|Ahead of print publication
Impact of obesity on leptin, leptin receptor gene polymorphism, and some adipokines in egyptian patients with knee osteoarthritis
Adel A H. Abdel-Rahman1, Hala E Hamouda2, Ibrahim F Zeid1, Amal M El-Barbary3, Aya A Al-Ashwah1
1 Department of Organic Chemistry, Faculty of Science, Menofia University, Shebin El-Kom, Egypt
2 Department of Medicinal Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Department of Rheumatology and Rehabilitation, Faculty of Medicine, Tanta University, Tanta, Egypt
Aya A Al-Ashwah,
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Kom
Source of Support: None, Conflict of Interest: None
Aim: The aim of this study was to investigate the role of leptin receptor (LEPR) gene polymorphism and adipokines in the pathogenesis of knee osteoarthritis (OA) in Egyptian female patients.
Materials and Methods: Ninety-five Egyptian females were classified into three groups: group I (control): 32 healthy females, Group II: included 30 non obese knee osteoarthritic patients and Group III: included 33 obese knee osteoarthritic patients. Genotyping of rs1137101 at LEPR gene was analyzed using allelic discrimination assay by real-time polymerase chain reaction technique, and then, adipokines and nitric oxide (NO) levels were measured.
Results: The frequency of GG genotype was found to be significantly higher in Group III when compared to Group II and controls (26% to 4%, 1%) (P < 0.001), while AA genotype was the most frequent in the control group (75%) (P < 0.001). rs1137101 was correlated with knee OA in the dominant genetic model (GG + GA vs. AA) in Group II (odds ratio = 8, 95% CI [2.6–24.2], P <.001). Moreover, there was a significant increase in serum levels of leptin, resistin, and NO with a concomitant decrease in adiponectin level in Group III as compared to the other two groups confirming the role of these adipokines in OA.
Conclusion: Our findings suggested that the genetic variation in rs1137101 is involved in the pathogenesis of both obesity and knee OA in Egyptian female patients. In addition, it seems that adipokines and oxidative stress are important factors linking obesity, adiposity, and inflammation in OA.
Keywords: Adipokines and Gln223Arg, knee osteoarthritis, leptin receptor
|How to cite this URL:|
H. Abdel-Rahman AA, Hamouda HE, Zeid IF, El-Barbary AM, Al-Ashwah AA. Impact of obesity on leptin, leptin receptor gene polymorphism, and some adipokines in egyptian patients with knee osteoarthritis. Indian J Rheumatol [Epub ahead of print] [cited 2020 Jun 2]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=282511
| Introduction|| |
Osteoarthritis (OA) is the most common cause of disability worldwide., It is characterized by a progressive degeneration in articular cartilage with a decrease in joint space and osteophyte formation. The knee joint is considered the most common site where OA is involved. Although the exact cause and pathogenesis of knee OA on a cellular and molecular level are not clear, there are several risk factors that are related, which include a combination of genetic and nongenetic factors as obesity, sex, age, and joint injury.
Obesity is associated with an elevated risk of chronic diseases and the implications for the musculoskeletal system which include both degenerative and inflammatory conditions. White adipose tissue (WAT) is considered the principal cellular component of adipose tissue and the main site of energy storage in mammals, and WAT has been emerged as a complex and a highly dynamic multifactorial organ with endocrine, metabolic, and immune regulatory roles involved in secreting inflammatory cytokines and adipokines.,
Adipokines are a group of molecules which relate to the inflammatory state, and they are responsible for several metabolic deviations, including autoimmune and inflammatory diseases that affect joints and bones. The exact role of these adipokines in knee OA is not well known, but they may play a significant indirect role through their effect on OA pathways in many patients. Leptin is an adipocyte factor which is mainly expressed by the obese gene in adipocytes, and it is involved in the body's metabolism and the immune adjustment. Leptin is produced by chondrocytes and other joint tissues such as synovium, osteophytes, meniscus, and bones.,,, Synovial fluid also contains soluble leptin receptor (sObR), which can bind and inactivate leptin; sObR modulates leptin responses as an endogenous leptin antagonist.
Several polymorphisms of leptin and its receptor gene including Q223R polymorphism result in the formation of inactive forms of leptin receptors (LEPRs), which lead to the inhibition of hormonal signal transduction, thus blocking leptin action. LEPR was reported to be expressed in human articular cartilage and chondrocytes. In addition, LEPR mediates the inflammatory and destructive responses of leptin in the cartilage and other joint tissues.,
Resistin is a newly identified adipocytokine that has demonstrated links between obesity, insulin resistance (IR), and pro-inflammatory properties in humans., It is expressed and secreted by adipose tissue. Resistin upregulates the pro-inflammatory cytokines including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha and triggers cytokine production in peripheral blood mononuclear cells.,
Adiponectin is one of the adipokines hormones, which controls appetite and metabolism and improves insulin sensitivity. It has been identified as a regulatory factor in inflammation and insulin sensitivity. In joints, several tissues have been proven to secrete adiponectin including synovium, meniscus, osteophytes, cartilage, bone, and fat.
The degenerative processes of the cartilage tissues are triggered by altered biomechanical patterns, which are associated with an increased impact of oxidative and nitrosative stress.,
Nitric oxide (NO) is a reactive free radical, which participates in the regulation of many physiological processes, such as vascular relaxation, neurotransmission, platelet aggregation, and immune regulation. NO has an important effect on bone cell functions, and the production of matrix metalloproteinases in chondrocytes, which contributes to OA progression.
The main aim of this study is to evaluate the exact role of leptin and LERP gene polymorphism, as well as resistin, adiponectin, and NO levels in the pathogenesis of knee OA in Egyptian female patients.
| Materials and Methods|| |
This study was carried out on 95 Egyptian females, including 32 healthy females (body mass index [BMI] = 18.5–25 kg/m2), aged (35–55) years, representing controls (Group I), and 63 patients with primary knee OA aged (32–65) years, who presented to outpatient clinic of the Physical Medicine and Rheumatology Department, Tanta University Hospitals, Egypt. The latter (63 patients) were divided into Group II including 30 nonobese female patients (BMI = 18.5–25 kg/m2) with confirmed knee OA and Group III including 33 obese female patients (BMI ≥30) with confirmed knee OA. The diagnosis of OA was based on the symptomatic criteria of the American College of Rheumatology and the presence of radiographic signs) Kellgren-Lawrence (K/L (grading ≥2) for OA in at least one knee.
Approval was obtained from the Local Research Ethics Committee at the Faculty of Medicine, Tanta University, and written informed consent was obtained from each participant enrolled in this study.
Participants were excluded on the basis of having other etiologies causing knee diseases such as inflammatory arthritis (rheumatoid, polyarthritic, or autoimmune disease), posttraumatic or postseptic arthritis, skeletal dysplasia, or developmental dysplasia. In addition, all participants having arthropathy due to gout, pseudogout, bilateral knee replacements, and other forms of arthritis were excluded. Patients with cancer or other chronic inflammatory diseases were excluded. In addition, controls who had any signs or symptoms of arthritis or joint diseases (pain, swelling, tenderness, or restriction of movement) were also excluded from this study.
All participants were subjected to the following:
Anthropometric measurements and treatment history
The demographic and clinical information was recorded. BMI was measured for all participants by dividing weight (in kilograms) by the squared height (in meters). Patients were classified according to BMI (by the World Health Organization) into normal weight (BMI = 18.5–25 kg/m2) and obese (BMI >30 kg/m2). The OA patients were subjected to complete history taking including disease onset, duration, and treatment history.
The severity of OA was evaluated according to the K/L grade classification system, and only patients with K/L grades of 2 or higher were included. Based on the K/L grade, participants were radiographically classified into three groups as follows: normal (K/L Grade 0 or 1), moderate (Grade 2), and severe (Grade 3 or 4).
After 12 h of overnight fasting, 10 ml of venous blood samples was taken from every investigated subject under complete aseptic conditions. Five milliliters of whole blood was separated in ethylenediaminetetraacetic acid-coated tubes and stored at −80°C for genotyping of the Gln223Arg (rs1137101) A/G polymorphism, as well as the estimation of plasma fasting blood glucose, postprandial blood glucose, and plasma insulin levels. The remaining whole blood samples were transferred slowly into a dry sterile centrifuge tube, allowed to clot at room temperature, and then centrifuged at 2000 rpm for 10 min. The separated sera were stored at −80°C until used for estimation of lipid profile, serum NO and serum leptin, adiponectin, and resistin levels.
Genotyping of the Gln223Arg (rs1137101) A/G polymorphism
DNA was extracted from whole blood samples using GeneJET Whole Blood Genomic DNA Purification Mini Extraction Kit (Thermo Fisher Scientific, USA). LEPR gene Gln223Arg polymorphism was genotyped using assay of allelic discrimination by real-time polymerase chain reaction (PCR) technique with TaqMan probe (Applied Biosystems, USA). Master mix (×40) primers and probes were also supplied from Thermo Scientific, USA. Ten microliters of master mix was added to 3.5 μL of nuclease-free water and 1.5 μL of the primer/probe mix. Five microliters of genomic DNA extract was applied for each sample. The following cycling conditions were implemented; initial denaturation was performed at 95°C for 10 min, followed by 40 cycles of denaturation at 94°C for 15 s, primer annealing at 50°C for 60 s, then extension at 72°C for 2 min, and finally, extension at 72°C for 1 min. Analysis of data was accomplished using real-time PCR instrument, software V.2.0.1, ABI 7500 (Biosystem, USA), as shown in [Figure 1] and [Figure 2].
|Figure 1: Allelic discrimination plot showing different sample genotypes|
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|Figure 2: Amplification plot showing normalized reporter dye fluorescence as a function of cycle|
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Other biochemical parameters
Fasting blood glucose, postprandial blood glucose, triglycerides, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and serum nitric acid were all determined using semiautomatic clinical chemistry analyzer (Chem 7).
Commercially available enzyme-linked immunosorbent assay kits were used to perform the measurements of serum leptin, adiponectin, resistin, and fasting plasma insulin levels. In addition, Insulin resistance was measured by homeostatic model assessment (HOMA) method, which calculated according to the following formula:
HOMA-IR = Glucose (mg/dL) × Insulin (μU/mL)/405.
The statistical analysis was performed using SPSS V. 23 (IBM, USA). Quantitative data were expressed in mean value and standard deviation and analyzed using Student's t-test, while qualitative data were expressed in frequency and percentage and then analyzed using Chi-square test. The association between the Gln223Arg polymorphism and the risk of knee OA was evaluated with odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for age and BMI with multivariate logistic regression analysis.
P < 0.05 is considered as statistically significant.
| Results|| |
A statistical comparison between the studied groups with respect to the demographic and laboratory biochemical findings is demonstrated in [Table 1] and [Table 2]. There was no statistically significant difference as regards age among the three groups (P > 0.05). BMI was significantly higher in patients of Group III compared to Group II and the control group (P < 0.001, P < 0.001). According to the radiographic K/L grading system, approximately 62% of Group II had a K/L grading of 2 and 50% of the Group III patients had a K/L grading of 3 or 4. In addition, there was a significant difference in BMI between the different K/L grading subgroups (P < 0.001) [Table 1].
Biochemistry parameter investigation
Erythrocyte sedimentation rate, C-reactive protein, cholesterol, triglycerides, low-density lipoprotein, postprandial glucose, insulin, and HOMA-IR levels were increased in both the patient groups with significant higher levels in the obese patient group in comparison to the control group, while there was no significant difference in uric acid and HDL-C among the different groups [Table 2].
As regards the biochemical assays, the levels of serum leptin, resistin, and serum NO were elevated in both the patient groups with significantly higher values in obese patients when compared to the control group. Adiponectin level decreased in both the patient groups with a significantly lower value in obese patients.
Genetic investigation results
Our results indicated that LEPR gene SNP rs1137101 (Gln223Arg) polymorphism was correlated with the risk of knee OA and obesity.
There was a statistically significant difference in genotype frequency of LEPR gene A/G polymorphism among the three studied groups, with the highest frequency of GG genotype in Group III compared to Group II patients and controls, while AA genotype was the most frequent in the control group.
When comparing polymorphism frequencies for rs1137101 between the obese knee OA group (Group III, n = 30) and healthy controls (Group I, n = 33), the frequency of the GG genotype was significantly increased in Group III (26%) compared to Group I (3%). The GG + AG vs. AA OR comparison between Groups III and I was 19.53 (95% CI [5.1–73]), while in the nonobese knee OA group (Group II), GG genotype was significantly increased in Group II (12%) compared to Group I (3%). The GG + AG vs. AA OR comparison between Group II and Group I was 8 (95% CI [2.6–24.2]) [Table 3].
|Table 3: Genotype frequencies and allelic distribution of leptin receptor gene (A/G) polymorphism between studied groups|
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Allelic distribution showed that G allele was dominant in Group III with an increased risk of knee OA, while A allele was more frequent in the control group (P < 0.001) [Table 3].
On the other hand, when comparing genotype variation with biochemical characters, there was a significant increase in BMI, insulin, NO, leptin, and resistin levels in GG genotype when compared to AA genotype. Adiponectin was significantly decreased in GG genotype as compared to AA genotype [Table 4].
|Table 4: Comparison between genotype distribution and biochemical markers and osteoarthritis grading|
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While knee OA Grade (2 and 3) was significantly increased in AG genotype when compared to AA and GG genotype [Table 4].
| Discussion|| |
Knee OA is considered the most common form of arthritis; therefore, many researches have focused on the early detection of knee OA. Radiography is used to diagnose OA; however, the radiographic evidences are seen only after a substantial cartilage loss has already taken place. Hence, researchers have paid more attention recently to the role of genetic factors in the susceptibility of knee OA.
Obesity is strongly associated with the initiation and progression of OA, not only due to joint overload but also because of the presence of WAT, which has been recognized as a secretory organ of adipokines such as leptin, adiponectin, and resistin. Adipokines are produced in knee OA joints by infrapatellar fat pads, synovium, chondrocytes, osteoblasts, as well as osteoclasts. Hence, adipokines levels could be related to cartilage degeneration and synovial inflammation.
Our result indicated that the levels of serum leptin and resistin are elevated in the OA patient groups as compared to controls, with significantly higher values in the obese OA group, suggesting the inflammatory role of leptin and resistin in OA. It also suggests that both obesity and OA are associated with an increase in leptin and resistin levels due to their overexpression in OA cartilage, which lead to cartilage destruction. On the other hand, adiponectin level decreased in both the patient groups with a significant decrease in obese OA patients.
Yan et al., 2018, reported the upregulation of leptin level in the synovial fluid of knee and in serum samples from knee OA and rheumatoid arthritis patients. Therefore, leptin can be easily considered as a cytokine-like hormone which plays a prototypical pro-inflammatory role in the pathogenesis of OA. The potential role of leptin in knee OA has been supported by a number of studies,, which indicated that leptin concentration significantly increased in synovial fluid of knee OA patients when compared to control individuals. Hence, leptin level is strongly associated with disease severity.
Furthermore, the results of the present study support previous studies which revealed the positive correlation between leptin and resistin with the presence and progression of radiographic knee OA, while adiponectin has a weak correlation with knee OA progression.,
As regards adiponectin, our results and some previous studies have indicated its protective role in knee OA., In our study, adiponectin levels were found to be lower in both the knee OA groups, with a significant decrease in the obese patient group (Group III). In contrast, some other studies indicated that adiponectin has a pro-inflammatory role by stimulating the production of PGE2 and MMP-13 activity in OA patients.,,
Since OA etiology is multifactorial, several studies have indicated its strong association with a variety of genetic susceptibility loci. Our study detects the possible role of LEPR polymorphism in susceptibility of knee OA as the pathophysiology of OA was suggested to be highly related to the impairment of leptin signal pathway. In addition, LEPR is mainly expressed in the native human cartilage chondrocytes and mediates the inflammatory and destructive responses of leptin in cartilage and other joint tissues.
Our results indicate that there was a significant relation between homozygous LEPR polymorphism and BMI; this result is congruous with Hassan et al., 2018, who concluded that the LEPR Gln223Arg, UCP2 G-866A, and INSR exon 17 polymorphisms are related to obesity in Egyptian population. In addition, Hastut et al., 2016, indicated that LEPR polymorphisms of rs1137100 and rs1137101 LEPR gene are associated with the increase of BMI in Yogyakarta population. In contrast, previous studies concluded that there was no relation between LEPR polymorphism and BMI.,, This contradiction of results may be due to several disorders associated with obesity, including combination of genetic, behavioral, and environmental causes; LEPR gene variants may not be the only cause for obesity, and many genetic and lifestyle aspects could act together to influence energy balance.
In addition, our results indicate that LEPR polymorphism was not associated with the elevation of lipid profile level or IR, while it was correlated with the elevation of leptin, resistin, NO, and insulin levels.
Our results indicate that LEPR gene SNP rs1137101 (Gln223Arg) polymorphism was associated with the risk of primary knee OA and obesity in Egyptian female patients. As both GG genotype distribution and G allelic frequencies of Gln223Arg were significantly higher in both the patient groups than the control group, with a higher frequency of GG genotype in obese knee OA patients compared to nonobese knee OA patients. Our result is congruous with Novoseletskyi et al., 2018, who reported an increased risk of knee OA in the homozygous GG (Arg/Arg) carriers of LEPR gene when compared to the control group of healthy females. The results also indicated that the proportion of AA (Gln/Gln) genotype carriers decreased at higher stages of knee OA. However, such a decrease did not have a sufficient level of statistical significance. At the same time, the incidence of heterozygous AG (Gln/Arg) carriers increased at Stages I, II, and III, respectively, but such growth was not statistically reliable too.
Moreover, Yang et al., 2016, documented that the genotype GG and G allele were associated with susceptibility to knee OA in females both young groups (≤65 years) and old groups (>65 years), as well as patients with mild knee OA, after adjustment for other potential confounders such as age, gender, and BMI. However, there were no associations between Gln223Arg polymorphism and knee OA susceptibility in male participants and patients with higher K/L grading. Meanwhile, Hämäläinen et al., 2017, reported a weak association of LEPR polymorphism (rs1137101 and rs1805094) haplotype with radiographic indices in Finnish women with hand OA.
Inflammation is a major factor associated with the risk of both progression of cartilage loss and symptoms of disease, including joint pain, swelling, and stiffness, which are indicators of synovitis. Synovitis, involve in infiltration of mononuclear cells into the synovial membrane and production of pro-inflammatory mediators, such as IL-1α, which induce the overproduction of inducible NO synthase., NO is one of the free radicals, which plays a role in several physiological and pathophysiological processes such as inflammation.,
The results of the present study showed a significant increase in the level of serum NO in both the patient groups when compared to the control group, with a significantly higher level in obese patients with OA. Our results are congruous with earlier studies which indicated the association between NO higher values and the pathogenesis of OA.,
Finally, we shall indicate that the main limitation in this study is the small size of the sample; hence, it is difficult to generalize our results as all participants from the same area (Gharbyia governorate). Repeating the study on a larger population with different lifestyles could be recommended, in order to present the potential role of Gln223Arg SNP in knee OA and the disease outcome among different populations.
| Conclusion|| |
Our data indicate that genetic variation in rs1137101 at LEPR gene is involved in the pathogenesis of both obesity and knee OA in Egyptian female patients. In addition, it seems that adipokines and oxidative stress are important factors linking obesity, adiposity, and inflammation in OA.
We hereby acknowledge Dr. Mohamed Mahmoud Alhousini Alashwah (MD, FRCR) for his diligent proofreading of this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]