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The arachidonate 5-lipoxygenase activating protein gene polymorphism is associated with the risk of scleroderma-related interstitial lung disease : A multicentre European Scleroderma Trials and Research group (EUSTAR) study

Kowal-Bielecka, Otylia; Chwiesko-Minarowska, Sylwia; Bernatowicz, Pawel L.; Allanore, Yannick; Radstake, Timothy; Matucci-Cerinic, Marco; Broen, Jasper; Hesselstrand, Roger LU ; Krasowska, Dorota and Riemekasten, Gabriella, et al. (2017) In Rheumatology 56(5). p.844-852
Abstract

Objectives. The arachidonate 5-lipoxygenase activating protein (ALOX5AP) regulates synthesis of leukotrienes (LTs), which are important mediators of inflammation and connective tissue remodelling. The aim of this study was to evaluate if single nucleotide polymorphisms (SNPs) of ALOX5AP confer risk of SSc and/ or SSc-related organ involvement. Methods. Seven SNPs of ALOX5AP (rs17222814, rs17216473, rs10507391, rs4769874, rs9551963, rs9315050 and rs7222842) were genotyped in a cohort of 977 patients with SSc and 558 healthy controls from centres collaborating within the European Scleroderma Trials and Research group. In 22 SSc patients, concentrations of cysteinyl LTs and LT B4 (LTB4) were measured in the supernatants of... (More)

Objectives. The arachidonate 5-lipoxygenase activating protein (ALOX5AP) regulates synthesis of leukotrienes (LTs), which are important mediators of inflammation and connective tissue remodelling. The aim of this study was to evaluate if single nucleotide polymorphisms (SNPs) of ALOX5AP confer risk of SSc and/ or SSc-related organ involvement. Methods. Seven SNPs of ALOX5AP (rs17222814, rs17216473, rs10507391, rs4769874, rs9551963, rs9315050 and rs7222842) were genotyped in a cohort of 977 patients with SSc and 558 healthy controls from centres collaborating within the European Scleroderma Trials and Research group. In 22 SSc patients, concentrations of cysteinyl LTs and LT B4 (LTB4) were measured in the supernatants of ionophorestimulated peripheral blood mononuclear cells (PBMCs) by means of commercially available enzyme immunoassay kits. Results. Significant association was found between rs10507391 polymorphism (T/A) of ALOX5AP and the risk of SSc [odds ratio (OR) 1.27 (95% CI 1.07, 1.50), P < 0.05 vs controls], the presence of SSc-related interstitial lung disease on high-resolution CT of the lungs [OR 1.45 (95% CI 1.17, 1.79), P < 0.05 vs patients without SSc-related interstitial lung disease] as well as with restrictive ventilatory defect [forced vital capacity < 70% of predicted; OR 1.51 (95% CI 1.16, 1.97), P < 0.05 vs SSc patients without pulmonary restriction]. PBMCs from SSc carriers of rs10507391 allele A synthesized greater amounts of cysteinyl LTs as compared with SSc patients with rs10507391 TT genotype (P < 0.05). Synthesis of LTB4 did not differ significantly between the two groups. Conclusion. The results of our study indicate that the genetic variants of ALOX5AP might play a role in the development of SSc-related pulmonary fibrosis.

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published
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keywords
ALOX5AP, Gene polymorphism, Leukotrienes, Lipoxygenase, Pulmonary fibrosis, Systemic sclerosis
in
Rheumatology
volume
56
issue
5
pages
9 pages
publisher
Oxford University Press
external identifiers
  • scopus:85019718696
  • wos:000402143000025
ISSN
1462-0324
DOI
10.1093/rheumatology/kew499
language
English
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yes
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80b110ea-0132-424f-9ebe-55f5f2003457
date added to LUP
2017-07-03 17:17:55
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2017-09-18 11:37:24
@article{80b110ea-0132-424f-9ebe-55f5f2003457,
  abstract     = {<p>Objectives. The arachidonate 5-lipoxygenase activating protein (ALOX5AP) regulates synthesis of leukotrienes (LTs), which are important mediators of inflammation and connective tissue remodelling. The aim of this study was to evaluate if single nucleotide polymorphisms (SNPs) of ALOX5AP confer risk of SSc and/ or SSc-related organ involvement. Methods. Seven SNPs of ALOX5AP (rs17222814, rs17216473, rs10507391, rs4769874, rs9551963, rs9315050 and rs7222842) were genotyped in a cohort of 977 patients with SSc and 558 healthy controls from centres collaborating within the European Scleroderma Trials and Research group. In 22 SSc patients, concentrations of cysteinyl LTs and LT B4 (LTB4) were measured in the supernatants of ionophorestimulated peripheral blood mononuclear cells (PBMCs) by means of commercially available enzyme immunoassay kits. Results. Significant association was found between rs10507391 polymorphism (T/A) of ALOX5AP and the risk of SSc [odds ratio (OR) 1.27 (95% CI 1.07, 1.50), P &lt; 0.05 vs controls], the presence of SSc-related interstitial lung disease on high-resolution CT of the lungs [OR 1.45 (95% CI 1.17, 1.79), P &lt; 0.05 vs patients without SSc-related interstitial lung disease] as well as with restrictive ventilatory defect [forced vital capacity &lt; 70% of predicted; OR 1.51 (95% CI 1.16, 1.97), P &lt; 0.05 vs SSc patients without pulmonary restriction]. PBMCs from SSc carriers of rs10507391 allele A synthesized greater amounts of cysteinyl LTs as compared with SSc patients with rs10507391 TT genotype (P &lt; 0.05). Synthesis of LTB4 did not differ significantly between the two groups. Conclusion. The results of our study indicate that the genetic variants of ALOX5AP might play a role in the development of SSc-related pulmonary fibrosis.</p>},
  author       = {Kowal-Bielecka, Otylia and Chwiesko-Minarowska, Sylwia and Bernatowicz, Pawel L. and Allanore, Yannick and Radstake, Timothy and Matucci-Cerinic, Marco and Broen, Jasper and Hesselstrand, Roger and Krasowska, Dorota and Riemekasten, Gabriella and Vonk, Madelon and Kowalczuk, Oksana and Bielecki, Marek and Milewski, Robert and Chyczewski, Lech and Niklinski, Jacek and Kowal, Krzysztof},
  issn         = {1462-0324},
  keyword      = {ALOX5AP,Gene polymorphism,Leukotrienes,Lipoxygenase,Pulmonary fibrosis,Systemic sclerosis},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {844--852},
  publisher    = {Oxford University Press},
  series       = {Rheumatology},
  title        = {The arachidonate 5-lipoxygenase activating protein gene polymorphism is associated with the risk of scleroderma-related interstitial lung disease : A multicentre European Scleroderma Trials and Research group (EUSTAR) study},
  url          = {http://dx.doi.org/10.1093/rheumatology/kew499},
  volume       = {56},
  year         = {2017},
}