Background/Purpose: Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by chronic inflammation, vascular injury and profound fibrosis of the skin and internal organ. Leukotrienes (LTs) are a family of arachidonic acid-derived lipid mediators which play a key role in the regulation of inflammation, vascular function and connective tissue remodeling. Studies in humans have shown that increased synthesis of LTs takes places in SSc. However, the mechanisms responsible for overproduction of LTs in SSc remain unclear. The arachidonate 5-lipoxygenase activating protein ( ALOX5AP) plays a key role in the regulation of synthesis of LTs through presenting arachidonic acid to 5-lipoxygenase.

In the present study we hypothesized that single nucleotide polymorphisms (SNPs) of ALOX5AP might 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 539 healthy controls from European centers collaborating within the EULAR Scleroderma Trials and Research (EUSTAR) group. SSc patients were classified as having diffuse or limited SSc, according to the Medsger and LeRoy criteria. Clinical characteristics of SSc patients included the presence of SSc-related interstitial lung disease (SSc-ILD, based on chest X-ray/HRCT), pulmonary hypertension (SPAP > 45 mmHg in echocardiography), scleroderma renal crisis and digital ulcers.

In 14 SSc patients concentrations of cysteinyl leukotrienes and leukotriene B4 were measured in the supernatants of ionophore-stimulated peripheral blood mononuclear cells (PBMC) by means of commercially available EIA kits (Cayman Chemicals, MI, USA).

Results: Significant association was found between rs10507391 polymorphism (T/A) of the ALOX5AP and the risk of SSc (Odds Ratio; 95%CI: 1.26; 1.0655 – 1.49, p=0.0078) and SSc-ILD (OR;95%CI: 1.4224; 1.1621 – 1.7412, p=0.0007). However, only the latter association remained significant when corrected for multiple testing (p=0.005).

PBMC from SSc carriers of rs10507391 allele A (N=5) synthesized greater amounts of cysteinyl leukotrienes (433 +/- 215 pg/mL/10⁵ cells) as compared with PBMC from SSc patients with rs10507391 TT genotype (N=9, 261 +/- 99 pg/mL/10⁵ cells, p<0.05). Synthesis of leukotriene B4 was comparable between the two groups (995 +/- 547 pg/mL/10⁵ cells vs 790 +/- 756 pg/mL/10⁵ cells, p=0.9).

No significant associations could be found between the remaining SNPs of ALOX5AP and the presence of SSc or SSc-related internal organ involvement.

Conclusion: The results of our study indicate, for the first time, that the genetic variants of ALOX5AP might play a role in the development of SSc-related pulmonary fibrosis. Moreover, our results might raise the possibility of developing genotype-specific therapy for SSc-related lung involvement. This appears particularly attractive since antileukotriene therapies are already in use in humans.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-arachidonate-5-lipoxygenase-activating-protein-alox5ap-polymorphism-is-associated-with-risk-of-scleroderma-related-interstitial-lung-disease-a-multicenter-study-from-the-eular-scleroderma-trial/