Tumor necrosis factor beta (TNF-β) NcoI polymorphism is associated with multiple sclerosis in Caucasian patients from Southern Brazil independently from HLA-DRB1

This study evaluated the association of tumor necrosis factor beta (TNF-β) NcoI polymorphism with the presence of multiple sclerosis (MS), disability, and HLA-DRB1 alleles in 208 Brazilian MS patients. As controls, 147 healthy individuals were included. The disability was evaluated at baseline and 5-year follow-up using the Expanded Disability Status Scale (EDSS). The TNF-β genotypes were determined using PCR and restriction fragment length polymorphism and serum TNF-α level was determined using enzyme-linked immunosorbent assay. Among the MS patients, 166 (79.8 %) were white, 39 (18.7 %) were brown, and three (1.4 %) were Asian descents (those were excluded from the further analysis). Among the 205 MS patients, 149 (72.6 %) presented remitting–relapsing MS. The baseline and 5-year follow-up EDSS ranged from 0.0 to 3.0 and from 1.0 to 5.7, respectively. The TNFB2/B2 genotype was associated with the presence of MS among the white patients (p?=?0.0443). Brown patients presented higher disability (p?=?0.0234) and higher TNF-α levels (p?=?0.0463) than white patients. White and brown patients carrying TNFB2/B2 genotype exhibited higher TNF-α levels (p?=?0.0354 and p?=?0.0309, respectively) than those with other geotypes. Association between TNF-β NcoI genotypes and HLA-DRB1 alleles was not observed among the MS patients (p?>?0.05). Taken together, TNFB2 allele was associated with the presence of MS independently of HLA-DRB1 in white patients and the TNFB2/B2 genotype was associated with increased TNF-α levels in white and brown patients, which could be an important genetic factor candidate for the susceptibility and pathogenesis of MS.     

Disability in multiple sclerosis is associated with age and inflammatory,metabolic and oxidative/nitrosative stress biomarkers: results of multivariate and machine learning procedures

The aim of this study was to evaluate the immune-inflammatory, metabolic, and nitro-oxidative stress (IM&NO) biomarkers as predictors of disability in multiple sclerosis (MS) patients. A total of 122 patients with MS were included; their disability was evaluated using the Expanded Disability Status Scale (EDSS) and IM&NO biomarkers were evaluated in peripheral blood samples. Patients with EDSS ≥3 were older and showed higher homocysteine, uric acid, advanced oxidized protein products (AOPP) and low-density lipoprotein (LDL)-cholesterol and higher rate of metabolic syndrome (MetS), while high-density lipoprotein (HDL)-cholesterol was lower than in patients with EDSS <3; 84.6% of all patients were correctly classified in these EDSS subgroups. We found that 36.3% of the variance in EDSS score was explained by age, Th17/T regulatory (Treg) and LDL/HDL ratios and homocysteine (all positively related) and body mass index (BMI) (inversely related). After adjusting for MS treatment modalities, the effects of the LDL/HDL and zTh17/Treg ratios, homocysteine and age on disability remained, whilst BMI was no longer significant. Moreover, carbonyl proteins were associated with increased disability. In conclusion, the results showed that an inflammatory Th17 profile coupled with age and increased carbonyl proteins were the most important variables associated with high disability followed at a distance by homocysteine, MetS and LDL/HDL ratio. These data underscore that IM&NO pathways play a key role in increased disability in MS patient and may be possible new targets for the treatment of these patients. Moreover, a panel of these laboratory biomarkers may be used to predict the disability in MS.

     

Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis

The aims of this study were to verify whether hyperhomocysteinemia is associated with disability progression in Multiple Sclerosis (MS) patients and whether TNF pathways and cellular adhesion molecules (CAM) are involved in this process. This study included 180 MS patients, who were divided according to their levels of homocysteine (Hyperhomocysteinemia ≥11.35 μmol/L) and 204 healthy individuals (control group). MS patients showed higher levels of homocysteine (p?<?0.001), tumor necrosis factor alpha (TNF-α, p?<?0.001), TNF receptor 1 (TNFR1, p?=?0.038), TNF receptor 2 (TNFR2, p?<?0.001), and lower levels of PECAM (p?=?0.001), ICAM (p?<?0.001) and VCAM (p?=?0.005) than controls. The multivariate binary logistic regression analysis showed that plasma levels of homocysteine, TNFR1, TNFR2 and PECAM were associated with the presence of disease. MS patients with hyperhomocysteinemia showed higher disease progression evaluated by the Multiple Sclerosis Severity Score (MSSS, p?<?0.001), disability evaluated by Expanded Disability Status Score EDSS (p?<?0.001), TNFR1 (p?=?0.039) and ICAM (p?=?0.034) than MS patients with lower levels of homocysteine. Hyperhomocysteinemia was independently associated with MSSS in MS patients, but were not associated with TNF-α, TNFR, and CAM. Homocysteine levels was higher in progressive forms than relapsing-remitting MS (p?<?0.001), independently of sex and age. In conclusion, this is the first study in which homocysteinemia was associated with progression of the disease (MSSS), although this finding was not directly related to TNF-α and TNFR pathways or to CAM.     

The rs3761548 FOXP3 variant is associated with multiple sclerosis and transforming growth factor β1 levels in female patients

Inflammation Research - The aim of this study was to evaluate the association between rs3761548 FOXP3 (-3279 C?&gt;?A) variant and multiple sclerosis (MS), disability, disability...     

Genetic polymorphisms associated with the development and clinical course of multiple sclerosis (review)

Multiple sclerosis (MS) is an autoimmune disease characterized by areas of inflammation, demyelination and axonal damage. The etiology of MS is multifactorial with an interaction between genetic, environmental and geographical factors. The objective of this study was to review the physiopathology and the genetic polymorphisms associated with the development and clinical course of MS. Studies carried out in populations worldwide showed that polymorphisms in the genes of the major histocompatibility complex (MHC) class II and class III have been associated with susceptibility, resistance and clinical forms of MS. Considerable attention has been focused on studies evaluating disease-modifying effects in MS that identified seven genes of probable importance such as the HLA class II, ApoE, IL-1ra, IL-1β, TNF-α, TNF-β and CCR5 genes. However, the results described in the literature about genetic biomarkers in MS are not consistent in the worldwide population. The detection of a single nucleotide polymorphism involved in the etiology and physiopathology of MS is very difficult and, it is likely that, several genetic polymorphisms are involved, each with a small contribution to the susceptibility or resistance to MS. Taken together the results show the need for continued research in genetically heterogeneous populations to identify new biomarkers associated with MS that could be used as prognostic markers or as therapeutic targets to modulate the autoimmune response in MS patients. This information may contribute to a better understanding of the physiopathology and treatment of MS, with the possibility of developing different therapeutic strategies according to the genetic profile of each individual.