FOXP3 variants are independently associated with transforming growth factor Β1 plasma levels in female patients with inflammatory bowel disease

Objective: The aim of this study was to evaluate the association of -924 G>A (rs2232365) and -3279 C>A (rs3761548) FOXP3 variants with IBD susceptibility, clinical and endoscopic activity, and IL-10 and TGF-β1 plasma levels. Method: The study included 110 IBD female patients, 60 with Ulcerative Colitis (UC) and 50 with Crohn's Disease (CD), and 154 female controls. FOXP3 variants were determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Plasma levels of IL-10 and TGF-β1 were determined using immunofluorimetric assay. Results: AA genotype of rs2232365 and rs3761548 was associated with CD (OR = 3.147, 95% CI 1.015–9.758, p = 0.047) and UC (OR = 3.221, 95% CI 1.050–9.876, p = 0.041) susceptibility, respectively. However, were not associated with TGF-β1 and IL-10 levels, and endoscopic/clinical activity disease. GAGA haplotype was associated with IBD (OR = 4.003, 95% CI 1.100–14.56, p = 0.035) and UC susceptibility (OR = 6.107, 95% CI 1.609–23.18, p = 0.008). In addition, IBD patients with the GAGA haplotype had lower TGF-β1 levels (p = 0.041). Moreover, G/C haplotype (dominant model) had a protective effect of 60% in CD susceptibility and lower Endoscopic Severity Index. Conclusions: These results suggest that FOXP3 variants could exert a role in the Treg, which could be one of the factors involved in the susceptibility and pathogenesis of IBD

Genetic polymorphisms associated with lipid metabolism involved in the pathophysiology of ischemic stroke

The stroke is a complex, multifactorial, and polygenic disorder that results from the interaction between the individual genetic components and environmental factors. Previous studies have established hypertension, smoking, diabetes mellitus, dyslipidemia, elevated body mass index, disturbances of coagulation and increasing age as predictors of stroke risk factors. The stroke is a more crippling than deadly disease that requires long-term institutionalization, as it decreases the quality of life of patients, resulting in higher costs to social and economic levels. It thus becomes increasingly important to emphasize the Preventive Medicine strategies. Dyslipidemia has been associated with pathophysiology of ischemic stroke and genetic polymorphisms that occur in the metabolic pathway, such as lipids metabolism, has been one of the hereditary factors related to ischemic stroke. The identification of the genetic component in the cause of dyslipidemia has been intensively investigated in recent years. Among the several genetic polymorphisms, the gene of the low-density lipoprotein receptor has been the object of many studies in the population worldwide. Data on lipid profile and study of polymorphisms of genes encoding structural proteins and enzymes related to lipid metabolism may reveal the prevalence of dyslipidemia in a population, enabling a targeted intervention for the control and prevention of atherosclerotic diseases such as ischemic stroke

Human Leukocyte Antigen Class I and Class II Polymorphisms and Serum Cytokine Profiles in Cervical Cancer

Only a small proportion of women who are exposed to infection with high-risk human papillomavirus (HR-HPV) progress to persistent infection and develop cervical cancer (CC). The immune response and genetic background of the host may affect the risk of progression from a HR-HPV infection to lesions and cancer. However, to our knowledge, no studies has been conducted to evaluate the relationship between variability of human leukocyte antigens (HLA) genes and serum cytokine expression in this pathology. In the current study, we examined the associations of HLA alleles and haplotypes including Class I (HLA-A, -B and -C) and II (HLA-DRB1, -DQA1 and -DQB1) with serum levels of cytokines interleukin (IL)-6, tumor necrosis factor-α (TNF-α), IL-10 and IL-17 as well as risks of HPV infections, lesions and CC among admixed Brazilian women. HLA polymorphisms were associated with an increased risk or protection from HPV, lesions and CC. Additionally, we demonstrated a potential association of a HLA class I haplotype (HLA-B*14-C*08) with higher IL-10 cytokine serum levels in cervical disease, suggesting an association between HLA class I and specific cytokines in cervical carcinogenesis. However, larger studies with detailed HPV types coupled with genetic data are needed to further evaluate the effects of HLA and CC by HPV genotype

Granulocyte-Colony Stimulating Factor (G-CSF) induces mechanical hyperalgesia via spinal activation of MAP kinases and PI(3)K in mice

Granulocyte-colony stimulating factor (G-CSF) is a current pharmacological approach to increase peripheral neutrophil counts after anti-tumor therapies. Pain is most relevant side effect of G-CSF in healthy volunteers and cancer patients. Therefore, the mechanisms of G-CSF-induced hyperalgesia were investigated focusing on the role of spinal mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated kinase). JNK (Jun N-terminal Kinase) and p38, and PI(3)K (phosphatidylinositol 3-kinase). G-CSF induced dose (30-300 ng/paw)-dependent mechanical hyperalgesia, which was inhibited by local post-treatment with morphine. This effect of morphine was reversed by naloxone (opioid receptor antagonist). Furthermore, G-CSF-induced hyperalgesia was inhibited in a dose-dependent manner by intrathecal pre-treatment with ERK (PD98059), JNK (SB600125), p38 (SB202190) or PI(3)K (wortmanin) inhibitors. The co-treatment with MAP kinase and PI(3)K inhibitors, at doses that were ineffective as single treatment, significantly inhibited G-CSF-induced hyperalgesia. Concluding, in addition to systemic opioids, peripheral opioids as well as spinal treatment with MAP kinases and PI(3)K inhibitors also reduce G-CSF-induced pain. (C) 2011 Elsevier Inc. All rights reserved.Fundo de Apoio ao Ensino Pesquisa e Extensao/Universidade Estadual de Londrina[FAEPE/UEL 01/2009]Fundacao AraucariaConselho Nacional de Pesquisa (CNPq)Coordenadoria de aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazi

TGFB1 +869 T > C (rs1800470) variant is independently associated with susceptibility, laboratory activity, and TGF-β1 in patients with systemic lupus erythematosus

The aim of this study was to evaluate the association of the +869 T > C (rs1800470) and −509 C > T (rs1800469) TGFB1 variants, individually or in haplotypes structure, with susceptibility, autoantibodies, disease activity, and TGF-β1 plasma levels in patients with systemic lupus erythematosus (SLE). The study included 203 patients with SLE and 165 healthy controls. TGFB1 variants were determined by real-time polymerase chain reaction (qPCR). Plasma levels of TGF-β1 were determined using immunofluorimetric assay. The TGFB1 + 869 CC genotype was associated with SLE susceptibility (OR: 1.710, 95%CI: 1.020–2.866, p = 0.042) and with reduction of C4 (p = 0.040) and TGF-β1 levels (p = 0.044). In addition, patients with TGFB1 + 869 TC and CC genotypes and positive anti-dsDNA had lower TGF-β1 levels than those with TT (p = 0.004). TGFB1 −509 TT genotype was associated with reduced levels of C4 (p = 0.032). There was no association between haplotypes and clinical and laboratory parameters. Our data demonstrated that the TGFB1 + 869 T > C variant could be used as a genetic marker for SLE susceptibility and both variants as predictors of laboratory activity. This is the first study to demonstrate that TGF-β1 levels could be modulated by the interaction between TGFB1 + 869 C allele, in homozygosity, or heterozygosity, and the presence of anti-dsDNA

Haplotype Structures and Protein Levels of TGFB1 in HPV Infection and Cervical Lesion: A Case-Control Study

This study aimed to verify the role of TGFB1 variants (c.–1638G>A, c.–1347C>T, c.29C>T, and c.74G>C) in HPV infection susceptibility and cervical lesions development, and their impact on TGFB1 cervical and plasma levels. TGFB1 genotypes were assessed with PCR-RFLP and haplotypes were inferred for 190 HPV-uninfected and 161 HPV-infected women. TGFB1 levels were determined with immunofluorimetric assay. Case-control analyses were performed with logistic regression adjusted for possible confounders. Women carrying –1347TT or –1347CT+TT as well as those with 29CT, 29CC, or 29CT+CC were more likely to have HPV than –1347CC and 29TT carriers, respectively. Regarding haplotypes, the most frequent were *4 (GCTG) and *3 (GTCG). Women *4/*4 were less likely to have HPV than those with no *4 copy. Comparing the inheritance of *3 and *4, carriers of *3/*4 or *3/*3 were more susceptible to HPV than *4/*4. The TGFB1 plasma and cervical levels were higher in the infected patients. Plasma levels were also higher in infected women with low-grade lesions. HPV-infected patients carrying *3/Other and *3/Other+*3/*3 presented lower TGFB1 plasma levels than those with no copy of *3. TGFB1 variants could contribute to the comprehension of the TGFB1 role in HPV-caused cervical disease