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Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

Robert Su, Michael M. Li, Nirav R. Bhakta, Owen D. Solberg, Eli P.B. Darnell, Joris Ramstein, Suresh Garudadri, Melissa Ho, Prescott G. Woodruff, Laura L. Koth
European Respiratory Journal 2014 44: 985-993; DOI: 10.1183/09031936.00039714
Robert Su
1Division of Rheumatology, University of California, San Francisco, CA, USA
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Michael M. Li
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
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Nirav R. Bhakta
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
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Owen D. Solberg
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
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Eli P.B. Darnell
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
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Joris Ramstein
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
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Suresh Garudadri
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
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Melissa Ho
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
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Prescott G. Woodruff
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
3Cardiovascular Research Institute, University of California, San Francisco, CA, USA
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Laura L. Koth
2Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA
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  • For correspondence: laura.koth@ucsf.edu
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  • Figure 1–
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    Figure 1–

    Schema used for classification of disease course among recruited sarcoidosis subjects. ATS: American Thoracic Society; PFT: pulmonary function testing; FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; IS: immunosuppression; TNF: tumour necrosis factor. #: 34 out of 45 nonprogressive subjects had never received IS or had IS tapered off within 2 years of diagnosis and 11 nonprogressive subjects were maintained on IS from diagnosis; ¶: 16 out of 46 chronic subjects had progressive declines in pulmonary function testing and 30 chronic subjects developed a sarcoidosis flare requiring escalation of IS (organ manifestations of flare: nine pulmonary, seven cutaneous, five neurological, four ocular, three cardiac and two hypercalcaemia).

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    Figure 2–

    Receiver operating characteristic curve analyses of discrimination between chronic and nonprogressive disease (n=91). Logistic regression-based prediction probabilities using CXCL9, T-cell receptor (TCR) and interferon (IFN) factors outperform lymphopenia, with the difference in area under curve (AUC) being associated with p=0.001.

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    Figure 3–

    Sarcoidosis subjects with high CXCL9 factor at enrolment more rapidly develop significant declines in pulmonary function or a sarcoidosis flare requiring escalation in immunosuppression during follow-up (p=0.009 by log-rank test). PFT: pulmonary function testing.

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    Figure 4–

    a) Longitudinal analysis demonstrates a persistent elevation of interferon factor (three-gene mean of STAT1, STAT2 and GBP1) in nonprogressive and chronic sarcoidosis compared with healthy controls. b) Longitudinal analysis reveals a suppression of T-cell receptor (TCR) factor (three-gene mean of CD28, ITK and LEF1) in nonprogressive and chronic sarcoidosis compared with healthy controls, and lower TCR factor in chronic subjects compared with nonprogressive subjects. c) CXCL9 expression remains persistently high among subjects with chronic sarcoidosis compared with both healthy control and nonprogressive sarcoidosis subjects. Mean values are presented; errors bars represent the standard error of the mean. Numbers of PAXgene samples processed at time of quantitative PCR analysis (V1: baseline visit; V2: 6-month visit; V3: 12-month visit) to generate data were as follows. Nonprogressive: V1, n=45; V2, n=27; V3, n=27; chronic: V1, n=46; V2, n=31; V3, n=27; healthy: V1, n=62; V2, n=40; V3, n=36. ns: nonsignificant. #: p=0.005. ***: p<0.001.

Tables

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  • Table 1– Genes selected for quantitative PCR analysis in longitudinal cohort
    Rationale for inclusion in studyGenes# nGene names
    Implicated in sarcoidosis inflammation11ICAM1, IFNG, IL15, IL17, IL6, CXCL9, CXCL10, TNFA, HGF, IL13, TNFSF13B
    Implicated in granulomatous inflammation7IL15RA, IL18R1, IL4, STAT6, B7H1, IL25, SAA4
    Invoked in Ingenuity Pathway Analysis16IRF1, ITK, JAK2, TYK2, LEF1, MYD88, TLR2, TLR4, TLR8, CTL4A, CD28, TAP1, IRF7, IRF9, STAT1, STAT2
    Differentially expressed in sarcoidosis derivation cohort but unknown role in disease11LRP1, PLAUR, TBXAS1, GBP1, GBP2, SKIL, CETP, USP15, PIK3AP1, TNFAIP2, LPCAT2
    Housekeeping genes3RPL13A, B2M, ACTB
    • #: 48 genes in total.

  • Table 2– Baseline cohort characteristics
    ControlSarcoidosisp-value
    Subjects n62103
    Female n (%)35 (56)64 (62)0.51
    Age years42.13±14.5550.88±10.31<0.01
    Follow-up period months31±11.4
    Race
     African-American6 (10)12 (12)0.80
     White42 (68)77 (75)0.37
     Other14 (22)14 (13)0.14
    Ethnicity
     Latino8 (13)8 (8)0.29
    Lymphocyte count ×109 cells·L−11.81±0.501.47±1.790.16
    • Data are presented as n (%) or mean±sd, unless otherwise stated.

  • Table 3– Sarcoidosis baseline characteristics by clinical course
    NonprogressiveChronicp-value
    Subjects4546
    Age years49.2±10.252.8±10.60.11
     Range(33–74)(30–76)
    Females26 (58)31 (67)0.39
    Time from diagnosis to enrolment years2.87±3.98.01±9.06<0.01
    Race
     African-American570.76
     White35310.35
     Other580.55
    Ethnicity
     Latino250.43
    Scadding stage 0/I/II/III/IV4/6/20/6/95/2/22/5/120.64
    Lymphocyte count ×109 cells·L−11.24±0.51.32±1.10.64
    Systemic immunosuppression at enrolment14 (31)30 (65)<0.01
    Pulmonary function testing % predicted
     FVC102.4±12.591.2±16.7<0.01
     FEV197.8±16.886.7±18.8<0.01
     DLCO89.8±18.1#73.4±20.2¶<0.01
    • Data are presented as n, mean±sd or n (%), unless otherwise stated. FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; DLCO: diffusing capacity of the lung for carbon monoxide. #: n=31; ¶: n=26.

Additional Files

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    Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

    Files in this Data Supplement:

    • Supplementary figures - Figures E1-E6
    • Supplementary methods - qPCR normalisation
    • Supplementary table - Table E1
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Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes
Robert Su, Michael M. Li, Nirav R. Bhakta, Owen D. Solberg, Eli P.B. Darnell, Joris Ramstein, Suresh Garudadri, Melissa Ho, Prescott G. Woodruff, Laura L. Koth
European Respiratory Journal Oct 2014, 44 (4) 985-993; DOI: 10.1183/09031936.00039714

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Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes
Robert Su, Michael M. Li, Nirav R. Bhakta, Owen D. Solberg, Eli P.B. Darnell, Joris Ramstein, Suresh Garudadri, Melissa Ho, Prescott G. Woodruff, Laura L. Koth
European Respiratory Journal Oct 2014, 44 (4) 985-993; DOI: 10.1183/09031936.00039714
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