Multifactorial Landscape Parses to Reveal a Predictive Model for Knee Osteoarthritis.

The present study attempted to investigate whether concerted contributions of significant risk variables, pro-inflammatory markers, and candidate genes translate into a predictive marker for knee osteoarthritis (KOA). The present study comprised 279 confirmed osteoarthritis patients (Kellgren and Lawrence scale >2) and 287 controls. Twenty SNPs within five genes (CRP, COL1A1, IL-6, VDR, and eNOS), four pro-inflammatory markers (interleukin-6 (IL-6), interleuin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and high sensitivity C-reactive protein (hsCRP)), along with significant risk variables were investigated. A receiver operating characteristic (ROC) curve was used to observe the predictive ability of the model for distinguishing patients with KOA. Multivariable logistic regression analysis revealed that higher body mass index (BMI), triglycerides (TG), poor sleep, IL-6, IL-1ß, and hsCRP were independent predictors for KOA after adjusting for the confounding from other risk variables. Four susceptibility haplotypes for the risk of KOA, AGT, GGGGCT, AGC, and CTAAAT, were observed within CRP, IL-6, VDR, and eNOS genes, which showed their impact in recessive ß(SE): 2.11 (0.76), recessive ß(SE): 2.75 (0.59), dominant ß(SE): 1.89 (0.52), and multiplicative modes ß(SE): 1.89 (0.52), respectively. ROC curve analysis revealed the model comprising higher values of BMI, poor sleep, IL-6, and IL-1ß was predictive of KOA (AUC: 0.80, 95%CI: 0.74-0.86, p< 0.001), and the strength of the predictive ability increased when susceptibility haplotypes AGC and GGGGCT were involved (AUC: 0.90, 95%CI: 0.87-0.95, p< 0.001).This study offers a predictive marker for KOA based on the risk scores of some pertinent genes and their genetic variants along with some pro-inflammatory markers and traditional risk variables.

Genetic Scores of eNOS, ACE and VEGFA Genes Are Predictive of Endothelial Dysfunction Associated Osteoporosis in Postmenopausal Women.

The present study aimed to examine the participation and contribution of endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE) and vascular endothelial growth factor (VEGFA) genes for the risk of endothelial dysfunction (ED)-associated osteoporosis risk in postmenopausal women of Punjab, India. Women with ED were categorized into women with osteoporosis (n = 346) and women without osteoporosis (n = 330). They were examined for selected SNPs within eNOS, ACE and VEGFA genes. Linear regression analysis revealed a positive association of ED with bone mineral densities (BMDs) at femoral neck (r2 = 0.78, p < 0.001) and lumbar spine (r2 = 0.24, p = 0.001) after Bonferroni correction. Three susceptibility haplotypes were exposed within eNOS (CTAAAT), ACE (ACDG) and VEGFA (GATA) genes. Bearers of CTAAAT (OR 2.43, p = 0.007), ACDG (OR 2.50, p = 0.002) and GATA (OR 2.10, p = 0.009) had substantial impact for osteoporosis after correcting the effects with traditional risk factors (TRD).With uncertainty measure (R2h) and Akaike information criterion (AIC), best fit models showed that CTAAAT manifested in multiplicative mode (ß ± SE: 2.19 ± 0.86, p < 0.001), whereas ACDG (ß ± SE: 1.73 ± 0.54, p = 0.001) and GATA (ß ± SE: 3.07 ± 0.81, p < 0.001) expressed in dominant modes. Area under receiver operating characteristic curve using weighted risk scores (effect estimates) showed substantial strength for model comprising TRD + GATA (AUC = 0.8, p < 0.001) whereas, model comprising TRD + GATA + CTAAAT exhibited excellent ability to predict osteoporosis (AUC = 0.824, p < 0.001).

Promoter polymorphisms in IL-6 gene influence pro-inflammatory cytokines for the risk of osteoarthritis.

BACKGROUND: Interleukin-6 (IL-6) gene regulates IL-6 levels, interplay of which has been found to influence pathophysiology of osteoarthritis (OA). Polymorphism within promoter region of IL-6 gene and its association with plasma levels of pro-inflammatory cytokines; IL-6, interleukin 1-beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) remained to be investigated in Punjab region of India, where OA is highly prevalent. METHODS: Six single nucleotide polymorphisms (SNPs) in the promoter region of IL-6 gene; rs1800795 (-174G/C), rs1800796 (-572G/C), rs1800797 (-597G/A), rs2069827 (-1363G/T), rs12700386 (-2954G/C) and rs10499563 (-6331G/T) were investigated by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 279 confirmed osteoarthritis patients and 287 controls. Plasma levels of pro-inflammatory cytokines; IL-6, IL-1ß and TNF-α were measured by sandwich Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: Allele frequency spectrum after adjusting the effect of systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein (LDL), triglycerides (TG) and body mass index (BMI) revealed that major allele G of rs1800795 and T of rs10499563 were significantly associated with increased risk of OA (P < 0.01) in all the three genetic models; co-dominant (OR 4.08 & 4.12, P < 0.001), recessive (OR 3.00 & 2.51, P < 0.001) and dominant (OR 2.56 & 3.09, P < 0.05). Major allele G of rs1800796 and rs1800797 was observed to enhance OA risk in recessive mode (OR 1.75, P < 0.001 & 1.62, P = 0.01 respectively). Disease risk analysis after adjusting the effect of confounders exposed a susceptibility haplotype GGGGCT, which increased the OA risk by 2.27 times (OR 2.27, 95%CI: 1.26-4.10, P = 0.009) and a protective haplotype CGAGGC which significantly reduced the OA risk (OR 0.47, 95%CI 0.27-0.92, P = 0.031). Both of these haplotypes manifested in the recessive mode of inheritance. Subjects who had one copy of the susceptibility haplotype had lower values of IL-6 (3.6 pg/ml) and IL-1ß levels (3.2 pg/ml) than those who had 2 copies of it (4.4 pg/ml & 4.2 pg/ml respectively). IL-6 and IL-1ß levels were observed to be negatively associated with protective haplotype CGAGGC (P < 0.05). Carriers of 1 copy of this haplotype showed decreased IL-1ß levels than those who had none (1.00 pg/ml vs. 1.3 pg/ml respectively) which further decreased to 0.9 pg/ml in those subjects who carried two copies of protective haplotype. CONCLUSION: The present study discovered susceptibility (GGGGCT) and protective (CGAGGC) haplotypes within promoter region of IL-6 gene which influenced the plasma levels of IL-6 and IL-1ß for the risk of osteoarthritis in the population of Punjab, India.