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The Clinical Value of Ficolin-3 Gene Polymorphism in Rheumatic Heart

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The Clinical Value of Ficolin-3 Gene Polymorphism in Rheumatic Heart Gomaa et al. BMC Res Notes (2021) 14:36 https://doi.org/10.1186/s13104-021-05450-w BMC Research Notes RESEARCH NOTE Open Access The clinical value of fcolin-3 gene polymorphism in rheumatic heart disease. An Egyptian adolescents study Maher H. Gomaa1, Emad Gamil Khidr1* , Ahmed Elshafei1, Hala S. Hamza2, Aya M. Fattouh2, Ahmed A. El‑Husseiny1, Ahmed Aglan1 and Mahmoud Gomaa Eldeib1 Abstract Objective: Ficolin‑3 is one of the innate immunity molecules that was thought to play a pivotal role in Streptococcus pyogenes autoimmunity and its complications; rheumatic fever (RF) and rheumatic heart disease (RHD). We aimed to disclose if there is an association between fcolin‑3 (FCN3) gene polymorphisms (rs4494157 and rs10794501) and RF with or without RHD for the frst time in Egyptian adolescents. Results: Serum fcolin‑3 level was signifcantly elevated in patients sufering from RF with and without RHD in comparison with control. Regarding FCN3 gene (rs4494157) polymorphism, a signifcant correlation was found between the A allele and the susceptibility to RF with or without RHD (OR 2.93, P 0.0002 and OR 2.23, P 0.008 respectively). Besides, AA homozygous genotype showed a signifcant association= with= RHD risk (OR= 3.47, P= 0.026). Patients carrying the A allele (CA AA) had signifcantly higher serum fcolin‑3 than those carrying the= CC genotype= + (P ˂ 0.0001). While the frequency of (rs10794501) polymorphism revealed no signifcant diferences between the con‑ trols and RF patients with or without RHD (OR 1.43, P 0.261 and OR 1.48, P 0.208 respectively). = = = = Keywords: Rheumatic fever, Rheumatic heart disease, FCN3 gene polymorphism, Ficolin‑3 Introduction factors [4]. Te pathogenesis of RF and its sequel, par- Rheumatic fever (RF) is a consequence of recurrent ticularly RHD is strongly dependent on autoimmun- group-A Streptococcus pyogenes (GAS) pharyngitis as an ity. Autoantibodies produced from molecular mimicry immune-mediated complication in genetically suscepti- between proteins of heart tissue and GAS mediate tissue ble individuals [1, 2]. Repeated or severe episodes of RF damage. It was found that GAS molecules as N-acetyl- lead to permanent harm to the heart valves, with subse- β-D-glucosamine (GlcNAc) and M protein display a quent development of rheumatic heart disease (RHD). A cross-reactivity with valves and myocellular contractile high prevalence (31 per 1000 children) of RHD in school- proteins of the host. As one of the pathogen associated age children in Egypt and other African countries was molecular patterns and a dominant antigen in GAS cell reported [3]. wall, GlcNAc serves as a target for identifcation by fco- Rheumatic fever and RHD are multifactorial disor- lins [2, 5–7]. ders that involve multiple environmental and genetic Ficolins are group of patterns recognizing proteins that activate the complement system. Currently, they are classifed into three types: fcolin-1 (M fcolin), fcolin-2 *Correspondence: [email protected] (L fcolin), and fnally fcolin-3 (H fcolin) [7]. Ficolin-3 1 Department of Biochemistry and Molecular Biology, Faculty is mainly synthesized in both liver and lungs, represent- of Pharmacy, Al‑Azhar University, Cairo, Egypt Full list of author information is available at the end of the article ing the most abundant circulating fcolins [8]. Serum © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gomaa et al. BMC Res Notes (2021) 14:36 Page 2 of 6 fcolin-3 has been reported to be widely variable among [25]. A free written informed consent form was signed healthy individuals, which may be attributed to the dif- by parents of both controls and patients. Approval of ference in the genetic makeup [9–11]. Functionally, like this study by the ethical committee of Children Hos- other fcolins, fcolin-3 has been shown to activate the pital, School of Medicine, Cairo University, Egypt was complement system [12, 13]. obtained. Patients with any infections, acute RF, infec- Ficolin-3 is encoded by the FCN3 gene which is located tive endocarditis, or any other infammatory disorders on chromosome 1p36 and contains eight exons. Few were excluded from this study. All enrolled patients studies showed an association between fcolin genes had a clinical history of RF. Te presence of mitral valve polymorphisms and infectious and autoimmune diseases regurge in patients with RHD was confrmed by an [14–19]. Additionally, it was reported that there are asso- echocardiogram. ciations between gene polymorphisms of fcolin-1 [20] A venous blood sample was withdrawn from all sub- and fcolin-2 [21], 22 with RF. However, the impact of jects and divided into two aliquots; one for serum sepa- fcolin-3/FCN3 gene polymorphisms on RF and RHD is ration and determination of serum fcolin-3 levels by currently obscure. enzyme-linked immunosorbent assay (ELISA) using Despite being a preventable disease, RHD may pro- commercial kits (Ray Bio Kit Inc., Georgia, USA) based ceed silently until patients are presented as debilitating on manufacturer’s instructions and recommendations, heart failure cases. In this case, surgery is the only pos- While the 2nd one for FCN3 gene polymorphisms sible choice for treatment [23], and deadly outcomes (rs4494157 and rs10794501) typing (Additional fle 1). ultimately occur [24]. Indeed, there is a need for a predic- Extraction of Genomic DNA (gDNA) from the whole tive tool or a marker for early detection of RF/RHD and blood sample was performed using Gene JET™ Whole preventing their progression, as well as facilitating early Blood DNA Purifcation Mini Kit (Termo Fisher Sci- medical follow-up. entifc Inc., USA). Polymorphisms at (rs4494157 and Tis study was designed to investigate for the frst rs10794501) in the FCN3 gene were typed by real- time the association of two FCN3 gene polymorphisms time polymerase chain reaction (RT-PCR) utilizing (rs4494157 and rs10794501) as well as serum fcolin-3 TaqMan® allele discrimination assay (Applied Biosys- levels with the susceptibility of RF and RHD develop- tems, CA, USA). ment in Egyptian adolescents. GraphPad Prism 6.2 (GraphPad Software, San Diego, USA) was utilized to perform the statistical analy- Main text sis of our data. Normality distribution of variables Methods was checked using D’Agostino-Pearson Omnibus test, Tis study was performed on 240 Egyptian subjects where normally distributed variables were presented locating in Cairo that were classifed into three groups. as mean ± SE while we used median (inter-quartile Te frst group consisted of 80 RF patients without range) to represent the skewed distributed variables. RHD. Te second group included 80 RF patients with Kruskal–Wallis test was used to compare between all RHD. While in the third group, eighty apparently groups followed by Dunn’s test. Genotypes distribu- healthy volunteers matching with the patients for age, tion for the polymorphism was checked for deviation sex, ethnic and geographic origin were selected as con- from the Hardy–Weinberg equilibrium and any devia- trols. Te demographic data of individuals enrolled in tions between observed and expected frequencies were the study were presented in Table 1. RF patients were examined for detection of signifcance depending on recruited from the Cardiology Outpatient Clinic, Chil- the χ2 test. Besides, odds ratios (ORs) and 95% conf- dren Hospital, Cairo University, Egypt. RF diagnosis dence intervals (CIs) were calculated. A P-value < 0.05 was carried out based on the modifed Jone’s criteria was considered statistically signifcant. Table 1 Demographic data of all studied groups Characteristics Controls (n. 80) RF (n. 160) = = Without RHD (n. 80) With RHD (n. 80) = = Gender Female n. (%) 48 (60.0) 46 (57.5) 48 (60.0) Male n. (%) 32 (40.0) 34 (42.5) 32 (40.0) Age (years) mean SE 15.2 0.29 14.5 0.43 14.3 0.33 Age range ± 13–20± 9–18.5± 9–18.5± Gomaa et al. BMC Res Notes (2021) 14:36 Page 3 of 6 Results Te genotypic and allelic results of FCN3 single nucleo- tide polymorphism (SNP) (rs4494157) analysis for the studied groups were listed in Table 2. Tis genotype distribution showed no deviation from Hardy–Wein- berg equilibrium (P > 0.05). Te genotypic distribution revealed a higher frequency of the heterozygous CA only and CA/AA genotypes in RF patients with and with- out RHD when compared to controls. Moreover, the homozygous variant AA genotype showed higher fre- quency in RF with RHD as compared to controls. Addi- tionally, a higher frequency of the A allele was observed in RF patients with and without RHD when compared to the controls. Te genotype distribution for FCN3 SNP (rs10794501) showed no deviation from Hardy–Weinberg equilibrium. No statistical signifcance was detected for the frequency Fig. 1 Distribution of Ficolin‑3 levels in the investigated groups.
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