The rs1477196 SNP of the FTO Gene is Associated with Primary Knee Osteoarthritis in a Female Population from Northern Mexico.

Background: Osteoarthritis is a frequent rheumatic disease. Some single-nucleotide polymorphisms of the gene associated with fat mass and obesity are associated with increased body mass index and knee osteoarthritis. Objective: The objective of this study was to analyze the association of single nucleotide polymorphism rs1477196 of the fat mass and obesity gene with primary knee osteoarthritis. Methods: This observational and cross-sectional study included 347 Mexican participants. We performed the genotypification analysis with TaqMan® probe C_2031262_10 for rs1477196 (Thermo Fisher Scientific). Multivariate analysis included covariables such as age, type 2 diabetes, obesity, and postmenopause. Results: Type 2 diabetes, obesity, and postmenopause were associated with primary knee osteoarthritis in female participants. We did not find an association between rs1477196 and obesity. In the codominant and dominant genetic models, rs1477196 was significantly associated with primary knee osteoarthritis only in the female group, including in the model adjusted by other covariables (odds ratio = 2.517; 1.035-6.123; p = 0.042 and odds ratio = 2.387; 1.054-5.407; p = 0.037, respectively). The interaction between rs1477196 and obesity was significantly associated with primary knee osteoarthritis in female participants (p = 0.039 and p = 0.043). Conclusions: Our findings suggest that the rs1477196 variant of the fat and obesity mass gene may be associated with the risk of primary knee osteoarthritis in women.

mtDNA haplogroup A enhances the effect of obesity on the risk of knee OA in a Mexican population.

To evaluate the influence of mitochondrial DNA haplogroups on the risk of knee OA in terms of their interaction with obesity, in a population from Mexico. Samples were obtained from (n = 353) knee OA patients (KL grade ≥ I) and (n = 364) healthy controls (KL grade = 0) from Mexico city and Torreon (Mexico). Both Caucasian and Amerindian mtDNA haplogroups were assigned by single base extension assay. A set of clinical and demographic variables, including obesity status, were considered to perform appropriate statistical approaches, including chi-square contingency tables, regression models and interaction analyses. To ensure the robustness of the predictive model, a statistical cross-validation strategy of B = 1000 iterations was used. All the analyses were performed using boot, GmAMisc and epiR package from R software v4.0.2 and SPSS software v24. The frequency distribution of the mtDNA haplogroups between OA patients and healthy controls for obese and non-obese groups showed the haplogroup A as significantly over-represented in knee OA patients within the obese group (OR 2.23; 95% CI 1.22-4.05; p-value = 0.008). The subsequent logistic regression analysis, including as covariate the interaction between obesity and mtDNA haplogroup A, supported the significant association of this interaction (OR 2.57; 95% CI 1.24-5.32; p-value = 0.011). The statistical cross-validation strategy confirmed the robustness of the regression model. The data presented here indicate a link between obesity in knee OA patients and mtDNA haplogroup A.

Epistasis Between Two Gene Variants of Leptin and Vascular Endothelial Growth Factor Genes in the Development of Primary Knee Osteoarthritis.

BACKGROUND: The association of leptin (LEP) and vascular endothelial growth factor A (VEGFA) genes with the susceptibility to knee osteoarthritis (OA) has been analyzed; however, the epistasis between them has not been investigated. OBJECTIVE: The objective of the study was to analyze the association of LEP and VEGFA variants and their interaction with primary knee OA in a Mexican Mestizo population. METHODS: A case-control study was developed. Cases were ≥40 years, BMI ≤27 kg/m2, with primary knee OA and radiologic Grade ≥2. Controls were participants with no knee OA and a radiologic Grade < 2. The rs2167270 of LEP and rs2010963 of VEGFA were genotyped. Genotypic association was tested under codominant, dominant, and recessive models. Uni- and multi-variate analyses were developed through non-conditional logistic regression. The multifactor dimensionality reduction algorithm was developed to detect epistasis. RESULTS: Participants comprised 103 cases and 179 controls. Allelic and genotypic distributions did not show differences between the groups. Notwithstanding, a statistically significant interaction was observed between the LEP and VEGFA genes (p = 0.02) with a testing accuracy of 0.5199 and cross-validation consistency of 10/10. This interaction model confers an increased risk to knee OA (OR [95% CI] = 1.8 [1.1-2.9]). CONCLUSION: Interaction between LEP and VEGFA is related with genetic susceptibility to developing primary knee OA.

Effects of photobiomodulation therapy in chondrocyte response by in vitro experiments and experimental model of osteoarthritis in the knee of rats.

The purpose of this study is to evaluate the effects of photobiomodulation (PBM) therapy in chondrocyte response by in vitro experiments and cartilage repair using an experimental model of osteoarthritis (OA) in the knee of rats. The in vitro experiment was performed with chondrocyte cells, and they were divided into two groups: non-irradiated and irradiated with PBM (808 nm; 0.8 J or 1.4 J). Then, cell proliferation was evaluated after 1, 3, and 5 days. The experimental model of osteoarthritis (OA) was performed in the knee of 64 Wistar rats, and they were assorted into control group (CG), PBM (808 nm; 1.4 J). The results of in vitro showed that PBM 1.4 J increased cell proliferation, on days 1 and 5. However, after 3 days was demonstrated a significant increase in cell proliferation in PBM 0.8 J. The in vivo experiment results demonstrated, on histological analysis, that PBM presented less intense signs of tissue degradation with an initial surface discontinuity at the superficial zone and disorganization of the chondrocytes in the cartilage region when compared to CG, after 4 and 8 weeks. These findings were confirmed by immunohistochemistry and qRT-PCR analysis which showed that PBM increased IL-4, IL-10, COL-2, Aggrecan, and TGF-ß which are anabolic factors and acts on extracellular matrix. Also, PBM reduces the IL1-ß, an inflammatory marker that operates as a catabolic factor on articular cartilage. In conclusion, these results suggest that PBM may have led to a return to tissue homeostasis, promoting chondroprotective effects and stimulating the components of the articular tissue.

Are functional variants of the microRNA-146a gene associated with primary knee OA? Evidence in Mexican mestizo population.

MicroRNA-146a (miR-146a) is an inflammatory response regulator whose expression is deregulated in osteoarthritis (OA); variations in the miR-146a gene could affect OA risk. This study aimed to analyze the association between two functional variants of the miR-146a gene and primary knee OA in Mexican mestizo population. Methods and Results. A case-control study was conducted with cases defined as individuals aged ≥ 40 years with primary knee OA grade ≥ 2, according to the Kellgren-Lawrence system. Controls were volunteers with no primary knee OA with radiographic grade < 2. TaqMan allelic discrimination assays genotyped the rs2910164 and rs57095329. Allelic and genotypic frequencies, as well as the Hardy-Weinberg equilibrium (HWE), were calculated. The genetic association was tested under codominant, dominant, and recessive models. Non-conditional logistic regressions were carried out to estimate the association magnitude. We included 310 cases and 379 controls. Despite rs2910164 being in HWE, there was no association under codominant, dominant, and recessive models. In women with OA grade 2, the codominant model found a trend between the CC genotype and increased risk [OR (95% CI) 1.6 (0.7-3.5)]; the same trend was found in OA grade 4 in the codominant and recessive models [1.8 (0.6-5.4) and 2.0 (0.7-5.9)]. Conversely, in men with OA grade 4, the CC genotype tended to be associated with a lower risk in the codominant and recessive models [0.6 (0.1-6.0) and 0.5 (0.1-5.1)]. Conclusion. Our results show that miR-146a gene variants are not significantly associated with primary knee OA in Mexican mestizos.

Ancestral contribution of the muscle-specific creatine kinase (CKM) polymorphism rs4884 in the knee osteoarthritis risk: a preliminary study.

INTRODUCTION/OBJECTIVES: Articular cartilage and periarticular muscle tissues are strongly affected during knee osteoarthritis (OA). Creatine kinase (CK) is an enzyme expressed in several tissues, but the isoform CK-MM is specific of skeletal muscle, and its serum concentration is used as a biomarker of muscle damage. Genetic variants of the CKM gene have been associated with various pathologies, but to date, there are no reports of association with OA. Due to the rs4884 polymorphism being well represented in the Mexican population, it is used as an ancestry informative marker; thus, the goal of this preliminary report was to evaluate the association of this polymorphism in primary knee OA Mexican patients. METHOD: Eighty-seven patients with primary knee OA were compared with 107 healthy controls. Serum CK-MM was determined using the dot blot system, and genotyping was performed using the OpenArray system. Logistic regression models were used to assess the association between the rs4884 polymorphism and OA susceptibility adjusting by gender, age, and body mass index. RESULTS: There were no significant differences in serum CK-MM values between patients and controls. The GG genotype and the G allele had a higher frequency in the control group compared with the OA group (24.3% vs. 12.6%, OR = 0.34, 95% CI = 0.14-0.84, P = 0.019; and 40.2% vs. 28.2%, OR = 0.51, 95% CI = 0.32-0.82, P = 0.005, respectively). CONCLUSIONS: Our results suggest a protection role of the rs4884 polymorphism against knee OA development; further studies are required to confirm it. Key Points • CK-MM enzyme catalyzes the conversion of creatine and ATP to create phosphocreatine and ADP; this reaction is reversible. • In tissues that consume ATP rapidly, such as skeletal muscle, the phosphocreatine serves as an important energy reservoir. • During knee OA, peripheral muscle tissues of the joint may be affected. • The rs4884 polymorphism of the CKM gene may participate as a protective factor in the development of OA.

Association between matrix metalloproteinase-1 (MMP-1) protein level and the risk of rheumatoid arthritis and osteoarthritis: a meta-analysis

Recent publications have investigated the potential role of the protein level of matrix metalloproteinase-1 (MMP-1) in the susceptibility to rheumatoid arthritis (RA) and osteoarthritis (OA). However, no unanimous conclusion was obtained. Therefore, we carried out a meta-analysis to explore the association between MMP-1 expression and these two clinical disorders. After database searching and screening, we enrolled a total of eighteen articles for the pooled analysis. We observed a significant association between RA cases and controls in the whole population [SMD (standard mean difference)=1.01, P=0.017]. There were similar positive results in the subgroup analysis of "population-based control" (SMD=1.50, P=0.032) and "synovial fluid" (SMD=1.32, P=0.049). In addition, we observed an increased risk in OA cases, compared with controls, in the overall analysis (SMD=0.47, P=0.004) and subsequent subgroup analysis of "knee OA" (SMD=0.86, P<0.001), "Asian/China" (SMD=0.76, P=0.003), "cartilage-Asian/China" (SMD=1.21, P<0.001), and "synovial fluid-Asian/China" (SMD=0.73, P=0.004). In summary, a high protein level of MMP-1 in synovial fluid may be associated with the susceptibility to RA, and the high MMP-1 level in the cartilage tissue or synovial fluid may be related to the pathogenesis of knee OA in the Chinese population. This should be confirmed by larger sample sizes.

Association between matrix metalloproteinase-1 (MMP-1) protein level and the risk of rheumatoid arthritis and osteoarthritis: a meta-analysis.

Recent publications have investigated the potential role of the protein level of matrix metalloproteinase-1 (MMP-1) in the susceptibility to rheumatoid arthritis (RA) and osteoarthritis (OA). However, no unanimous conclusion was obtained. Therefore, we carried out a meta-analysis to explore the association between MMP-1 expression and these two clinical disorders. After database searching and screening, we enrolled a total of eighteen articles for the pooled analysis. We observed a significant association between RA cases and controls in the whole population [SMD (standard mean difference)=1.01, P=0.017]. There were similar positive results in the subgroup analysis of "population-based control" (SMD=1.50, P=0.032) and "synovial fluid" (SMD=1.32, P=0.049). In addition, we observed an increased risk in OA cases, compared with controls, in the overall analysis (SMD=0.47, P=0.004) and subsequent subgroup analysis of "knee OA" (SMD=0.86, P<0.001), "Asian/China" (SMD=0.76, P=0.003), "cartilage-Asian/China" (SMD=1.21, P<0.001), and "synovial fluid-Asian/China" (SMD=0.73, P=0.004). In summary, a high protein level of MMP-1 in synovial fluid may be associated with the susceptibility to RA, and the high MMP-1 level in the cartilage tissue or synovial fluid may be related to the pathogenesis of knee OA in the Chinese population. This should be confirmed by larger sample sizes.

Analyses of the Genetic Polymorphisms rs3740199 and rs1871054 of the ADAM12 Gene and the Alleles at the rs2073508 Loci of the TGFB1 Gene and Their Contribution to Susceptibility to Primary Knee Osteoarthritis.

Aims: To analyze the association of polymorphisms in the ADAM12 (rs3740199 and rs1871054) and TGFB1 (rs2073508) genes with knee osteoarthritis (KOA) in a population from northern Mexico. Methods: A total of 296 individuals were included in the study. Primary KOA was confirmed according to the criteria established by the American College of Rheumatology. A real-time PCR-based DNA genotyping method was used to evaluate the rs3740199, rs1871054, and rs2073508 polymorphisms in 132 cases and 164 controls. Results: Our results demonstrate that the ADAM12 rs3740199 polymorphism was significantly associated with primary KOA under the recessive model (p = 0.036). However, after performing a multinomial logistic regression model, no significant association was found (p = 0.722). Furthermore, no associations for the rs1871054 and rs2073508 polymorphisms were observed in this study. Conclusion: These findings suggest that polymorphisms within the ADAM12 and TGFB1 genes may not have a significant influence on primary KOA susceptibility in the Mexican Mestizo population; however, inclusion of other ethnic groups and a larger sample size are needed to more fully analyze the role of these polymorphisms with KOA risk.

Multifactor dimensionality reduction reveals a strong gene-gene interaction between STC1 and COL11A1 genes as a possible risk factor of knee osteoarthritis.

Articular cartilage is an avascular tissue with a structure that allows it to support and cushion the overload of the surfaces in contact. It maintains its metabolic functions due to the contribution of different signaling pathways. However, several factors play a role in its deterioration, allowing to the development of osteoarthritis (OA), and one of the major factors is genetic. Our goal was to identify gene-gene interactions (epistasis) between five signaling pathways involved in the articular cartilage metabolism as possible indicators of OA risk. We applied the Multifactor-Dimensionality Reduction (MDR) method to identify and characterize the epistasis between 115 SNPs located in 73 genes related to HIF-1α, Wnt/ß-catenin, cartilage extracellular matrix metabolism, oxidative stress, and uric acid transporters. Ninety three patients diagnosed with primary knee OA and 150 healthy controls were included in the study. Genotyping was performed with the OpenArray system, the statistical analysis was carried out with the STATA software v14, and epistasis was analyzed with the MDR software v3.0.2. The MDR analysis revealed that the best interaction model was between polymorphisms rs17786744 of the STC1 gene and rs2615977 of the COL11A1 gene, with an entropy value of 4.44%, CVC 8/10, OR 5.60, 95% CI 3.27-9.59, p < 0.0001. Under this interaction model, we identified high and low risk genotypes involved in OA development. Our results suggest complex interactions between STC1 and COL11A1 genes that might have an impact on genetic susceptibility to develop OA. Further studies are required to confirm it.

Analysis of Polymorphisms in the MATN3 and DOT1L Genes and CTX-II Urinary Levels in Patients with Knee Osteoarthritis in a Northeast Mexican-Mestizo Population.

Aims: To investigate the possible roles of the single nucleotide polymorphisms (SNPs) MATN3 (rs77245812) and DOT1L (rs12982744) with susceptibility to knee osteoarthritis (KOA) among mestizos from the northeast region of Mexico. In addition, we analyzed the relationship of their urinary levels of carboxy terminal telopeptide of collagen type II (CTX-II) and the radiological grade of disease. Materials and Methods: A total of 223 individuals from a Northeast Mexico Mestizo population were included in this study: 110 patients with primary KOA and 113 healthy controls. Genotyping of the MATN3 (rs77245812) and DOT1L (rs12982744) SNPs was performed by real-time polymerase chain reaction. Results: No association was found between the polymorphisms MATN3 (rs77245812), DOT1L (rs12982744), and the risk of developing KOA (odds ratio [OR] = 1.33, 95% confidence interval [CI] = 0.42-6.48, p = 0.621) (OR = 2.03, 95% CI = 0.35-11.5, p = 0.422). However, urinary CTX-II levels were considerably higher by radiographic grade. Conclusions: An increase in CTX-II per radiographic grade was observed in the case group, but no association was found between MATN3 and DOT1L genes and the risk of KOA in Mexican mestizos.

DNA methyltransferase genes polymorphisms are associated with primary knee osteoarthritis: a matched case-control study.

DNA methylation is an epigenetic mechanism involved in the development of primary osteoarthritis (OA). The association between DNA methyltransferases (DNMTs) genes polymorphisms and diseases in which DNA methylation plays a role in their pathogenesis has been described (e.g., cancer); however, its relationship with OA has not been investigated. The aim of this study was to analyze the association between DNMT1, DNMT3A, and DNMT3B polymorphisms with radiologic primary knee OA in Mexican mestizo population. A matched case-control study was conducted (ratio, 1:1). Cases included 244 subjects with definite radiographic knee OA (grade ≥ 2). Controls were matched by age and gender and were subjects with no definite radiographic knee OA/normal (grade < 2). The DNMTs polymorphisms were genotyped by TaqMan allelic discrimination assays. Conditional logistic regression was carried out, and the genetic association was tested under co-dominant, dominant, and recessive inheritance models. Haplotypes for DNMT1 polymorphisms were constructed and their associations were also tested. The CC genotypes of rs2228611 and rs2228612 of DNMT1 were associated with a lower risk for primary knee OA under a co-dominant and a recessive model [OR (95% CI) 0.4 (0.2-0.8)/0.5 (0.3-0.8) and 0.3 (0.1-0.8)/0.3 (0.1-0.7), respectively]. The CT haplotype of DNMT1 polymorphisms was associated with a lower risk [OR (95% CI) 0.71 (0.51-0.97)]. The CC genotype of rs2424913 of DNMT3B was associated with an increased risk under a co-dominant and a dominant model [OR (95% CI) 3.0 (1.1-8.0), and 1.6 (1.1-2.4), respectively]. Our results show that DNMTs polymorphisms are associated with primary knee OA.

Functional status and severity of osteoarthritis in elderly is associated to the polymorphism of TNFA gene.

BACKGROUND: Osteoarthritis (OA) is a major musculoskeletal disease with high prevalence in the elderly. The study of genetic polymorphisms of inflammatory mediators involved in OA may contribute to the elucidation of the complex pathophysiology of this disease and identification of susceptibility individuals. AIM: This study aimed to evaluate the association between polymorphism at tumor necrosis factor alpha gene (SNP - 308 G/A TNFA) with presence, severity and functional status of osteoarthritis in elderly. METHODS: This study was characterized as case-control and encompassed 257 physically independent elderly (Mean Age: 68.55 ± 5.2; Minimum age: 60 and Maximum age: 82) were recruited. After this selection, the groups were divided in: 92 elderly individuals with osteoarthritis (case group) and 165 without the disease (control group). METHODS: The individuals were genotyped by the TaqMan real-time PCR system. The subjects were classified based on the degree of radiological impairment according to the criteria of Kellgren-Laurence and regarding functional impairment using the WOMAC and LEQUESNE questionnaires. RESULTS: TNFA gene polymorphic individuals (subjects harboring allele A) are more affected by OA (χ2 = 8.7, p = 0.003), once they have major radiological lesion both in hip (Fisher-Freeman-Halton Test = 3.9, p = 0.04) and knee (Fisher-Freeman-Halton Test = 4.0, p = 0.04) as well as worse functional status assessed by the Lequesne questionnaire (Mann-Whitney, p = 0.04). At the multivariate analysis, after adjustment for age, gender, body mass index, the presence of rare allele for TNFA (allele A) increases the susceptibility to OA development [OR: 1.87 (95% CI: 1.1-3.2)]. CONCLUSION: We conclude that the SNP - 308 G/A of TNFA gene may affect osteoarthritis susceptibility, severity and functional status of individuals with osteoarthritis.

Impact of the gene-gene interactions related to the HIF-1α signaling pathway with the knee osteoarthritis development.

INTRODUCTION/OBJECTIVES: Articular cartilage is the target tissue of osteoarthritis (OA), and because it lacks capillary networks, the microenvironment is hypoxic. Hypoxia inducible factor-1 alpha (HIF-1α) regulates the homeostasis of this tissue. The aim of this study was to investigate whether genetic polymorphisms of the HIF-1α signaling pathway are involved in the development of knee OA. METHOD: We performed a case-control association study and genotyped 134 knee OA patients and 267 healthy controls. All participants were genotyped in order to evaluate 42 SNPs from 22 genes involved in the HIF-1α signaling pathway using the OpenArray technology. Gene-gene interactions (epistasis) were analyzed using the multifactor dimensionality reduction (MDR) method. RESULTS: The MDR analysis showed epistasis between AKT2 (rs8100018) and IGF1 (rs2288377), AKT2 (rs8100018) and IGF1 (rs35767), IGF1 (rs35767) and COL2A1 (rs1793953), and between GSK3B (rs6438552) and IGF1 (rs35767) polymorphisms, with information gain values of 21.24%, 8.37%, 9.93%, and 5.73%, respectively. Additionally, our model allowed us to identify high- and low-risk genotypes among COL2A1 rs1793953, GSK3B rs6438552, AKT2 rs8100018, and IGF1 rs35767 polymorphisms. CONCLUSIONS: Knowing the interactions of these polymorphisms involved in HIF-1α signaling pathway could provide a new diagnostic support tool to identify individuals at high risk of developing knee OA.

A preliminary analysis of microRNA profiles in the subchondral bone between Kashin-Beck disease and primary knee osteoarthritis.

INTRODUCTION: Kashin-Beck disease (KBD) is a chronic osteochondral disorder primarily associated with cartilage degeneration. The bone texture structure in KBD was also changed but it was not identical to primary knee osteoarthritis (OA). This study investigates the differences in microRNA (miRNA) profiles of subchondral bone collected from patients suffering from KBD in comparison with those with primary knee osteoarthritis (OA). METHODS: Subchondral bone tissues were taken from four patients with KBD and four patients with primary knee OA undergoing total knee replacement. The miRNA array profiling was performed using an Affymetrix miRNA 4.0 Array, and then the target gene predictions and function annotations of the predicted targets were performed. RESULTS: Our results showed that 124 miRNAs had lower expression levels in the subchondral bone sampled from KBD patients in comparison with OA patients. Gene ontology (GO) and KEGG pathway analyses of the predicted targets demonstrated numerous significantly enriched GO terms and signal pathways essential for bone development and integrity, such as metabolic processes, PI3K-Akt, and MAPK signaling pathways. CONCLUSIONS: Our study confirms that a large set of miRNAs are differentially expressed in the subchondral bone of patients with KBD and OA and contributes new insights into potential pathological changes in the subchondral bone of KBD patients.

Knee osteoarthritis induces atrophy and neuromuscular junction remodeling in the quadriceps and tibialis anterior muscles of rats.

Knee osteoarthritis (KOA) is associated with muscle weakness, but it is unclear which structures are involved in the muscle changes. This study assessed morphological alterations and the expression of genes and proteins linked to muscular atrophy and neuromuscular junctions (NMJs) in KOA, induced by anterior cruciate ligament transection (ACLT) in rats. Two groups of rats were assessed: control (without intervention) and KOA (ACLT surgery in the right knee). After 8 weeks, quadriceps, tibialis anterior (TA) and gastrocnemius muscles were analyzed (area of muscle fibers, NMJ, gene and protein expression). KOA group showed atrophy in quadriceps (15.7%) and TA (33%), with an increase in atrogin-1 and muscle RING-finger protein-1 (MuRF-1). KOA group showed quadriceps NMJ remodeling (reduction area and perimeter) and decrease in NMJ diameter in TA muscle. The expression of nicotinic acetylcholine receptor (nAChR) γ-nAChR increased and that of α-nAChR and muscle specific tyrosine kinase (MuSK) declined in the quadriceps, with a decrease in ε-nAChR in TA. MuRF-1 protein expression increased in quadriceps and TA, with no changes in neural cell adhesion molecule (NCAM). In conclusion, ACLT-induced KOA promotes NMJ remodeling and atrophy in quadriceps and TA muscles, associated with inflammatory signs and changes in muscle gene and protein expression.

Epistasis between ADIPOQ rs1501299 and PON1 rs662 polymorphisms is potentially associated with the development of knee osteoarthritis.

Overweight produces oxidative stress (OS) on the articular cartilage, with the subsequent risk of developing knee osteoarthritis (OA). Associations between genetic polymorphisms related to OS and OA have been reported, but it is currently unknown whether there exist interactions among them that affect OA development. To identify and evaluate interactions between multiple SNPs related to OS in Mexican knee OA patients. Ninety-two knee OA patients were included in the study, which were compared to 147 healthy controls. Nine variants of six genes (PEPD, AGER, IL6, ADIPOQ, PON1, and CA6) related to OS were genotyped in both study groups through the OpenArray system. Epistasis was analyzed with the multifactor dimensionality reduction (MDR) method. The MDR analysis revealed a significant interaction (p = 0.0107) between polymorphisms rs1501299 (ADIPOQ) and rs662 (PON1), with an entropy value of 9.84%; in addition, high and low risk genotypes were identified between these two polymorphisms. The effect of the interaction between rs1501299 (ADIPOQ) and rs662 (PON1) polymorphisms seems to play an important role in OA pathogenesis; so the epistasis analysis may provide an excellent tool for identifying individuals at high risk for developing OA.

Genetic variation of aggrecanase-2 (ADAMTS5) in susceptibility to osteoarthritis.

Aggrecanase-2 (ADAMTS5) gene is responsible for aggrecan degradation that may contribute to cartilage destruction in a mouse osteoarthritis (OA) model. We aimed to investigate the effects of ADAMTS5 gene polymorphisms on OA risk in a Chinese population. A total of 300 OA patients and 300 controls were recruited and their genotypes for ADAMTS5 gene rs226794 and rs2830585 polymorphisms were determined using a custom-by-design 48-Plex single nucleotide polymorphism Scan™ kit. ADAMTS5-associated genes were identified by co-expression analysis and their functions were investigated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Bioinformatics analysis showed that ADAMTS5 was significantly related to the components, structural constituent, and organization of the extracellular matrix. The rs2830585 polymorphism, but not rs226794 polymorphism, was significantly associated with an increased risk of knee OA. Stratified analysis further confirmed this significant association in patients at age ≥55 years. In conclusion, the ADAMTS5 rs2830585 polymorphism may be involved in the development of knee OA by destroying the extracellular matrix, but this finding should be further confirmed by larger studies.

Genetic association analysis of Osteopontin and Matrix Gla Protein genes polymorphisms with primary knee osteoarthritis in Mexican population.

Primary osteoarthritis (OA) is a complex entity in which several loci related to different molecular pathways or classes of molecules are associated with its development as demonstrated through genetic association studies. Genes involved in bone formation and mineralization, such as osteopontin (OPN) and Matrix Gla protein (MGP), could also be related with OA. The aim of this study was to evaluate the association between the genetic variants of OPN and MGP with primary knee osteoarthritis in a Mexican population. A case-control study was conducted in 296 patients with primary knee osteoarthritis and in 354 control subjects. Study groups were assessed radiologically. The rs11730582 of OPN and rs1800802, rs1800801, and rs4236 of MGP were determined by TaqMan allele discrimination assays. The haplotypes of the polymorphisms of MGP were constructed. The association was tested through univariate and multivariate non-conditional logistic regression analyses. The polymorphisms of MGP complied with Hardy-Weinberg (HW) equilibrium. The polymorphisms of OPN and MGP were not significantly associated with primary knee osteoarthritis in the codominant, dominant, and recessive models (p > 0.05). Our study suggests that there are no associations between OPN and MGP polymorphisms with primary knee osteoarthritis in Mexican population.

Common gene variants interactions related to uric acid transport are associated with knee osteoarthritis susceptibility.

BACKGROUND: The presence of genetic variants in uric acid (UA) transporters can be associated with hyperuricemia, and therefore with an increased risk of monosodium urate (MSU) crystal precipitation. The inflammatory process triggered by these crystals leads to cartilage damage, which, in turn, could promote knee osteoarthritis (KOA). OBJECTIVE: To determine whether genetic polymorphisms of the UA transporters and their interactions are associated with KOA. MATERIALS AND METHODS: Two hundred forty-three unrelated Mexican-mestizo individuals were recruited for this case-control study. Ninety-three of them were KOA patients but without gout, and one hundred and fifty healthy individuals with no symptoms or signs of KOA were recruited as controls. Forty-one single-nucleotide polymorphisms (SNPs) involved in the UA transporters were genotyped with OpenArray technology in a QuantStudio 12K flex-System with both cases and controls. RESULTS: After adjusting by age, gender, BMI, and ancestry, significant associations were found for eight SNPs: rs1260326 (GCKR), rs780093 (GCKR), rs17050272 (INHBB), rs1471633 (PDZK1), rs12129861 (PDZK1), rs7193778 (IGF1R), rs17786744 (STC1), and rs1106766 (R3HDM2). With respect to gene-gene interactions, the pairwise interactions of rs112129861 (PDZK1) and rs7193778 (IGF1R); rs17050272 (INHBB) and rs1106766 (R3HDM2); rs1106766 (R3HDM2) and rs780093 (GCKR); rs1260326 (GCKR) and rs17786744 (STC1); and rs17786744 (STC1) and rs1106766 (R3HDM2) make it possible to visualize the synergistic or antagonistic effect of their genotypes or alleles on KOA development. CONCLUSIONS: Our preliminary results show that the common gene variants related to UA transport are associated with KOA in the Mexican population. Further studies must be carried out to corroborate it.