Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease

Simona E. Budulac; H. Marike Boezen; Pieter S. Hiemstra; Therese S. Lapperre; Judith M. Vonk; Wim Timens; Dirkje S. Postma; H. F. Kauffman; D. de Reus; D. F. Jansen; M. D.W. Barentsen; M. Zeinstra-Smit; A. J. Luteijn; T. van der Molen; G. ter Veen; M. M.E. Gosman; N. H.T. ten Hacken; H. A.M. Kerstjens; M. S. van Maaren; C. A. Veltman; A. Verbokkem; I. Verhage; H. K. Vink-Klooster; J. B. Snoeck-Stroband; H. Thiadens; J. K. Sont; I. Bajema; J. Gast-Strookman; K. Janssen; K. F. Rabe; A. van Schadewijk; J. Smit-Bakker; J. Stolk; A. C.J.A. Tire'; H. van der Veen; M. M.E. Wijffels; L. N.A. Willems; P. J. Sterk; T. Mauad

doi:10.1371/journal.pone.0043124

Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease

Simona E. Budulac^*
, H. Marike Boezen
, Pieter S. Hiemstra
, Therese S. Lapperre
, Judith M. Vonk
, Wim Timens
, Dirkje S. Postma
, H. F. Kauffman
, D. de Reus
, D. F. Jansen
, M. D.W. Barentsen
, M. Zeinstra-Smit
, A. J. Luteijn
, T. van der Molen
, G. ter Veen
, M. M.E. Gosman
, N. H.T. ten Hacken
, H. A.M. Kerstjens
, M. S. van Maaren
, C. A. Veltman

A. Verbokkem, I. Verhage, H. K. Vink-Klooster, J. B. Snoeck-Stroband, H. Thiadens, J. K. Sont, I. Bajema, J. Gast-Strookman, K. Janssen, K. F. Rabe, A. van Schadewijk, J. Smit-Bakker, J. Stolk, A. C.J.A. Tire', H. van der Veen, M. M.E. Wijffels, L. N.A. Willems, P. J. Sterk, T. Mauad

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV₁ and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV₁ and accelerated decline of FEV₁ and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV₁ level. Eleven out of 17 SNPs were associated with FEV₁ decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.

Original language	English
Article number	e43124
Journal	PLoS ONE
Volume	7
Issue number	8
DOIs	https://doi.org/10.1371/journal.pone.0043124
Publication status	Published - 28 Aug 2012

Bibliographical note

Funding:
This work was supported by the Graduate School for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen, the
Netherlands; The GLUCOLD study was supported by unrestricted grants of the Netherlands Organization for Scientific Research (NWO; 940-35-033), the
Netherlands Asthma Foundation (NAF; 37.97.74 and 3.2.02.51), GlaxoSmithKline (NL), Leiden University Medical Center (LUMC), and University of Groningen (RUG).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Budulac, S. E., Boezen, H. M., Hiemstra, P. S., Lapperre, T. S., Vonk, J. M., Timens, W., Postma, D. S., Kauffman, H. F., de Reus, D., Jansen, D. F., Barentsen, M. D. W., Zeinstra-Smit, M., Luteijn, A. J., van der Molen, T., ter Veen, G., Gosman, M. M. E., ten Hacken, N. H. T., Kerstjens, H. A. M., van Maaren, M. S., ... Mauad, T. (2012). Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease. PLoS ONE, 7(8), Article e43124. https://doi.org/10.1371/journal.pone.0043124

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title = "Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease",

abstract = "Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.",

author = "Budulac, \{Simona E.\} and Boezen, \{H. Marike\} and Hiemstra, \{Pieter S.\} and Lapperre, \{Therese S.\} and Vonk, \{Judith M.\} and Wim Timens and Postma, \{Dirkje S.\} and Kauffman, \{H. F.\} and \{de Reus\}, D. and Jansen, \{D. F.\} and Barentsen, \{M. D.W.\} and M. Zeinstra-Smit and Luteijn, \{A. J.\} and \{van der Molen\}, T. and \{ter Veen\}, G. and Gosman, \{M. M.E.\} and \{ten Hacken\}, \{N. H.T.\} and Kerstjens, \{H. A.M.\} and \{van Maaren\}, \{M. S.\} and Veltman, \{C. A.\} and A. Verbokkem and I. Verhage and Vink-Klooster, \{H. K.\} and Snoeck-Stroband, \{J. B.\} and H. Thiadens and Sont, \{J. K.\} and I. Bajema and J. Gast-Strookman and K. Janssen and Rabe, \{K. F.\} and \{van Schadewijk\}, A. and J. Smit-Bakker and J. Stolk and Tire', \{A. C.J.A.\} and \{van der Veen\}, H. and Wijffels, \{M. M.E.\} and Willems, \{L. N.A.\} and Sterk, \{P. J.\} and T. Mauad",

note = "Funding: This work was supported by the Graduate School for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen, the Netherlands; The GLUCOLD study was supported by unrestricted grants of the Netherlands Organization for Scientific Research (NWO; 940-35-033), the Netherlands Asthma Foundation (NAF; 37.97.74 and 3.2.02.51), GlaxoSmithKline (NL), Leiden University Medical Center (LUMC), and University of Groningen (RUG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",

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month = aug,

day = "28",

doi = "10.1371/journal.pone.0043124",

language = "English",

volume = "7",

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Budulac, SE, Boezen, HM, Hiemstra, PS, Lapperre, TS, Vonk, JM, Timens, W, Postma, DS, Kauffman, HF, de Reus, D, Jansen, DF, Barentsen, MDW, Zeinstra-Smit, M, Luteijn, AJ, van der Molen, T, ter Veen, G, Gosman, MME, ten Hacken, NHT, Kerstjens, HAM, van Maaren, MS, Veltman, CA, Verbokkem, A, Verhage, I, Vink-Klooster, HK, Snoeck-Stroband, JB, Thiadens, H, Sont, JK, Bajema, I, Gast-Strookman, J, Janssen, K, Rabe, KF, van Schadewijk, A, Smit-Bakker, J, Stolk, J, Tire', ACJA, van der Veen, H, Wijffels, MME, Willems, LNA, Sterk, PJ & Mauad, T 2012, 'Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease', PLoS ONE, vol. 7, no. 8, e43124. https://doi.org/10.1371/journal.pone.0043124

TY - JOUR

T1 - Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease

AU - Budulac, Simona E.

AU - Boezen, H. Marike

AU - Hiemstra, Pieter S.

AU - Lapperre, Therese S.

AU - Vonk, Judith M.

AU - Timens, Wim

AU - Postma, Dirkje S.

AU - Kauffman, H. F.

AU - de Reus, D.

AU - Jansen, D. F.

AU - Barentsen, M. D.W.

AU - Zeinstra-Smit, M.

AU - Luteijn, A. J.

AU - van der Molen, T.

AU - ter Veen, G.

AU - Gosman, M. M.E.

AU - ten Hacken, N. H.T.

AU - Kerstjens, H. A.M.

AU - van Maaren, M. S.

AU - Veltman, C. A.

AU - Verbokkem, A.

AU - Verhage, I.

AU - Vink-Klooster, H. K.

AU - Snoeck-Stroband, J. B.

AU - Thiadens, H.

AU - Sont, J. K.

AU - Bajema, I.

AU - Gast-Strookman, J.

AU - Janssen, K.

AU - Rabe, K. F.

AU - van Schadewijk, A.

AU - Smit-Bakker, J.

AU - Stolk, J.

AU - Tire', A. C.J.A.

AU - van der Veen, H.

AU - Wijffels, M. M.E.

AU - Willems, L. N.A.

AU - Sterk, P. J.

AU - Mauad, T.

N1 - Funding: This work was supported by the Graduate School for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen, the Netherlands; The GLUCOLD study was supported by unrestricted grants of the Netherlands Organization for Scientific Research (NWO; 940-35-033), the Netherlands Asthma Foundation (NAF; 37.97.74 and 3.2.02.51), GlaxoSmithKline (NL), Leiden University Medical Center (LUMC), and University of Groningen (RUG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2012/8/28

Y1 - 2012/8/28

N2 - Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.

AB - Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.

UR - https://www.scopus.com/pages/publications/84865583892

U2 - 10.1371/journal.pone.0043124

DO - 10.1371/journal.pone.0043124

M3 - Article

C2 - 22952638

AN - SCOPUS:84865583892

SN - 1932-6203

VL - 7

JO - PLoS ONE

JF - PLoS ONE

IS - 8

M1 - e43124

ER -

Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease

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Bibliographical note

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