 6.61 Acetylserotonin 1.91 1.88E-03 1.22E-03

507.3642 14.30 Isotope of LysoPC(p-18:1) 1.33 1.88E-03 1.22E-03

510.3553 14.20 LysoPC(17:0) 1.50 1.88E-03 1.22E-03

220.1081 6.40 C9H17NO5 0.69 1.89E-03 1.57E-03

168.9984 0.70 Dihydroxyacetone phosphate 1.22 1.91E-03 1.47E-03

437.2671 14.97 LysoPA(18:0) 1.30 1.91E-03 1.47E-03

149.0265 0.70 Oxo-methylthiobutanoic acid 0.28 1.95E-03 1.27E-03

130.0859 1.17 Alloleucine 1.25 2.01E-03 1.55E-03

515.3096 14.07 C30H44O7 1.45 2.07E-03 1.60E-03

469.2262 9.52 Lucidenic acid 1.52 2.07E-03 1.60E-03

164.1166 15.23 Acetyl-dihydromethyl

pyrrolizine

0.55 2.08E-03 1.73E-03

175.0714 19.70 Acetylasparagine 0.73 2.12E-03 1.76E-03

148.0683 18.10 Methyladenine 1.45 2.18E-03 1.70E-03

51

474.2863 4.28 Hydrocortamate 0.44 2.22E-03 1.73E-03

536.3709 14.52 LysoPE(22:1) 1.53 2.24E-03 1.51E-03

339.0937 12.97 Ketolactose 2.30 2.24E-03 1.75E-03

480.3094 13.68 LysoPE(18:0) 1.26 2.25E-03 1.74E-03

551.3096 12.45 Triterpenoid 1.51 2.27E-03 1.76E-03

508.3759 15.40 LysoPC (p-18:0) 1.33 2.28E-03 1.54E-03

329.2141 16.11 Megestrol 0.40 2.28E-03 1.54E-03

227.0636 0.63 Nitrotyrosine 0.53 2.28E-03 1.54E-03

211.0599 11.54 Vanilpyruvic acid 2.59 2.28E-03 1.90E-03


889.5724 7.60 Phosphatidylinositol 0.80 2.32E-03 1.81E-03

231.0986 9.24 Succinyl ornithine 2.31 2.33E-03 1.82E-03

141.0111 7.28 Muconic acid 1.38 2.35E-03 1.83E-03

595.3808 15.12 Astaxanthin 1.51 2.40E-03 1.86E-03

415.1979 6.07 Ethyl-hydroxyjasmonate

glucoside

1.66 2.42E-03 1.89E-03

119.0335 0.52 Deoxythreonic acid 1.75 2.43E-03 1.89E-03

283.2537 16.60 Vaccenic acid 1.36 2.49E-03 1.70E-03

183.0720 5.67 Hydroxyphenyllactic acid 0.17 2.49E-03 1.71E-03

204.1383 5.51 Crotamiton 0.74 2.52E-03 2.09E-03

52

319.2316 4.27 Hydroxyeicosatetraenoic acid 0.66 2.55E-03 1.99E-03

518.3211 13.67 LysoPC(18:3) 1.12 2.58E-03 1.78E-03

93.0332 5.01 Phenol 3.43 2.62E-03 2.05E-03

163.1157 15.23 Isotope of Carnitine 0.56 2.63E-03 2.19E-03

496.3396 13.67 LysoPC(16:0) 1.36 2.68E-03 1.85E-03

263.1040 6.61 Phenylacetyl glutamine 1.71 2.68E-03 2.10E-03

193.0695 6.00 Aminohippuric acid 1.65 2.69E-03 2.10E-03

162.1124 15.26 Carnitine 0.56 2.70E-03 2.25E-03

548.3707 14.26 LysoPC(20:2) 1.54 2.70E-03 1.87E-03

295.1172 9.33 C17H14N2O3 1.36 2.71E-03 1.88E-03

379.1566 4.21 C20H28O5S 0.62 2.75E-03 2.15E-03

331.0465 16.97 Inosine Monophosphate 1.87 2.77E-03 2.16E-03

217.0735 14.17 Glutamyl-alanine 2.19 2.79E-03 2.18E-03

145.0608 6.61 Ureidoisobutyric acid 1.71 2.80E-03 2.19E-03

587.2879 5.59 Urobilin 2.12 2.80E-03 2.19E-03

329.2474 11.74 C22H32O2 1.35 2.83E-03 1.98E-03

389.2697 12.55 Hydroxy-oxocholanoic acid 1.65 2.94E-03 2.29E-03

174.9947 5.00 C15H20O5 2.46 2.95E-03 2.31E-03

201.1636 16.37 Hexenoylcholine 1.36 2.97E-03 2.09E-03

53

192.0744 0.51 Acetyl-L-methionine 1.33 2.99E-03 2.10E-03

230.0640 0.55 Succinylglutamic acid

semialdehyde

1.54 3.02E-03 2.35E-03

583.3177 13.60 Cholic acid glucuronide 1.49 3.05E-03 2.37E-03

112.0504 15.32 Pyrroline-carboxylic acid 0.63 3.08E-03 2.41E-03


298.1010 0.54 Methylthioadenosine 2.03 3.22E-03 2.28E-03

181.0496 5.34 Hydroxyphenyllactic acid 1.54 3.26E-03 2.54E-03

250.1516 10.90 Desmethylnortriptyline 0.79 3.28E-03 2.33E-03

347.2247 11.11 Deoxycortisol 0.32 3.35E-03 2.39E-03

182.0529 5.34 Isotope of Hydroxyphenyllactic

acid

1.54 3.36E-03 2.62E-03

452.2783 12.45 LysoPE(16:0) 1.74 3.36E-03 2.62E-03

141.1274 5.64 Nonenol 1.42 3.39E-03 2.65E-03

340.1023 6.61 Hydroxymethoxy indole-

glucuronide

0.51 3.40E-03 2.42E-03

185.0763 13.45 Phosphorylcholine 1.25 3.40E-03 2.42E-03

324.2209 15.24 C18H29NO4 0.34 3.40E-03 2.83E-03

481.2069 13.59 C24H32O10 0.73 3.45E-03 2.88E-03

483.3429 6.26 C31H46O4 0.34 3.49E-03 2.91E-03

54

181.0361 11.10 Methyluric acid 0.57 3.49E-03 2.74E-03

323.2519 9.36 C20H34O3 1.52 3.50E-03 2.92E-03

206.0815 7.12 Phenylpropionylglycine 1.92 3.52E-03 2.74E-03

214.0061 6.39 Isotope of Carmustine 1.71 3.54E-03 2.78E-03

423.2517 14.31 Tetrahydroxy-cholanoic acid 1.55 3.58E-03 2.79E-03

337.0629 0.80 Nicotinate-ribonucleotide 1.23 3.61E-03 2.59E-03

212.0020 6.37 Carmustine 1.67 3.70E-03 2.90E-03

566.3340 6.65 LysoPC(22:6) 1.75 3.73E-03 2.92E-03

221.0600 15.79 Allocystathionine 1.40 3.78E-03 2.96E-03

192.1244 18.69 Cotinine methonium 2.51 3.94E-03 3.29E-03

481.2084 5.99 Hydroxyandrosterone-

glucuronide

1.93 4.01E-03 3.15E-03

497.2790 14.24 C21H36N8O6 2.08 4.03E-03 2.92E-03

188.1757 0.52 Acetylspermidine 0.72 4.05E-03 2.94E-03

312.1270 3.78 Dimethylguanosine 1.29 4.05E-03 2.94E-03

338.0341 6.51 Carboxyaminoimidazole

ribonucleotide

1.63 4.05E-03 3.17E-03


135.0437 5.34 Hydroxyphenylacetaldehyde 1.25 4.24E-03 3.31E-03

171.0345 34.80 Trihydroxybenzoic acid 1.80 4.24E-03 3.53E-03

55

146.0639 6.21 Indole-carbinol 1.60 4.26E-03 3.33E-03

367.2235 11.38 Cortol 1.46 4.28E-03 3.35E-03

158.0599 7.26 Indole acetaldehyde 1.81 4.31E-03 3.37E-03

303.2529 5.54 MG(14:0) 1.55 4.41E-03 3.68E-03

524.3709 14.69 LysoPC(18:0) 1.42 4.47E-03 3.27E-03

168.0017 0.48 Cysteic acid 1.21 4.48E-03 3.50E-03

538.3851 5.90 LysoPE(22:0) 0.34 4.50E-03 3.75E-03

471.3476 15.32 Maslinic acid 1.47 4.60E-03 3.60E-03

288.0602 5.38 Scolymoside 1.81 4.62E-03 3.61E-03

546.3524 14.96 LysoPC(20:3) 1.45 4.65E-03 3.41E-03

299.1267 12.60 Phenylethanol glucuronide 1.55 4.76E-03 3.50E-03

403.2205 4.73 Cortisone acetate 1.88 4.78E-03 3.99E-03

183.0150 5.38 Dihydroxymandelic acid 1.72 5.03E-03 3.94E-03

257.0808 13.60 Dihydrodaidzein 0.79 5.06E-03 4.22E-03

747.5174 11.97 Phosphatidylglycerol 0.83 5.06E-03 3.98E-03


347.2579 5.49 C22H34O3 1.28 5.09E-03 4.25E-03

476.3006 4.29 Hydrocortamate 0.52 5.09E-03 4.25E-03

279.0992 19.89 Isovalerylglucuronide 1.78 5.09E-03 4.25E-03

56

583.3368 13.94 Cholic acid glucuronide 1.32 5.13E-03 4.02E-03

570.3674 14.97 LysoPC(22:4) 1.36 5.13E-03 4.02E-03

174.0761 1.16 Arginic acid 1.32 5.34E-03 4.18E-03

255.2324 13.68 Trimethyltridecanoic acid 1.39 5.47E-03 4.29E-03

475.2972 4.29 C28H42O6 0.53 5.49E-03 4.58E-03

410.2264 9.56 Decanoyllysolecithin 1.55 5.52E-03 4.32E-03

167.5528 14.32 Hydroxymethylglutathione 1.39 5.55E-03 4.35E-03

305.2139 11.23 Dihydroxyandrostenone 0.73 5.68E-03 4.75E-03

280.1305 8.86 Methyladenosine 3.66 5.80E-03 4.54E-03

512.2497 12.67 Sulfolithocholylglycine 1.78 5.84E-03 4.58E-03


149.0442 0.52 Ribose 1.36 6.22E-03 4.88E-03


b Fold change relative to severe untreated



57

Supplemental Table 8. OPLS-DA model classification performance statistics for the

exploratory and validation cohorts.a

Cohort Comparison R2Y Q2

No

Comp.b p-valuec

Exploratory

mild vs. control 0.580 0.258 1+1 8.00×10-2

severe vs. control 0.762 0.741 1+0 3.20×10-9

severe vs. mild 0.807 0.605 1+1 3.23×10-5

Validation

mild vs. control 0.840 0.626 1+1 8.23×10-5

severe vs. control 0.895 0.891 1+0 4.46×10-14

severe vs. mild 0.821 0.794 1+0 1.12×10-10

severetreated vs. severeuntreated 0.827 0.645 1+1 8.18×10-6

control vs. severetreated 0.702 0.534 1+1 2.76×10-4

a All OPLS-DA models underwent two rounds of variable selection based upon the criteria of

p(corr) ≥0.4 and VIP≥1.0. All models were generated with the same metabolites shown in

either Figure 2B (n=24 metabolites) or Figure 2D (n=25 metabolites) for the exploratory and

validation cohorts, respectively.

b The number of components used to fit the model (predictive + orthogonal).

c significance of CV-ANOVA statistic for the indicated model.

58

Supplemental Table 9. Biochemical pathway enrichment analysis of psoriasis-associated

metabolic perturbations in common to the exploratory and validation cohorts.

Pathwaya p-valueb impactc

Alanine, aspartate and glutamate metabolism 8.69E-03 0.649

Glycine, serine and threonine metabolism 2.04E-05 0.492

Arginine and proline metabolism 2.04E-05 0.414

Cysteine and methionine metabolism 4.16E-05 0.219

Aminoacyl-tRNA biosynthesis 2.77E-09 0.169

D-Glutamine and D-glutamate metabolism 2.49E-02 0.139

Glutathione metabolism 2.49E-02 0.011

Nitrogen metabolism 2.92E-07 0.001

Cyanoamino acid metabolism 2.92E-03 0

D-Arginine and D-ornithine metabolism 1.61E-02 0

a Based on the KEGG database (http://www.genome.jp/kegg/)

b False discovery rate adjusted p-value based on the hypergeomtric test

c impact of metabolic changes on pathway topology based on relative-betweeness centrality

59

Amino acidAA

symbol/Protein

MMP-2

Loricrin

Involucrin

Filaggrin-

2

Filaggrin

Hornerin

Repetin

Envoplaki

n

Periplakin

SPRP-1

SPRP-2

LCE2B

LCE3A

LCE5A

TGM1

TGM3

TGM5

Coll α I

Score Score adja

Ala A 7.1 1.0 1.2 1.5 6.1 0.8 1.7 8.7 7.4 2.3 0.0 2.7 5.6 0.9 5.3 6.1 5.7 9.0 65.8 2267.0

Arg R 3.9 0.0 0.5 6.1 10.8 5.7 8.0 9.1 8.9 0.0 0.0 4.6 7.9 4.2 6.7 4.9 4.2 4.8 86.5 3084.0

Asn N 3.6 0.0 0.7 1.0 1.5 0.5 2.6 1.5 3.3 1.1 0.0 1.8 2.3 0.0 4.4 6.6 5.4 2.2 34.9 955.0

Asp D 8.2 0.3 1.4 2.2 5.5 0.8 7.8 4.8 5.4 0.0 0.0 0.9 1.1 0.0 6.5 5.6 5.8 4.2 52.3 528.0

Cysb C 2.9 6.1 0.3 1.0 0.1 0.6 1.4 1.1 0.6 9.0 15.3 20.9 16.9 20.3 1.7 0.9 2.4 1.3 99.7 6952.0

Gln Q 2.9 4.5 25.6 10.2 9.0 9.4 19.4 9.7 9.3 19.1 16.7 7.3 11.2 9.3 3.7 3.6 6.0 4.0 178.0 5780.0

Glu E 5.0 0.0 19.8 4.9 6.3 2.6 5.6 11.6 14.2 6.7 2.8 1.8 1.1 0.9 5.4 5.3 4.6 5.3 99.0 1060.0

Gly G 10.0 46.5 6.5 20.3 12.8 24.5 10.5 4.3 3.0 0.0 0.0 12.7 10.1 13.6 10.4 8.1 6.1 27.3 216.6 4354.0

His H 1.5 0.3 5.0 10.3 10.2 9.6 8.4 1.7 2.2 2.3 0.0 4.6 4.5 3.4 2.5 1.2 1.9 0.5 68.5 1987.0

Ile I 3.8 1.6 0.2 1.0 0.9 0.3 1.4 3.1 3.0 1.1 0.0 0.9 0.0 0.0 4.2 5.8 5.6 2.3 31.3 122.0

Leu L 7.1 0.0 15.2 1.2 1.1 1.3 3.4 12.1 12.3 0.0 0.0 2.7 2.3 1.7 7.3 8.5 9.6 3.8 82.4 1083.0

Lys K 6.8 2.2 7.7 1.3 1.4 0.7 3.1 6.8 7.6 12.4 11.1 4.6 2.3 5.1 3.1 4.8 5.1 4.5 83.7 1759.0

Met M 1.8 0.3 1.0 0.2 0.1 0.1 0.5 1.0 1.0 1.1 1.4 0.9 1.1 0.9 2.2 2.7 1.7 1.1 17.3 529.0

Phe F 7.1 2.9 0.2 2.3 0.6 1.3 1.5 1.1 1.3 0.0 0.0 0.9 0.0 0.0 3.1 4.0 4.2 1.7 25.1 73.0

Pro P 6.7 2.9 7.5 1.1 1.7 1.9 2.3 4.3 2.7 30.3 37.5 17.3 10.1 16.1 5.8 4.5 5.4 18.2 169.6 6082.0

Ser S 4.4 23.1 1.0 22.5 24.1 33.6 11.7 6.6 5.5 2.3 5.6 13.6 23.6 21.2 8.3 9.1 8.6 3.2 223.5 9608.0

Thr T 6.4 1.9 1.4 8.0 4.1 1.5 4.3 3.9 3.3 5.6 2.8 0.9 0.0 1.7 5.5 5.5 5.1 3.0 58.5 427.0

Trp W 2.3 0.3 0.3 0.3 0.5 0.4 0.6 0.7 0.7 0.0 0.0 0.0 0.0 0.0 1.8 2.3 2.1 0.5 10.6 36.0

Tyr Y 4.6 2.6 0.3 2.6 1.3 3.8 4.7 1.7 2.1 0.0 4.2 0.0 0.0 0.0 3.3 2.5 3.5 0.7 33.1 216.0

Val V 3.9 3.5 4.1 2.0 2.0 0.6 1.0 6.2 6.3 6.7 2.8 0.9 0.0 0.9 8.9 8.1 7.1 2.6 63.7 512.0

Average FC 0.3 7.3 0.5 0.2 17.9 0.9 1.0 1.2 43.0 24.0 0.3 365.3 0.1 6.2 3.3 1.9 1.0

a amino acid requirement score adjusted for reported fold change in de Koning et al(7) bCysteine could not be measured due to stability problems

Table S10. Requirement of amino acids for the regulated proteins in psoriasis.

60

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