Knee Osteoarthritis Susceptibility Research Articles

The potential impact of polymorphisms in METTL3 gene on knee osteoarthritis susceptibility

ObjectiveThis study was aimed to explore the correlation between METTL3 polymorphisms and susceptibility to knee osteoarthritis (KOA). MethodsThe relationship of five single nucleotide polymorphisms (SNPs) in the METTL3 gene with the susceptibility of KOA was analyzed through multinomial logistic regression analysis in this a case-control study. Genotyping was performed on 228 KOA patients and 252 unaffected individuals from South China based on the TaqMan method. The MDR software (version 3.0.2) was utilized for the analysis of SNP interactions. ResultsOut of the five SNPs examined, the T > G change in the METTL3 gene at the rs1061026 locus increased the risk of KOA, while rs1139130 A > G and rs1263802 C > T variants were found to be linked with a reduced risk of developing KOA with statistical significance. The rs1061027 A > C and rs1263801 C > G variants did not show significant association (p＞0.05). The rs1061026 TG/GG genotype showed a significant correlation with an increased risk of KOA in the following subgroups: the males, individuals with a BMI ranging from 24 to 28, smokers, those who were not engaged in physical exercise (PE), patients who had experienced KOA symptoms for eight years or longer, and those without a family history of the disease or reported swelling. On the other hand, the rs1139130 AG/GG genotype demonstrated a protective effect against KOA among the females, individuals with a BMI greater than or equal to 24, a unilateral KOA, or a KOA duration of 8 years or less, non-smokers, non-alcohol drinkers, those who were not engaged in PE, and those who had no injury or family history, or no experience of knee swelling. Additionally, it was observed that the rs1263802 CT/TT genotypes showed a protective effect among patients without a history of injury. Furthermore, individuals with the haplotypes GAT, GGC, TAT, and TGC were found to have a significantly lower susceptibility to KOA compared to the reference haplotype TAC. ConclusionsThe METTL3 gene variant rs1061026 could increase the risk of KOA, whereas the variants of rs1139130 as well as rs1263802 might exert a protective effect against KOA. These variants could potentially function as susceptibility markers for KOA among the population from South China.

Genetic polymorphisms of interleukin-16 in Egyptian patients with primary knee osteoarthritis

BackgroundThe pro-inflammatory cytokine, interleukin 16 (IL-16), has been shown to be secreted in low levels in knee osteoarthritis (KOA). The aim of the study was to examine the relationship between IL-16 polymorphisms and the risk of KOA in the Egyptian population, as well as the clinical and radiographic severity of KOA.ResultsIL16 rs11556218 thymidine triphosphate (T) T G (guanosine triphosphate), GG, TG + GG genotypes, and G allele (odd ratio (OR) = 0.315; 95% confidence interval (CI) = 0.191–0.518; P < 0.001; OR = 0.363; 95% CI = 0.162–0.815, P = 0.014; OR = 0.323; 95% CI = 0.202–0.519, P < 0.001; OR = 0.480; 95% CI = 0.338–0.683, P < 0.001 respectively); rs4778889 cytidine triphosphate (C) T,CC, TC + CC genotypes, and C allele (OR = 0.519, 95% CI = 0.319–0.844, P = 0.008; OR = 0.309, 95% CI = 0.105–0.916, P = 0.034; OR = 0.485, 95% CI = 0.304–0.775, P = 0.002; OR = 0.537, 95% CI = 0.365–0.791, P = 0.001 respectively); and rs4072111 CT, TT, CT + TT genotypes, and T allele (OR = 0.537, 95% CI = 0.323–0.893, P = 0.017, OR = 0.316, 95% CI = 0.096–0.843, P = 0.049, OR = 0.502, 95% CI = 0.309–0.816, P = 0.005; OR = 0.534, 95% CI = 0.353–0.809, P = 0.004 respectively) were associated with a decreased KOA risk, and they were significantly associated with decreased the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Kellgren-Lawrence (K/L) scores.Neither IL-16 serum levels nor IL-16 polymorphisms were associated with the susceptibility to KOA. Low KOA risk was associated with the haplotypes GTC and TCT.ConclusionThere was no correlation between serum IL-16 levels and KOA susceptibility or IL-16 polymorphisms. GTC and TCT haplotypes were associated with low KOA risk. The variant alleles rs11556218GG, TG + GG; rs4778889 CC, TC + CC; and rs4072111 TT, CT + TT were associated with a reduced risk of KOA.

The effect of ITLN1, XCL2 and DOT1L variants on knee osteoarthritis risk in the Han population.

Knee osteoarthritis (KOA) is a complex multifactorial disease, in which genetic factors account for 50% of the risk of osteoarthritis. This study investigated the association between ITLN1, XCL2 and DOT1L variants and KOA risk in the Han population. We applied Agena MassARRAY technology platform to genotype five single-nucleotide polymorphisms (SNPs) in 710 KOA patients and 709 controls. The correlation between ITLN1, XCL2 and DOT1L SNPs (rs2274908, rs4282797, rs4301615 and rs3815308) and KOA risk was calculated by logistic regression analysis, with odds ratio (OR) and 95% confidence intervals (CIs). Also, the relationship between genotypes at these different loci and clinical parameters (White blood cell, Eosinophil ratio, Neutrophil count, Eosinophil count, Monocyte ratio and Monocyte count) among patients and controls was analyzed. In the overall results, rs2274908, rs4301615 and rs3815308 were correlated with KOA susceptibility. After gender stratification analysis, ITLN1 rs2274908 and XCL2 rs4301615 were related to an increased risk of KOA in males, and ITLN1 rs2274908 and DOT1L rs3815308 were related to an increased risk of KOA in females. After age stratification analysis, ITLN1 rs2274908 and XCL2 rs4301615 were correlated with an increased risk of KOA in people aged > 65year old. After smoking stratification analysis and drinking stratification analysis, ITLN1 rs2274908, XCL2 rs4301615 and DOT1L rs3815308 were still associated with the risk of KOA. In short, ITLN1 rs2274908, XCL2 rs4301615 and DOT1L rs3815308 were related to KOA risk in the Han population, which was helpful to clarify the pathogenesis of these sites in KOA.

Intergenic Interactions of SBNO1, NFAT5 and GLT8D1 Determine the Susceptibility to Knee Osteoarthritis among Europeans of Russia.

This study was conducted to examine the associations between genome-wide association studies (GWAS)-important single nucleotide polymorphisms (SNPs) and knee osteoarthritis (KOA) among Europeans of Russia. The present replicative study ("patient-control" design has been used) was carried out on 1000 DNA samples from KOA (n = 500) and KOA-free (n = 500) participants. Ten GWAS-important for KOA SNPs of eight candidate genes (LYPLAL1, GNL3, GLT8D1, SBNO1, WWP2, NFAT5, TGFA, GDF5) were studied. To assess the link between SNPs and KOA susceptibility, logistic regression (to establish independent SNP effects) and MB-MDR (to identify SNP-SNP interactions) were used. As a result of this genetic analysis, the associations of individual SNPs with KOA have not been proven. Eight loci out of ten tested SNPs interacted with each other (within twelve genetic models) and determined susceptibility to KOA. The greatest contribution to the disease development were made by three polymorphisms/genes such as rs6976 (C>T) GLT8D1, rs56116847 (G>A) SBNO1, rs6499244 (T>A) NFAT5 (each was included in 2/3 [8 out 12] KOA-responsible genetic interaction models). A two-locus epistatic interaction of rs56116847 (G >A) SBNO1 × rs6499244 (T>A) NFAT5 determined the maximum percentage (0.86%) of KOA entropy. KOA-associated SNPs are regulatory polymorphisms that affect the expression/splicing level, epigenetic modification of 72 genes in KOA-pathogenetically significant organs such as skeletal muscles, tibial arteries/nerves, thyroid, adipose tissue, etc. These putative KOA-effector genes are mainly involved in the organization/activity of the exoribonuclease complex and antigen processing/presentation pathways. In conclusion, KOA susceptibility among Europeans of Russia is mediated by intergenic interactions (but not the main effects) of GWAS-important SNPs.

Association between Common Variants in VEGFA Gene and the Susceptibility of Primary Knee Osteoarthritis.

This study aimed to analyze the relationship between vascular endothelial growth factor A (VEGFA) gene polymorphisms, plasma VEGFA, and the susceptibility of knee osteoarthritis (OA). A total of 404 subjects, 202 knee OA subjects and 202 healthy volunteers, were enrolled into the study. Four distinct polymorphisms of the VEGFA gene were evaluated using polymerase chain reaction-restriction fragment length polymorphism: -2578C/A (rs699947), -1154G/A (rs1570360), -634C/G (rs2010963), and +936C/T (rs3025039). Plasma VEGFA levels were analyzed using enzyme-linked immunosorbent assay. The most common nucleotides in both knee OA subjects and healthy controls were CC for -2578C/A, GG for -1154G/A, CG for -634C/G, and CC for +936C/T in the VEGFA gene. Genotype distribution and allele frequencies of VEGFA -2578C/A, -1154G/A, -634C/G, and +936C/T single nucleotide polymorphisms did not differ between OA patients and the controls. Plasma VEGFA levels showed no difference between OA patients and the controls. In contrast, plasma VEGFA levels of -634C/C genotype were significantly higher in OA patients than in the controls (P = 0.035). According to the -2578A/A genotype, patients with early stage OA had a higher odds ratio than those with advanced stage OA (P = 0.023). VEGFA -2578C/A (rs699947), -1154G/A (rs1570360), -634C/G (rs2010963), and +936C/T (rs3025039) polymorphisms may not be responsible for OA susceptibility in the Thai population. However, the OA patients with A/A genotype at the -2578C/A seemed to have a lower potential risk of developing severe OA than those with the C/A and C/C genotypes. These findings would help elucidate and facilitate a better understanding of the genetic fundamentals of OA.

Association of X-linked TLR-7 gene polymorphism with the risk of knee osteoarthritis: a case–control study

Knee osteoarthritis (OA) is the most prevalent type of OA, and Toll-like receptor 7 (TLR7) may lead to the pathogenesis of OA. Recently, X-linked TLR7 polymorphism has been confirmed to be associated with arthritis. However, there is a lack of studies on TLR7 gene polymorphism associated with knee OA susceptibility. The current study aimed to determine whether TLR7 gene polymorphism is associated with the risk of knee OA. Genotyping of two polymorphic sites (rs3853839 and rs179010) in the TLR7 gene was performed in 252 OA patients, and 265 healthy controls using the SNaPshot sequencing technique. Data were analyzed statistically by Chi-square tests and logistic regression. Rs3853839-C allele showed frequencies of 28% and 27% in the healthy control and female knee OA groups, respectively. The differences were not statistically significant (P > 0.05). The rs3853839-CG genotype frequency was significantly lower in the female knee OA group as compared to the healthy control group (OR 0.60; 95%CI 0.36–0.99; P = 0.044). In the male hemizygote population, the rs3853839-CC showed significantly lower frequencies in the male knee OA group as compared to the healthy control group (OR 0.35; 95%CI 0.17–0.71; P = 0.0025). Regarding rs179010, there were no differences in the genotype distribution and allele frequencies between OA patients and healthy subjects under any models (P > 0.05). Stratified analysis showed that the frequency of the rs3853839-CG genotypes was lower in high Kellgren-Lawrence grades (KLG) (OR 0.48; 95%CI 0.21–1.08; P = 0.066), and significantly lower in OA patients with effusion synovitis (OR 0.38; 95%CI 0.17–0.88; P = 0.013). TLR7 rs3853839 polymorphism may play a role in the susceptibility of knee OA in the Chinese Han Population and may be associated with OA severity and the risk of effusion synovitis in Knee OA.

The Association of Angiopoietin-2 1064 C/T Rs3020221 Gene Polymorphism with Knee Osteoarthritis

ABSTRACT Osteoarthritis (OA) is a common type of arthritis, affecting millions of people around the world. Angiopoietin-2 (Angpt-2) has a role in the development of chronic inflammatory diseases. We aimed to assess the serum Angpt-2 levels in knee OA patients and to investigate the association of Angpt-2 gene polymorphism(rs3020221 C/T) with knee OA susceptibility and severity. Angiopoietin-2(rs3020221C/T) gene polymorphism was identified in 254 knee OA patients and 227 healthy controls using real-time polymerase chain reaction. Serum Angpt-2 was measured using ELISA. The Arabic version of the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Kellgren-Lawrence (KL) grading score were used to assess the clinical and radiological severity of OA and their relationship with Angpt-2(rs3020221C/T) gene polymorphism was investigated. Serum Angpt-2 levels were significantly higher in knee OA patients than in the controls (P = .001). OA patients with C/T genotype had a four times greater risk of developing OA than other genotypes (OR = 4.39, 95% CI = 2.85–6.76). Additionally, the T allele presented more in OA patients 224/508 (44%) with two times risk of developing OA (OR = 1.86, 95% CI = 1.43–2.43, p = .001). Angpt-2 SNP (rs3020221C/T) genotype C/T was significantly associated with elevated serum Angpt-2 levels (14.15 ± 5.62 ng/ml). The serum Angpt-2 levels are significantly elevated in OA patients and Angpt-2 gene polymorphism (rs3020221 C/T) may be a risk factor for OA development and both are associated with the severity of knee OA. Carriers of the C/T genotype have a significantly higher serum Angpt-2 levels and a greater risk of developing OA.

Tetra-primers ARMS-PCR Based Association Analyses of Synonymous and Intronic Variants in the ADAM12 Gene with Susceptibility to Knee Osteoarthritis: A Case-Control Study.

Genetic variations in a disintegrin and metalloprotease 12 (ADAM12) gene may contribute to develop Osteoarthritis (OA) that is characterized by cartilage matrix degradation and osteophytes formation. Therefore, the aim of present study was to analyze the association between the ADAM12 gene variants and knee OA predisposition. Tetra-primers ARMS-PCR was employed, to genotype the ADAM12 gene polymorphisms (rs1044122 and rs1871054) in 400 knee OA patients and equal number of age-matched controls. The association between ADAM12 gene variants and OA susceptibility was estimated using the Chi-square, logistic regression, haplotypes and linkage analyses. A significant association of rs1044122 (genotype: χ2 = 18.94; P < 0.001, allele: χ2 = 19.10; P < 0.001) and rs1871054 (genotype: χ2 = 10.04; P = 0.007, allele: χ2 = 10.57; P = 0.001) was observed with increased OA susceptibility. The variant genotype of rs1044122 increased OA risk more than twice [odds ratio (OR) 2.20; P = 0.001] and the risk was higher in females (OR 2.43; P = 0.001). The variant genotype of rs1871054 was perceived to almost double the risk in females (OR 1.97; P = 0.003). Moreover, a significant association of rs1044122 and rs1871054 under the additive genetic model (P < 0.001 and P = 0.002, respectively) was observed. The targeted ADAM12 gene polymorphisms, showed significant association with knee OA susceptibility. Females harboring the polymorphisms might be at risk. Besides, the haplotype CC of rs1044122 and rs1871054 in the ADAM12 gene may double knee OA risk. These findings may help in determining the etiology of OA and recognizing the people at risk of developing knee OA.

Lack of association between MMP13 (rs3819089), ADAM12 (rs3740199-rs1871054) and ADAMTS14 (rs4747096) genotypes and advanced-stage knee osteoarthritis.

Objectives The aim of this study was to investigate the relationship between MMP13 rs3819089, ADAM12 rs3740199 and rs1871054, and ADAMTS14 rs4747096 genotypes in patients with radiologically diagnosed knee osteoarthritis (OA). Patients and methods A total of 300 patients (68 males, 232 females; mean age: 61.6 years; range, 25 to 89 years) who were admitted to the orthopedics and traumatology clinic and diagnosed with knee OA according to the 2000 American College of Rheumatology (ACR) criteria between October 2018 and March 2019 were prospectively analyzed. Patients with Grades III-IV OA according to the Kellgren- Lawrence (K-L) grading system were included in the patient group (n=150) and those without radiological features of knee OA (K-L Grades I-II) were included in the control group (n=150) voluntarily. The presence of single nucleotide polymorphisms (SNPs) in the targeted genes in both groups was assessed by real-time polymerase chain reaction in the peripheral blood sample.Results The most common nucleotides in both the control and patient groups were CG for rs3740199 and CT for rs1871054 in the ADAM12 gene, and the most common nucleotides in alleles were GG for MMP13 rs3819089 and AA for ADAMTS14 rs4747096. No statistically significant relationship was detected between the gene polymorphisms and advanced OA. Conclusion The study results suggest that ADAM12 rs3740199 and rs1871054, MMP13 rs3819089, and ADAMTS14 rs4747096 polymorphisms have no relationship with knee OA susceptibility in the Turkish population. However, as this is the first study to investigate the relationship between the SNPs of ADAM12, ADAMTS14, and MMP13 genes and the development of OA in the Turkish population, it would contribute to our understanding of the molecular bases of OA.

Genetic polymorphism of interleukin-16 and its association with the clinical and radiographic severity in primary knee osteoarthritis patients

Aim of the workTo investigate the association between IL and 16 genetic (rs4072111) single nucleotide polymorphism (SNP) and susceptibility to primary knee osteoarthritis (KOA) and to elaborate its connection with clinical and radiographic severity of KOA. Patients and methods80 primary KOA patients and 35 matched healthy controls. IL-16 gene rs4072111 SNP was genotyped in KOA patients and control using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique and verified by direct DNA sequencing. Western Ontario and McMaster Universities Arthritis Index (WOMAC) was used to assess the clinical severity of KOA and Kellgren lawrence (K/L) radiographic grading was evaluated. ResultsThe 80 KOA patients were 60 female and 20 male patients with mean of 55.8 ± 8.9 years (38–71 years), BMI 25.5 ± 1.8 (16.5–27) and disease duration 5.8 ± 4.3 years (1–20 years). The mean WOMAC index was 52.9 ± 17.9 and the K/L score was 2.49 ± 0.73. Patients carrying the wild (CC) genotype had a significantly higher WOMAC index compared those carrying the TT and CT genotypes (p = 0.0.046) also, KL sore had tendency to increase in patient carrying the wild (CC) compared to patients carrying the TT and CT genotypes (p = 0.08), However, no direct genetic association was detected between the SNP and KOA. On performing a regression with WOMAC as the dependant factor only the triglycerides (p = 0.001) and K/L (p < 0.0001) were independent risk factors. ConclusionIl-16 gene (rs4072111) SNP might be associated with clinical severity of KOA. Furthermore, the SNP is not likely to be associated with KOA susceptibility in the Egyptian population.

Correlation between single nucleotide polymorphisms in CXCR4 microRNA binding site and the susceptibility to knee osteoarthritis in Han Chinese population.

BackgroundThis study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) at the microRNA target sequence in CXCR4 and the susceptibility to knee osteoarthritis (KOA).MethodsA total of 305 patients with KOA and 305 healthy controls were recruited into this study. The genotypes of CXCR4 rs1804029 and rs17848060 loci were analyzed.ResultsThe susceptibility to KOA of CXCR4 rs1804029 G allele carriers was 1.33 times (95% CI: 1.09‐1.54, P = .006) that of T allele carriers. The KOA susceptibility in individuals carrying T allele at CXCR4 rs17848060 locus was 1.38 times that of individuals carrying A allele (95% CI: 1.17‐1.57, P < .001). The G allele at CXCR4 rs1804029 locus was the target of hsa‐miR‐146a‐3p, while the A allele at CXCR4 rs17848060 locus could be targeted by hsa‐miR‐20a‐3p. The plasma level of hsa‐miR‐146a‐3p was lower in rs1804029 G allele carriers than T allele carriers (P < .001), whereas plasma level of hsa‐miR‐20a‐3p was higher in rs17848060 T allele carriers than A allele carriers (P < .001).ConclusionThe SNPs at rs1804029 and rs17848060 loci in CXCR4 were significantly associated with the susceptibility to KOA in Han Chinese population.

Association between growth differentiation factor 5 rs143383 genetic polymorphism and the risk of knee osteoarthritis among Caucasian but not Asian: a meta-analysis

BackgroundA few months ago, the Bioscience Reports journal showed that growth differentiation factor 5 (GDF5) rs143383 genetic polymorphism increases the susceptibility of knee osteoarthritis (KOA), but previous studies’ results have debates about available data. Considering the availability of more recent data, we focus on clarifying the relationship of KOA and GDF5 rs143383 genetic polymorphism by a meta-analysis of case-control trial data.MethodsThe eligible studies from the time of database established to Oct. 2019 were collected from PubMed, Springer, Cochrane library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan Fang library. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate the association between these polymorphisms and KOA risk. The meta-analysis was completed by STATA 18.0 software.ResultsA total of 196 studies were collected, 16 of them included in final meta-analysis (7997 cases and 12,684 controls). There was significant association between GDF5 rs143383 polymorphism and KOA in all genetic models (for Allele model (C versus T): OR = 0.84 (95% CI = 0.76–0.91); dominate model (CC+CT versus TT): OR = 0.80 (95% CI = 0.72–0.90); recessive model (CC versus CT+TT): OR = 0.79 (95% CI = 0.68–0.92); heterozygote model (CT versus CC+TT): OR = 0.89 (95% CI = 0.80–0.97); homozygous model (CC versus TT): OR = 0.71 (95% CI = 0.60–0.85)). In the subgroup analysis, we obtained the results that there is no significance among Asians.ConclusionGDF5 rs143383 genetic polymorphism increases the risk of KOA among Caucasians; CC genotype and C allele are protective factors for the susceptibility of KOA among Caucasians.

A novel variant near LSP1P3 is associated with knee osteoarthritis in the Chinese population.

Previous genome-wide association study showing a novel variant near LSP1P3 was associated with knee osteoarthritis (KOA) in Caucasians. Replication study in different populations was essential to validate the association of novel susceptible genes with KOA. To our knowledge, there is a lack of study concerning the role of the LSP1P3 gene in Chinese KOA patients. We aimed to determine the association between the novel variant near LSP1P3 gene and the susceptibility of KOA in the Chinese population and to further investigate its relationship with the severity of KOA. A total of 532 primary KOA patients who received treatment in our clinic center were included in the current study. Nine hundred twenty-seven age- and gender-matched healthy subjects were recruited as controls. The severity of KOA was graded according to the Kellgren-Lawrence (KL) grading system, with KL grade of 1 or 2 classified as mild KOA and KL grade of 3 or 4 classified as severe KOA. Three variants were genotyped using TaqMan SNP genotyping assay, including rs4867568 of LSP1P3 gene, rs143383 of GDF5, and rs1558902 of FTO. The differences in terms of genotype and allele distributions between the cases and the controls were analyzed by the chi-square test. There were 215 male and 317 female patients with a mean age of 58.1 ± 7.2years. According to the KL score, 172 (32.3%) patients had mild KOA and 360 (67.7%) had severe KOA. There were remarkably lower frequencies of allele T of rs4867568 and allele C of rs143383 in the patients than in the controls (31.5% vs. 36.0%, p = 0.01 for rs4867568; 24.6% vs. 28.7%, p = 0.02 for rs143383), with an OR of 0.82 and 0.81, respectively. As for rs1558902, no significant difference regarding the frequency of allele and genotype was found between the patients and the controls. Patients with severe KOA had remarkably lower incidence of genotype TT of rs4867568 than patients with mild KOA (6.7% vs. 12.2%, p = 0.04). There was significantly higher frequency of allele T in patients with mild KOA than in those with severe KOA (36.3% vs. 29.2%, p = 0.02, OR = 0.72). The association of rs4867568 and rs143383 with KOA was successfully replicated in the Chinese Han population. Moreover, rs4867568 was found significantly associated with the severity of KOA. More studies are warranted to explore the functional role of rs4867568 in the development of KOA. Key Points • A novel variant near Lsp1p3 is associated with knee osteoarthritis. • Baseline characteristics of the subjects. • Comparison of the genotype and allele frequency of the Lsp1p3, GDF5, and FTO. • Association of the Lsp1p3, GDF5, and FTO with KOA severity.

Putative functional variants of PI3K/AKT/mTOR pathway are associated with knee osteoarthritis susceptibility.

BackgroundOsteoarthritis (OA) is a degenerative musculoskeletal disease which causes joint deformity and pain and finally leads to limb dysfunction. Knee osteoarthritis (KOA) has the highest incidence among all kinds of OA. Strong evidence leads to the understanding that P13K/AKT/mTOR signaling is very important in cartilage degeneration.MethodsThis research sought to understand the association between genetic variation of PI3K/AKT/mTOR genes and KOA susceptibility among Chinese population. All the genetic variants of PI3K/AKT/mTOR pathway were graded and selected using RegulomeDB database, and then, an association study including 278 osteoarthritis patients and 289 controls was conducted.ResultsFinally, eight SNPs' genotypes' distributions and susceptibility to KOA were presented. AKT1 rs2498789 was associated with KOA susceptibility in dominate genetic model (AA + GA vs GG) after adjusted for BMI, age, and gender: OR = 1.46, 95% CI: 1.03‐2.05, P = .03. PIK3CA rs7646409 was also associated with KOA susceptibility (TC vs TT) after adjusted for BMI, age, and gender: OR = 0.58, 95% CI: 0.36‐0.93, P = .02. PIK3CA rs7646409 (TC vs TT) with KOA risk was more significant in age < 60 group (P for heterogeneity was .03). Risk score showed significant association with KOA susceptibility after cumulative analysis (OR = 2.45, 95% CI: 1.35‐4.45, P = .003).ConclusionsThis study shows that genetic variation of PI3K/AKT/mTOR is associated with KOA susceptibility in Chinese Han population, indicating that PI3K/AKT/mTOR is very important in KOA pathogenesis.

Evaluation of Relationship Between Common Variants in FGF18 Gene and Knee Osteoarthritis Susceptibility

Osteoarthritis (OA) is the most common type of arthritis disease. Previous etiological studies indicated that both environmental and genetic factors play important roles in the occurrence and development of knee OA (KOA). In the present study, we aimed to investigate the association between the FGF18 gene and susceptibility to KOA in Han Chinese population. A total of 2,556 unrelated Han Chinese individuals, including 866 KOA patients and 1,688 healthy controls, were recruited. Nine tag SNPs located within the gene region of FGF18 were selected for genotyping. Logistic models were fitted for single marker-based association analyses. Age, gender and BMI were included in each model as covariates. To investigate the functional consequences of significant SNP, we extracted expression quantitative trait loci (eQTL) data from the GTEx database. SNP rs3884606 was significantly associated with the risk of KOA (OR [95% CI]=1.25 [1.11-1.41], p=0.0002) after adjusting for age, gender and BMI. The G allele was significantly associated with an increased risk of KOA. No significant eQTL signals could be identified for SNP rs3884606 on FGF18. In this study, we identified a genetic polymorphism in FGF18 that was significantly associated with the risk of KOA based on samples with Chinese Han ancestry. Our findings replicated the recent GWAS report and supported an association between KOA and FGF18.

Is leptin receptor gene (Gln223Arg) polymorphism associated with disease susceptibility and severity in patients of primary knee osteoarthritis?

Aim of the workA significant role of Leptin receptor (LEPR) is documented in inflammation, body weight homeostasis and maintenance of cartilage. This study was conducted to detect the existence of genetic association between Knee osteoarthritis (KOA) susceptibility and severity; and LEPR (Gln223Arg) single nucleotide polymorphism (SNP). Patients and methods73 primary KOA patients and 73 matched healthy controls were studied. Kellgren Laurence (K/L) radiographic grading system, Western Ontario and McMaster Universities Arthritis Index (WOMAC) score and Visual Analogue Scale (VAS) were used to assess the severity of KOA. LEPR Gln223Arg SNP (rs1137101) was genotyped in KOA patients and controls using polymerase chain reaction-restriction fragment length polymorphism (PCR –RFLP) technique and verified by direct DNA sequencing. ResultsIn the current study, a significant genetic association was found between KOA patients carrying the AA genotype of LEPR and the extent of radiological severity (p < 0.044). In addition, a significant difference was detected within the patients between Body Mass Index (BMI) and the SNP. Patients carrying the wild type (GG) genotype showed lower body mass index (BMI) in comparison to patients carrying the heterozygous (AG) genotype and the mutant (AA) genotype (p < 0.032). However, no direct genetic association was detected between the SNP and KOA. ConclusionLeptin receptor gene (Gln223Arg) SNP might be associated with severity of KOA. There is a significant genetic association between the SNP and BMI hence, LEPR SNP might be indirectly associated with the incidence of KOA. Furthermore, the SNP is not directly associated with KOA susceptibility in the Egyptian population.

Role of SREBP2 gene polymorphism on knee osteoarthritis in the South Indian Hyderabad Population: A hospital based study with G595C variant

IntroductionOsteoarthritis (OA) is a multifactorial disease with genetic factors playing a crucial role, and it has been associated with a family history of obesity. G595C polymorphism in the sterol regulatory element-binding protein 2 (SREBP2) gene has demonstrated an association with knee osteoarthritis (KOA) patients. However, this polymorphism has been never explored in an Indian population. Hence, the current study aimed to examine whether G595C (rs2228314) polymorphism in SREBP2 gene was associated with KOA susceptibility in the South Indian Hyderabad population. MethodsG595C polymorphism was genotyped with 200 KOA cases and 200 healthy controls using polymerase chain reaction-restriction fragment length polymorphism analysis. ResultsA significant association was observed between age, body mass index (BMI), and family histories in KOA cases and controls (p < 0.05). The current allele (C vs G; OR-2.8 [95%CI = 2.1–3.7]; p < 0.0001) and genotype analysis confirms the significant association with (GC + CC vs GG; OR-3.5 [95%CI = 2.3–5.3]; p < 0.0001 & GC vs GG + CC; OR-1.7 [95%CI = 1.0–2.9]; p = 0.02) KOA vs. control subjects. On stratification analysis, genotype CC and C allele were associated with KOA. Gender association failed to demonstrate positive genotype frequencies (p > 0.05). Multifactor-dimensionality reduction (MDR) analysis showed a positive association with BMI and G595C genotypes (p < 0.05); 51% of the homozygous variant CC genotypes were present in obesity subjects. ConclusionIn conclusion, our findings suggest that G595C polymorphism in SREBP2 gene is associated with KOA in the South Indian Hyderabad population and presents scope for further investigation of the gene's function in KOA.

A genome-wide association study in Japanese identified a new knee osteoarthritis susceptibility locus

A genome-wide association study in Japanese identified a new knee osteoarthritis susceptibility locus

Role of resistin genetic variations in knee osteoarthritis pathogenesis, a cross sectional study.

Osteoarthritis (OA) is a serious health concern globally and is recognized by degradation of articular cartilage, bone remodeling and synovial inflammation. Resistin is an adipokine that shown to be involved in inflammatory process associated with OA. Aim of the current study was to estimate the link of resistin gene polymorphisms (- 420 C>G, + 299 G>A) with genetic susceptibility of knee OA in a Pakistani population. 280 patients and 308 age and sex matched controls were recruited in this case-control study. Genotype and allele frequencies were evaluated by Polymerase chain reaction-Restriction Fragment Length Polymorphism. Resistin concentration was measured by immunoassay. A significant difference in allele and genotype frequency was observed for both study groups. Resistin - 420 mutant genotype was associated with an increased susceptibility to OA (p = 0.001). Similarly, resistin + 299 GA + AA genotypes showed a relation with an elevated risk of knee OA compared to GG genotype (p = 0.01). Moreover, the mutant alleles frequency was significantly high in patient group as compared to healthy individuals for both loci (p < 0.01). Resistin - 420/+ 299 alleles haplotype analysis demonstrated that mutant alleles were more prevalent in OA affected individuals compared to healthy subjects (p < 0.05). The serum resistin levels were not remarkably different in patient vs. control group (p = 0.9). Further, the circulating resistin level was not found to be influenced by - 420G and + 299A alleles and non significant differences were observed in resistin concentration in mutant vs. wild type genotypes for both SNPs (p > 0.05). Our data suggest an association between investigated resistin genetic variants and knee OA susceptibility in our population. This is the first report to show association between investigated single nucleotide polymorphisms and OA among any population.

Association of IL-6, IL-8, MMP-13 gene polymorphisms with knee osteoarthritis susceptibility in the Chinese Han population.

Objective: To identify the association between the interleukin (IL) 6 (IL-6) rs1800795 (-174 G>C), IL-8 rs4073 (-251T>A), and matrix metalloproteinase-13 (MMP-13) rs2252070 (-77G>A) gene polymorphisms and knee osteoarthritis (KOA) susceptibility in the Chinese Han population. Methods: Genomic DNA was extracted from a total of 400 KOA patients and 400 healthy subjects. Sanger sequencing was performed to determine the genotypes of the IL-6 rs1800795 (-174 G/C), IL-8 rs4073 (-251A/T), and MMP-13 rs2252070 (-77A/G) loci. The mRNA expression levels of IL-6, IL-8, and MMP-13 in osteoblasts and the protein expression levels of IL-6, IL-8, and MMP-13 in the synovial fluids of KOA patients were analyzed. Results: The recessive model of IL-6 rs1800795 locus was found to be associated with KOA risk (adjusted odds ratio (OR) = 1.657, 95% confidence interval (CI) = 1.396–1.866, P<0.001). The IL-8 rs4073 locus dominant and recessive model showed no significant association with KOA risk (P>0.05). The dominant and recessive models of the MMP-13 rs2252070 locus showed higher risk for developing KOA (dominant model: adjusted OR = 1.271, 95%CI = 1.095–1.480, P=0.001; recessive model: adjusted OR = 1.361 95%CI = 1.151–1.569, P<0.001). The G>C mutation in IL-6 rs1800795 and the G>A mutation in MMP-13 rs2252070 were associated with significantly higher KOA disease severity. The G>C mutation in the IL-6 rs1800795 locus was associated with up-regulation of IL-6 expression. The G>A mutation in the MMP-13 rs2252070 locus was associated with up-regulation of MMP-13 expression. Conclusion: The IL-8 rs4073 (-251T>A) mutation was not associated with KOA susceptibility. The IL-6 rs1800795 (-174 G>C) and MMP-13 rs2252070 (-77G>A) mutations were associated with KOA susceptibility, increased disease severity, and up-regulation of IL-6 and MMP-13 expression levels.