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Association of Growth Differentiation Factor 5 (GDF5) Gene ISSN: 2378-3672 Alrehaili et al. Int J Immunol Immunother 2020, 7:048 DOI: 10.23937/2378-3672/1410048 Volume 7 | Issue 1 International Journal of Open Access Immunology and Immunotherapy ORIGINAL RESEARCH ARTICLE Association of Growth Differentiation Factor 5 (GDF5) Gene -Poly morphisms with Susceptibility to Knee Osteoarthritis in Saudi Population Amani A Alrehaili1 , Khadiga A Ismail1,2 , Ashjan Shami1 , Maha K Algethami3, Hadeer W Elsawy4 and Amal F Gharib1,5*# 1Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Saudi Arabia 2Department of Parasitology, Faculty of Medicine, Ain Shams University, Egypt 3King Faisal Medical Complex, Saudi Arabia 4 Department of Clinical Biochemistry, Theodore Bilharz Research Institute, Egypt Check for 5Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Egypt updates *Corresponding author: Amal F Gharib, Professor of Medical Biochemistry and Molecular Biology, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Saudi Arabia; Professor of Medical Biochemistry and Molecular Biology, Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Egypt, Tel: +966- 580-278-110 Abstract GDF5 gene polymorphism were statistically more frequent in KOA patients than in the controls. TT genotype may be a Background: Osteoarthritis (OA) is among the most prev- risk factor to KOA. The T allele was more frequent in KOA alent joint diseases. Reduced patient life quality and pro- and C allele was more frequent in the controls. GDF5 pol- ductivity represent a major personal and community strains. ymorphism was not related to BMI and functional disability GDF5 gene is involved in the development of bone and of KOA. GDF5 polymorphism was found to be significantly cartilage. Studies reported a clear and highly reproducible related to high ESR and CRP. association between susceptibility of knee osteoarthritis Conclusions: The present study revealed a possible ge- (KOA) and GDF5. This study aims to detect GDF5 gene netic link between KOA and GDF5 polymorphism and that polymorphism and to evaluate its association with suscep- the TT genotype may increase the risk of development of tibility to KOA. KOA. However, a future study with a large number of pa- Methods: This study is a case-control carried out at the fe- tients is needed to confirm our results. male section of College of Applied Medical Sciences, Taif Keywords University. 50 Samples with KOA were collected from pa- Knee osteoarthritis (KOA), Gene polymorphism, Growth dif- tients at King Faisal Medical Complex (Rheumatology Clin- ferentiation Factor 5 (GDF5) ic), Taif, KSA. The body mass index (BMI) and the functional disability were estimated in all patients. CRP and RF were Abbreviations estimated in the serum of all included subjects by ELISA. OA: Osteoarthritis; GDF5: Growth Differentiation Factor 5; ESR was determined by Westergren method. GDF5 T > C BMP: Bone Morphogenetic Protein Group; TGF-β: Trans- (rs143383) promoter polymorphism was assessed by PCR- forming Growth Factor-β; BMPR-IB: BMP Receptor IB; RFLP. ActR- Type IIB: Activin Receptor (ActR) Type IIB; SNP: Single Nucleotide Polymorphism; 5′UTR: 5′ Untranslated We observed a statistically significant elevation Results: Region; GWAS: Genome-Wide Association; CRP: C Reac- of CRP, RF, and ESR on the patients with KOA relative tive Protein; KOA: Patients with Knee Osteoarthritis; ESR: to the controls. Seventy-two percent of our patients have Erythrocyte Sedimentation Rate; RF: Rheumatoid Factor; obesity grade I and II and 56% have severe functional BMI: Body Mass Index; WOMAC: The Western Ontario And disability on Womac index. The TT and TC genotypes of Mcmaster Universities Citation: Alrehaili AA, Ismail KA, Shami A, Algethami MK, Elsawy HW, et al. (2020) Association of Growth Differentiation Factor 5 (GDF5) Gene Polymorphisms with Susceptibility to Knee Osteoarthritis in Saudi Population. Int J Immunol Immunother 7:048. doi.org/10.23937/2378-3672/1410048 Accepted: May 06, 2020: Published: May 08, 2020 Copyright: © 2020 Alrehaili AA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Alrehaili et al. Int J Immunol Immunother 2020, 7:048 • Page 1 of 7 • DOI: 10.23937/2378-3672/1410048 ISSN: 2378-3672 Introduction expression of the GDF5 protein in knee joint [22]. In Eu- ropean and Asian populations, rs143383 polymorphism Osteoarthritis (OA) is a widespread polygenic multi- in the 5’-untranslated regions of GDF5 is associated with factorial disorder accompanied by joint cartilage dege- knee OA [23]. In this regard, studies on OA-associated neration and synovial inflammatory changes [1]. OA is single nucleotide polymorphism (SNP) rs143383 is a C the primary cause of physical disability in the elderly, to T transition located within the 5′ untranslated region and is characterized by pain in the joints, inflammation, (5′UTR) of GDF5, which codes for the extracellular si- and rigidity [2,3]. It is among the most prevalent joint gnaling molecule GDF5. About the association between diseases [4]; the incidence of hip and/or knee OA with rs143383 and OA, the investigators demonstrated that symptoms is about ~ 242 million worldwide [5], with the OA-risk T-allele of the SNP-mediated reduced mRNA other disorders it is Slisted as the eleventh highest inter- expression relative to the C-allele in an luciferase assay national disability cause [4]. Reduced patient life quality conducted in a chondrocyte cell line; chondrocytes are and productivity represent a major personal and com- the only cell type present in cartilage [22]. This study munity strain with a universal occurrence of 3.8% [6,7]. stressed rs143383 as the vital functional SNP responsi- Knee OA has a higher prevalence than other joints, ble for OA. It was also shown that the T-allele was asso- with an incidence rate of approximately 45 percent, ciated with diminished production of GDF5 in cartilage rising to 60.5 percent among obese individuals [8]. [17]. Incidence rises with each decade of age and with the Studies of genome-wide association (GWAS) repor- highest annual occurrence between ages 55-65 [9]. ted a clear and highly reproducible association between Knee OA is considered to be a widespread joint dege- susceptibility of knee OA and GDF5. In particular, single nerative disorder primarily affecting the elderly [10]. It nucleotide polymorphisms (SNPs) span a length of 130 is characterized by destruction of the cartilage of joints kb comprising GDF5 and downstream UQCC1 (ubiqui- [11]. Precise etiology for OA evolution remains lacking. nol-cytochrome C reductase complex assembly factor 1) However, age, genetic factors, environmental condi- was related with a 1.2 to 1.8-fold raise in knee OA risk tions and inappropriate lifestyles are the known threa- [24]. ts for OA [12]. The effect of certain genes is examined, as the genetic influence of the primary OA is high, i.e. Genetic factors are known to be important in the 40% for the knee, 60% for the hip and 65% for the hand pathogenesis of osteoarthritis. The etiology of osteoar- joints [13]. Growth differentiation factor 5 (GDF5) gene thritis remains complex, and the latest genetic informa- is located on the chromosome 20q11.2 and it regulates tion indicates that susceptibility to osteoarthritis occurs the expression of GDF5 protein. It is classified within the from unique combinations of multiple gene-gene and bone morphogenetic protein group (BMP) [14]. It invol- gene-environment interactions. This study was carried ves in development of bone and cartilage, particularly out to detect GDF5 gene polymorphism and to evaluate in endochondral ossification process [15]. The mutation its association with susceptibility to knee osteoarthritis. of GDF5 gene associates with generalized osteoarthritis Methods and skeletal related congenital diseases [16]. This study is a case-control conducted in the fema- GDF5 is recognized also as the cartilage-derived le section at College of Applied Medical Sciences, Taif morphogenetic protein of the superfamily transforming University. The study has been accepted by the ethi- growth factor-β (TGF-β), have been found to play a key cal board of Collage of Applied Medical Sciences, Taif role in the growth, repair and reconstruction of cartila- University and all participants gave informed consent ge and bone [17]. GDF-5 binds to the transmembrane to participate in the research.We included 50 patients serine/threonine kinase type I and II receptors to acti- with Knee OA (13 males and 37 females, their age ran- vate its signaling pathway [18]. BMPR-IB (BMP receptor ged between 25 and 66 years) who attended in King Fai- IB), BMPR-II, and activin receptor (ActR) type IIB have sal Medical Complex (Rheumatology Clinic), Taif, KSA. higher affinities for the GDF-5 ligand [19]. Upon GDF- Fifty healthy individuals with matched age and sex with 5 binding, the receptors are phosphorylated to activa- the Knee OA patients and with no clinical and laboratory te the downstream Smad pathway. The Smad proteins evidences of OA or other diseases were also included then translocate into the nucleus to regulate the tran- as a control group. Inclusion criteria include all patien- scription of various genes [20]. ts with KOA were diagnosed according American Colle- Several studies have revealed that GDF5 performs a ge of Rheumatology [25]. Antero-posterior and lateral major role in musculoskeletal processes, influencing en- view of knee radiographs were taken to confirm the dochondral calcification, joint development, tendon -re diagnosis of OA by Kellgren and Lawrence scores [26]. pair and bone formation [17]. Defects of this gene were Exclusion criteria include patients with other rheumato- shown to be correlated to abnormal joint development logial diseases such as: Systemic lupus erythematosus, or skeletal disorders in humans and mice [21]. Moreo- mixed connective tissue diseases, Scleroderma, and Der- ver, the polymorphism in GDF5 gene is related with low matomyositis.
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