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Single Nucleotide Polymorphism in the IL17A Gene Is Associated with Interstitial Lung Disease Positive to Anti-Jo1 Antisynthetase Autoantibodies

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Single Nucleotide Polymorphism in the IL17A Gene Is Associated with Interstitial Lung Disease Positive to Anti-Jo1 Antisynthetase Autoantibodies life Article Single Nucleotide Polymorphism in the IL17A Gene Is Associated with Interstitial Lung Disease Positive to Anti-Jo1 Antisynthetase Autoantibodies Marco Antonio Ponce-Gallegos 1 , Montserrat I. González-Pérez 2, Mayra Mejía 2, Karol J. Nava-Quiroz 1 , Gloria Pérez-Rubio 1 , Ivette Buendía-Roldán 3 , Espiridión Ramos-Martínez 4 , Jorge Rojas-Serrano 2,* and Ramcés Falfán-Valencia 1,* 1 HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Calzada de Tlalpan 4502, Sección XVI, Tlalpan, México City 14080, Mexico; [email protected] (M.A.P.-G.); [email protected] (K.J.N.-Q.); [email protected] (G.P.-R.) 2 Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas, Calzada de Tlalpan 4502, Sección XVI, Tlalpan, México City 14080, Mexico; [email protected] (M.I.G.-P.); [email protected] (M.M.) 3 Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Calzada de Tlalpan 4502, Sección XVI, Tlalpan, Mexico City 14080, Mexico; [email protected] 4 Experimental Medicine Research Unit, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 06720, Mexico; [email protected] * Correspondence: [email protected] (J.R.-S.); [email protected] (R.F.-V.) Citation: Ponce-Gallegos, M.A.; González-Pérez, M.I.; Mejía, M.; Abstract: Antisynthetase syndrome (ASSD) is a rare multisystemic connective tissue disease affecting Nava-Quiroz, K.J.; Pérez-Rubio, G.; the skin, joints, muscles, and lungs, characterized by anti-aminoacyl transfer-RNA-synthetases Buendía-Roldán, I.; Ramos-Martínez, (anti-tRNA) autoantibodies production, being anti-Jo1 the most frequent. We included one-hundred E.; Rojas-Serrano, J.; Falfán-Valencia, twenty-one ASSD patients and 340 healthy subjects (HS), and also, we divided the case group into R. Single Nucleotide Polymorphism anti-Jo1 and non-anti-Jo1. Two single nucleotide polymorphisms (SNPs) in the IL17A gene were in the IL17A Gene Is Associated with Interstitial Lung Disease Positive to evaluated. Anti-Jo1 was the most common anti-tRNA antibody in our cohort, and the most frequent Anti-Jo1 Antisynthetase tomographic pattern was non-specific interstitial pneumonia (NSIP). Anti-Jo1 ASSD patients had Autoantibodies. Life 2021, 11, 174. higher levels of creatine phosphokinase than the non-anti-Jo1 group. Significant differences in https://doi.org/10.3390/life11020174 genotype frequencies with rs8193036/CC between anti-Jo1 vs. non-anti-Jo1 ASSD patients (p < 0.001), maintaining the association after Bonferroni correction (p = 0.002). Additionally, in the anti-Jo1 group Academic Editors: Der Yuan Chen vs. HS comparison, we found a statistically significant difference with the same SNP (p = 0.018, and Chi-Chien Lin OR = 2.91, 95% CI = 1.15–7.35), maintaining the association after Bonferroni correction (p = 0.036). The rs8193036/CC genotype in IL17A is associated with ASSD patients with anti-Jo1. Also, anti-Jo1 and Received: 22 January 2021 non-anti-Jo1 patients display differences in genotype frequencies. Accepted: 19 February 2021 Published: 23 February 2021 Keywords: IL17A; anti-tRNA; SNPs; ASSD; anti-Jo1 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Antisynthetase syndrome (ASSD) is defined as a rare multisystemic connective tissue disease, characterized by affects predominantly the skin, joints, muscles, and lungs [1], as well as the presence of the anti-aminoacyl transfer-RNA-synthetases (anti-tRNA) au- toantibodies, which include anti-Jo1 (anti-histidyl), anti-PL12 (anti-alanyl), anti-PL7 (anti- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. threonyl), anti-EJ (anti-glycyl), anti-OJ (anti-isoleucyl), anti-SC (anti-lysil), anti-KS (anti- This article is an open access article asparaginyl), anti-JS (anti-glutaminyl), anti-Ha (anti-tyrosyl) or anti-YRS (anti-threonyl), distributed under the terms and anti-tryptophanyl, and anti-Zo (anti-phenylalanyl), being anti-Jo1 the most frequent, with a conditions of the Creative Commons frequency of 68% in patients with ASSD, and 25% in patients with idiopathic inflammatory Attribution (CC BY) license (https:// myopathies (IIM) [2–4]. creativecommons.org/licenses/by/ Traditionally, the ASSD was firstly described in association with IIM, such as der- 4.0/). matomyositis (DM) and polymyositis (PM) [1,5]. However, nowadays, it seems that these Life 2021, 11, 174. https://doi.org/10.3390/life11020174 https://www.mdpi.com/journal/life Life 2021, 11, 174 2 of 12 patients can only present interstitial lung disease (ILD) and anti-tRNA autoantibodies without fulfilling IIM classification criteria [6,7]. Additionally to anti-tRNA autoantibodies, patients with IIM present diverse myositis associated antibodies, being Ro52 the most prevalent. In this way, previous studies have described that Ro52 is an independent risk factor for IIM-related ILD [8]. Among the principal ASSD clinical manifestations, ILD is the most frequent and severe, with an incidence of approximately 80–90% [9,10]. Due to the heterogenicity of the ASSD, little is known about its pathophysiology and its genetic background. Few previous reports have shown a relationship between anti-tRNA autoantibodies and the human leukocyte antigen (HLA) loci, specifically with the HLA-DRB1*08:03 allele in the Korean population. Also, HLA-DRB1*12:02 and HLA- DRB1*14:03 were associated with DM and PM, respectively [11]. Also, Chinoy et al. [12] described that in PM/DM combined, HLA-DRB1*03, DQA1*05, and DQB1*02 were all influential risk factors for the presence of anti-tRNA synthetase autoantibodies. Another important gene that has been widely studied in diverse autoimmune diseases is the IL17A gene, which has been described as an important genetic risk factor. For example, there are studies of single nucleotide polymorphisms (SNPs) in IL17A associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [13–16]. However, there are no previous reports about the relationship between ASSD and genetic variants in IL17A. Interestingly, our research group recently described an association between cytokines of the Th17 inflammatory profile and ASSD patients who presented disease progression [4], suggesting an essential role of the Th17 related cytokines in the disease pathogenesis. For all the above described, we aimed to evaluate two promoter SNPs in the IL17A gene in the genetic susceptibility for ASSD and the various anti-tRNA autoantibodies. 2. Materials and Methods 2.1. Subjects Included 2.1.1. Cases Groups We included 121 patients with ASSD diagnosis in this case-control study. All of them were evaluated and managed in the Interstitial Lung Disease and Rheumatology Unit (ILD&RU) at the Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas (INER) in Mexico City, Mexico. In this reference center, patients are evaluated by a mul- tidisciplinary group (pulmonologists, radiologists, and rheumatologists). We included patients ≥18 years old, with the diagnosis of ILD confirmed by high resolution computed tomography (HRCT) and being positive to at least one of the aminoacyl-tRNA synthetase autoantibodies: Jo1, PL7, PL12, EJ, or OJ, as well as Ro52, measured by EUROLINE: Myosi- tis Profile 3 immunoblot 16 strips (EUROIMMUN AG, Lübeck, Germany) according to the manufacturer’s instructions; also, in the Supplementary Material, a brief test principle description is included. In the Supplementary Material (Figure S1), we included two immunoblots’ examples. In addition, we included baseline data of pulmonary function obtained from the patient’s clinical records of carbon monoxide diffusing capacity (DLco) and forced vital capacity (FVC). Furthermore, baseline serum creatinine phosphokinase (CPK) levels were recorded, as well as the clinical characteristics, such as Raynaud’s phe- nomenon, arthritis, mechanic hands, fever, and smoking history. Patients were evaluated between January 2008 to January 2019. The case group was divided into anti-Jo1 and non-anti-Jo1 patients for further analysis and ASSD patients positive and negative to Ro52. 2.1.2. Control Group A group of three hundred and forty-six healthy volunteer subjects (HS) was also included. These subjects were recruited from INER’s blood bank as healthy subjects. They had the following characteristics: clinically healthy (with neither chronic nor acute self-reported diseases), ≥18 years old, men and women, born as Mexican-Mestizos (MM, parents, and grandparents born in Mexico, not biologically related among themselves or with the patients), and no history of family pulmonary and/or inflammatory/autoimmune diseases. All participants underwent a background questionnaire of demographic and Life 2021, 11, 174 3 of 12 pathological personal history. The subjects who did not meet the inclusion criteria were excluded from this study. 2.2. Ethics Approval and Informed Consent This study was approved by the Institutional Committees for Research, Ethics in Research, and Biosecurity of the INER (approval code numbers: C08-17, B11-19). All participants were previously invited to participate in the study; they signed a written informed consent document and provided a privacy statement describing personal data protection. 2.3. DNA Extraction Firstly, we obtained 15 mL of peripheral blood via venipuncture in two EDTA (ethylene- diaminetetraacetic
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