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.
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.



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 ionophore-stimulated peripheral blood mononuclear cells (PBMCs) by means of commercially available enzyme immunoassay kits.



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.



The results of our study indicate that the genetic variants of ALOX5AP might play a role in the development of SSc-related pulmonary fibrosis.
Department of Rheumatology and Internal Medicine.
Otylia
O
Kowal-Bielecka
Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland.
Sylwia
S
Chwiesko-Minarowska
Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland.
Pawel L
PL
Bernatowicz
Rheumatology A Department, Cochin Hospital, APHP, Paris Descartes University, Paris, France.
Yannick
Y
Allanore
Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen.|Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Timothy
T
Radstake
Department of Experimental and Clinical Medicine, Section of Internal Medicine and Division of Rheumatology, AOUC, University of Florence, Florence, Italy.
Marco
M
Matucci-Cerinic
Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Jasper
J
Broen
Department of Rheumatology, Lund University, Skåne University Hospital, Lund, Sweden.
Roger
R
Hesselstrand
Department of Dermatology, Venereology and Pediatric Dermatology, Medical University of Lublin, Lublin, Poland.
Dorota
D
Krasowska
Clinic of Rheumatology, University of Lübeck, Lübeck, Germany.
Gabriella
G
Riemekasten
Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen.
Madelon
M
Vonk
Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland.
Oksana
O
Kowalczuk
Department of Orthopedics and Traumatology.
Marek
M
Bielecki
Department of Statistics and Medical Informatics.
Robert
R
Milewski
Department of Medical Pathomorphology.
Lech
L
Chyczewski
Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok, Poland.
Jacek
J
Niklinski
Department of Allergology and Internal Medicine.|Department of Experimental Allergology and Immunology, Medical University of Bialystok, Bialystok, Poland.
Krzysztof
K
Kowal
D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000235:genetics*; D012120:Respiration Disorders / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics*
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human
ALOX5AP; gene polymorphism; leukotrienes; lipoxygenase; pulmonary fibrosis; systemic sclerosis