ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 722

Biomarkers/Pathways Discovery of Lupus Nephritis By Urine Proteomics

Michelle Petri1, Wei Fu2, Adnan Kiani1, Lauren DeVine1, Conover Talbot Jr.1 and Robert Cole1, 1Johns Hopkins University School of Medicine, Baltimore, MD, 2Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: , ,

Session Information

Date: Sunday, November 8, 2015

Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment Poster Session I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: We have previously validated several urine proteomic biomarkers for Lupus Nephritis (osteoprotegerin, MCP-1, VCAM-1 and urine TWEAK). In this discovery effort we looked for urine biomarkers for Class IV and V Lupus Nephritis. 

Methods: This analysis is based on specimens from six different SLE patients, three with Class IV Lupus Nephritis, two with Class V and one SLE control. Protein differences in urine samples were determined by quantitative proteomics using TMT 6-plex isobaric mass tags after immunoaffinity depletion of albumin on an Agilent MAR6 column.  Raw spectrum-level values were extracted and filtered to less than 1% FDR and 30% isolation interference using Thermo Scientific Proteome Discoverer software.  These data were imported into the Partek Genomics Suite for normalization and further analyses.   

Results: Some urine biomarkers such as afamin and orosomucoid 1(alpha-1-acid glycoprotein) were consistently higher in Class IV/V, compared to control. Some other biomarkers such as apolipoprotein A-I and transthyretin were only higher in Class V, which might allow them to serve as a biomarker to distinguish Class V from IV.  Some of the biomarkers discovered might not be surprising. For example, several hemoglobin urine biomarkers (HBG2, HBB, etc.) were found to be higher in Class V, but are common in any patient with poor renal function. 

Based on these lower/higher levels of urine proteins, possible pathways potentially important in Lupus Nephritis were identified using Ingenuity Pathway Analysis software. Table 2 presents the most likely pathways. The second column shows the protein modules associated in the pathway. The third column shows the comparisons from which the pathway was identified. 

Table 1 Biomarkers identified in different comparisons

Gene Name (NCBI)

IV vs. Cont

V vs. Cont

IV vs. V

IV and V vs. Cont

Fc fragment of IgG, low affinity IIIa, receptor (CD16a)

Lower in IV

CADM2

cell adhesion molecule 2

Lower in IV

APOC1

apolipoprotein C-I

Higher in V

LCP1

lymphocyte cytosolic protein 1 (L-plastin)

Higher in IV

IV higher than V

ADIPOQ

adiponectin, C1Q and collagen domain containing

IV higher than V

CFHR1

complement factor H-related 1

Higher in IV

Higher in V

Higher in Cases

AZGP1

alpha-2-glycoprotein 1, zinc-binding

Higher in IV

Higher in V

Higher in Cases

HMGN2

high mobility group nucleosomal binding domain 2

IV higher than V

PGLYRP2

peptidoglycan recognition protein 2

IV higher than V

HYAL1

hyaluronoglucosaminidase 1

Lower in V

Lower in Cases

PZP

pregnancy-zone protein

Higher in IV

Higher in V

Higher in Cases

AFM

afamin

Higher in IV

Higher in V

Higher in Cases

TTC26

tetratricopeptide repeat domain 26

IV higher than V

ORM1

orosomucoid 1

Higher in IV

Higher in V

Higher in Cases

FCGRT

Fc fragment of IgG, receptor, transporter, alpha

Lower in IV

Lower in Cases

MPO

myeloperoxidase

Higher in IV

SERPINA6

serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 6

Higher in V

Higher in Cases

CARD18

caspase recruitment domain family, member 18

Lower in V

BCHE

butyrylcholinesterase

Higher in IV

Higher in Cases

ORM2

orosomucoid 2

Higher in IV

Higher in V

Higher in Cases

APOA1

apolipoprotein A-I

Higher in V

IV lower than V

MB

myoglobin

Higher in V

KRT85

keratin 85, type II

IV lower than V

SELL

selectin L

Higher in IV

Higher in Cases

S100A12

S100 calcium binding protein A12

IV higher than IV

MUC5B

mucin 5B, oligomeric mucus/gel-forming

Higher in V

IV lower than V

APOA2

apolipoprotein A-II

IV lower than V

FUCA2

fucosidase, alpha-L- 2, plasma

Higher in V

TTR

transthyretin

Higher in V

Higher in Cases

CA1

carbonic anhydrase I

Higher in V

IV lower than V

Higher in Cases

UBE2V2

ubiquitin-conjugating enzyme E2 variant 2

IV lower than V

CD300LF

CD300 molecule-like family member f

Higher in V

AHSP

alpha hemoglobin stabilizing protein

Higher in V

HBG2

hemoglobin, gamma G

Higher in V

IV lower than V

ZNF648

zinc finger protein 648

Higher in V

IV lower than V

HBB

hemoglobin, beta

Higher in V

IV lower than V

KRT33B

keratin 33B, type I

Higher in V

IV lower than V

SERPINA1

serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1

IV higher than IV

HBD

hemoglobin, delta

Higher in V

RBP2

retinol binding protein 2, cellular

Higher in IV

KRT86

keratin 86, type II

IV lower than V

HBA1

hemoglobin, alpha 1

IV lower than V

KRT36

keratin 36, type I

IV lower than V

POMC

proopiomelanocortin

Lower in V

FABP4

fatty acid binding protein 4, adipocyte

IV higher than IV

Table 2 Pathways identified by comparing Class IV and V with control

 

Name

Modules

Associated Comparisons

Acute Phase Response Signaling

CP,ORM2,ITIH3,CRP,A2M,

C4A/C4B, ORM1,RBP2,

SERPINA1,IL1RAP,FTL,TTR,ALB

IV, V

Production of Nitric Oxide and Reactive Oxygen Species in Macrophages

LYZ,APOB,ORM1,MPO,ORM2,

SERPINA1,APOC1,ALB

IV,V

LXR/RXR Activation

LYZ,C4A/C4B,APOB,ORM1,ORM2,

SERPINA1,IL1RAP,APOC1,A1BG,ALB,TTR

IV, V

IL-12 Signaling and Production in Macrophages

LYZ,APOB,ORM1,ORM2,SERPINA1,

APOC1,ALB

IV,V

FXR/RXR Activation

C4A/C4B,APOB,ORM1,ORM2,

SERPINA1,APOC1,A1BG,ALB,TTR

IV,V

Atherosclerosis Signaling

LYZ,APOB,ORM1,ORM2,SERPINA1,

APOC1,VCAM1,ALB

IV,V

LPS/IL-1 Mediated Inhibition of RXR Function

GSTM1,FABP4,IL1RAP,GSTA2,

APOC1,ALDH1A3,FABP2

IV,V

Clathrin-mediated Endocytosis Signaling

LYZ,APOB,ORM1,ORM2,

SERPINA1,APOC1,TFRC,ALB

IV,V

Melatonin Degradation III

MPO

IV,V

Glutathione-mediated Detoxification

GSTM1,GSTA2

IV,V

Retinoate Biosynthesis I

RBP2,ALDH1A3

IV

Pyrimidine Ribonucleotides De Novo Biosynthesis

NUDT5,CMPK1

IV

Pyrimidine Ribonucleotides Interconversion

NUDT5,CMPK1

IV

RAR Activation

RBP2,RPL7A,ALDH1A3

IV

PXR/RXR Activation

GSTM1,GSTA2

IV

Xenobiotic Metabolism Signaling

GSTM1,GSTA2,FTL,ALDH1A3

IV

Extrinsic Prothrombin Activation Pathway

FGB,SERPINC1,FGG

V

Lymphotoxin β Receptor Signaling

VCAM1,DIABLO

V

Coagulation System

A2M,FGB,SERPINC1,FGG

V

IL-17 Signaling

CRP,MUC5B

V

Conclusion: In this discovery effort several interesting pathways were identified that might be important in Lupus Nephritis overall or differentially in Class IV versus Class V. In particular, reactive oxygen species, IL-12, LPS/IL-1, IL-17, atherosclerosis and coagulation pathways might be novel targets. Validation of this discovery effort is underway.

Disclosure: M. Petri, None; W. Fu, None; A. Kiani, None; L. DeVine, None; C. Talbot Jr., None; R. Cole, None.

To cite this abstract in AMA style:

Petri M, Fu W, Kiani A, DeVine L, Talbot C Jr., Cole R. Biomarkers/Pathways Discovery of Lupus Nephritis By Urine Proteomics [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/biomarkerspathways-discovery-of-lupus-nephritis-by-urine-proteomics/. Accessed .

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