A large hypothesis-free proteomics study investigating serum inflammatory markers as biomarkers of dry eye disease

Jelle Vehof; Amber Rhee; Niccolò Rossi; Mario Falchi; Christopher J. Hammond; Frances M. K. Williams

doi:10.1016/j.jtos.2025.01.011

A large hypothesis-free proteomics study investigating serum inflammatory markers as biomarkers of dry eye disease

Jelle Vehof, Amber Rhee, Niccolò Rossi, Mario Falchi, Christopher J. Hammond, Frances M. K. Williams

King's College London

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Abstract

PURPOSE: To test the association between serum inflammatory markers and dry eye disease (DED) using a hypothesis-free proteomic approach in a population-based cohort.

METHODS: A total of 2602 unselected community-based participants (mean age 61.5 (range 21-92 years), 94.4 % female) from the TwinsUK cohort were examined. DED was assessed with the validated Women's Health Study (WHS) questionnaire; cases were defined by either a previous clinician diagnosis or presence of highly symptomatic dry eye. Serum inflammatory markers were assessed with the Olink Target 96 Inflammation panel. We performed logistic regression mixed effect models, adjusted for age, BMI, sex, and twin relatedness, with false discovery rate (FDR) correction.

RESULTS: Prevalence of WHS-defined DED was 29.1 %, with 26.2 % having a previous diagnosis of DED and 16.5 % having highly symptomatic dry eye. Of 74 inflammatory markers, significant associations with WHS-defined DED were found for neurotrophin-3 (NT-3; OR: 0.68, FDR p-value: 0.043), natural killer-cell receptor 2B4 (CD244; OR: 0.68, FDR p-value: 0.043), C-X-C motif chemokines (CXCL) 9 (OR: 1.23, FDR p-value: 0.043) and CXCL10 (OR: 1.22, FDR p-value: 0.043). Significant association with highly symptomatic dry eye were found with increased levels of CCL19, CXCL9, CXCL10, CCL20, CX3CL1 (fractalkine), TNF, CDCP1, and CCL25.

CONCLUSIONS: This large population-based study found several serum inflammatory proteins to be associated with DED, confirming and adding to previous targeted tear and corneal and conjunctival expression studies in murine models and clinic-based case-control studies. Of interest, a novel potential biomarker NT-3, which plays a role in corneal nerve function, was identified.

Original language	English
Pages (from-to)	198-208
Number of pages	11
Journal	OCULAR SURFACE
Volume	36
Early online date	6 Feb 2025
DOIs	https://doi.org/10.1016/j.jtos.2025.01.011
Publication status	Published - Apr 2025

Keywords

Humans
Dry Eye Syndromes/blood
Female
Middle Aged
Male
Biomarkers/blood
Aged
Proteomics/methods
Adult
Aged, 80 and over
Young Adult
Inflammation/blood
Surveys and Questionnaires

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10.1016/j.jtos.2025.01.011Licence: CC BY

A large hypothesis-free_VEHOF_Publihsedonline6February2025_GOLD_VoR (CC BY)Final published version, 825 KBLicence: CC BY

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@article{58ebb32c0d054277af0d49da77de70a6,

title = "A large hypothesis-free proteomics study investigating serum inflammatory markers as biomarkers of dry eye disease",

abstract = "PURPOSE: To test the association between serum inflammatory markers and dry eye disease (DED) using a hypothesis-free proteomic approach in a population-based cohort.METHODS: A total of 2602 unselected community-based participants (mean age 61.5 (range 21-92 years), 94.4 % female) from the TwinsUK cohort were examined. DED was assessed with the validated Women's Health Study (WHS) questionnaire; cases were defined by either a previous clinician diagnosis or presence of highly symptomatic dry eye. Serum inflammatory markers were assessed with the Olink Target 96 Inflammation panel. We performed logistic regression mixed effect models, adjusted for age, BMI, sex, and twin relatedness, with false discovery rate (FDR) correction.RESULTS: Prevalence of WHS-defined DED was 29.1 %, with 26.2 % having a previous diagnosis of DED and 16.5 % having highly symptomatic dry eye. Of 74 inflammatory markers, significant associations with WHS-defined DED were found for neurotrophin-3 (NT-3; OR: 0.68, FDR p-value: 0.043), natural killer-cell receptor 2B4 (CD244; OR: 0.68, FDR p-value: 0.043), C-X-C motif chemokines (CXCL) 9 (OR: 1.23, FDR p-value: 0.043) and CXCL10 (OR: 1.22, FDR p-value: 0.043). Significant association with highly symptomatic dry eye were found with increased levels of CCL19, CXCL9, CXCL10, CCL20, CX3CL1 (fractalkine), TNF, CDCP1, and CCL25.CONCLUSIONS: This large population-based study found several serum inflammatory proteins to be associated with DED, confirming and adding to previous targeted tear and corneal and conjunctival expression studies in murine models and clinic-based case-control studies. Of interest, a novel potential biomarker NT-3, which plays a role in corneal nerve function, was identified.",

keywords = "Humans, Dry Eye Syndromes/blood, Female, Middle Aged, Male, Biomarkers/blood, Aged, Proteomics/methods, Adult, Aged, 80 and over, Young Adult, Inflammation/blood, Surveys and Questionnaires",

author = "Jelle Vehof and Amber Rhee and Niccol{\`o} Rossi and Mario Falchi and Hammond, {Christopher J.} and Williams, {Frances M. K.}",

year = "2025",

month = apr,

doi = "10.1016/j.jtos.2025.01.011",

language = "English",

volume = "36",

pages = "198--208",

journal = "OCULAR SURFACE",

issn = "1542-0124",

publisher = "Ethis Communications, Inc.",

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T1 - A large hypothesis-free proteomics study investigating serum inflammatory markers as biomarkers of dry eye disease

AU - Vehof, Jelle

AU - Rhee, Amber

AU - Rossi, Niccolò

AU - Falchi, Mario

AU - Hammond, Christopher J.

AU - Williams, Frances M. K.

PY - 2025/4

Y1 - 2025/4

N2 - PURPOSE: To test the association between serum inflammatory markers and dry eye disease (DED) using a hypothesis-free proteomic approach in a population-based cohort.METHODS: A total of 2602 unselected community-based participants (mean age 61.5 (range 21-92 years), 94.4 % female) from the TwinsUK cohort were examined. DED was assessed with the validated Women's Health Study (WHS) questionnaire; cases were defined by either a previous clinician diagnosis or presence of highly symptomatic dry eye. Serum inflammatory markers were assessed with the Olink Target 96 Inflammation panel. We performed logistic regression mixed effect models, adjusted for age, BMI, sex, and twin relatedness, with false discovery rate (FDR) correction.RESULTS: Prevalence of WHS-defined DED was 29.1 %, with 26.2 % having a previous diagnosis of DED and 16.5 % having highly symptomatic dry eye. Of 74 inflammatory markers, significant associations with WHS-defined DED were found for neurotrophin-3 (NT-3; OR: 0.68, FDR p-value: 0.043), natural killer-cell receptor 2B4 (CD244; OR: 0.68, FDR p-value: 0.043), C-X-C motif chemokines (CXCL) 9 (OR: 1.23, FDR p-value: 0.043) and CXCL10 (OR: 1.22, FDR p-value: 0.043). Significant association with highly symptomatic dry eye were found with increased levels of CCL19, CXCL9, CXCL10, CCL20, CX3CL1 (fractalkine), TNF, CDCP1, and CCL25.CONCLUSIONS: This large population-based study found several serum inflammatory proteins to be associated with DED, confirming and adding to previous targeted tear and corneal and conjunctival expression studies in murine models and clinic-based case-control studies. Of interest, a novel potential biomarker NT-3, which plays a role in corneal nerve function, was identified.

AB - PURPOSE: To test the association between serum inflammatory markers and dry eye disease (DED) using a hypothesis-free proteomic approach in a population-based cohort.METHODS: A total of 2602 unselected community-based participants (mean age 61.5 (range 21-92 years), 94.4 % female) from the TwinsUK cohort were examined. DED was assessed with the validated Women's Health Study (WHS) questionnaire; cases were defined by either a previous clinician diagnosis or presence of highly symptomatic dry eye. Serum inflammatory markers were assessed with the Olink Target 96 Inflammation panel. We performed logistic regression mixed effect models, adjusted for age, BMI, sex, and twin relatedness, with false discovery rate (FDR) correction.RESULTS: Prevalence of WHS-defined DED was 29.1 %, with 26.2 % having a previous diagnosis of DED and 16.5 % having highly symptomatic dry eye. Of 74 inflammatory markers, significant associations with WHS-defined DED were found for neurotrophin-3 (NT-3; OR: 0.68, FDR p-value: 0.043), natural killer-cell receptor 2B4 (CD244; OR: 0.68, FDR p-value: 0.043), C-X-C motif chemokines (CXCL) 9 (OR: 1.23, FDR p-value: 0.043) and CXCL10 (OR: 1.22, FDR p-value: 0.043). Significant association with highly symptomatic dry eye were found with increased levels of CCL19, CXCL9, CXCL10, CCL20, CX3CL1 (fractalkine), TNF, CDCP1, and CCL25.CONCLUSIONS: This large population-based study found several serum inflammatory proteins to be associated with DED, confirming and adding to previous targeted tear and corneal and conjunctival expression studies in murine models and clinic-based case-control studies. Of interest, a novel potential biomarker NT-3, which plays a role in corneal nerve function, was identified.

KW - Humans

KW - Dry Eye Syndromes/blood

KW - Female

KW - Middle Aged

KW - Male

KW - Biomarkers/blood

KW - Aged

KW - Proteomics/methods

KW - Adult

KW - Aged, 80 and over

KW - Young Adult

KW - Inflammation/blood

KW - Surveys and Questionnaires

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U2 - 10.1016/j.jtos.2025.01.011

DO - 10.1016/j.jtos.2025.01.011

M3 - Article

C2 - 39884388

SN - 1542-0124

VL - 36

SP - 198

EP - 208

JO - OCULAR SURFACE

JF - OCULAR SURFACE

ER -

A large hypothesis-free proteomics study investigating serum inflammatory markers as biomarkers of dry eye disease

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