Genetic variation of TGF-ΒR2 as a protective genotype for the development of colorectal cancer in men.

BACKGROUND: The role of transforming growth factor beta (TGF-ß) signaling, including both the cytokine and their receptors, in the etiology of colorectal cancer (CRC) has been of particular interest lately. AIM: To investigate the association between promoter polymorphism in TGF-ß receptor 2 TGF-ΒR2G[-875]A with a CRC risk in a cohort of Bulgarian patients using a case-control gene association study approach, as well as the protein levels of TGF-ß1 in the peripheral blood. METHODS: A cohort of 184 CRC patients and 307 sex and age-matched healthy subjects were recruited in the study. A genotyping of the TGF-ΒR2G[-875]A (rs3087465) polymorphism was performed by primer-introduced restriction analyses-polymerase chain reaction approaches. RESULTS: The frequency of TGF-ΒR2G[-875]A genotype was decreased in male patients with CRC than in healthy men (31.3% vs 44.8%; P = 0.058). Among males, the TGF-ΒR2G[-509]G genotype was related to a significantly increased risk of CRC development (OR = 1.820, 95%CI: 0.985-3.362, P = 0.055) than the GA + AA genotype. Also, TGF-ΒR2[-875]*A-allele itself was rarer in men with CRC than healthy men (19.1% vs 26.9%, P = 0.086) and was associated with a protective effect (OR = 0.644; 95%CI: 0.389-1.066; P = 0.086). Regarding the genotypes, we found that TGF-ß1 serum levels were higher in GG genotype in healthy persons above 50 years than the CRC patients [36.3 ng/mL interquartile range (IQR) 19.9-56.5 vs 22.4 ng/mL IQR 14.8-29.7, P = 0.014]. We found significant differences between higher levels of TGF-ß1 serum levels in healthy controls above 50 years (GG genotype) and CRC patients (GG genotype) at the early stage (36.3 ng/mL IQR 19.9-56.5 vs 22.8 ng/mL IQR 14.6-28.6, P = 0.037) and advanced CRC (36.3 ng/mL IQR 19.9-56.5 vs 21.6 ng/mL IQR 15.9-33.9, P = 0.039). CONCLUSION: In summary, our results demonstrated that TGF-ΒR2 AG and AA genotypes were associated with a reduced risk of CRC, as well as circulating levels of TGF-ß could prevent CRC development in a gender-specific manner. Notably, male carriers of TGF-ΒR2 -875A allele genotypes had a lower risk of CRC development and progression, suggesting that TGF-ΒR2 -875A/G polymorphism significantly affects the protective biological factors that also impact the risk of colon and rectal carcinogenesis.

Association of polymorphism -308G/A in tumor necrosis factor-alpha gene (TNF-α) and TNF-α serum levels in patients with relapsing-remitting multiple sclerosis.

TNF-α is an important cytokine of the inflammatory response involved in the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). The aim of this study is to explore the association between the promoter polymorphism -308G/A in the TNF-α gene (rs1800629) with genetic susceptibility to RRMS.Methods: A group of 183 RRMS patients and 169 age and gender-matched healthy controls were enrolled in the study. Genotyping of the polymorphism was performed by PCR-restriction fragment length polymorphism and quantification of TNF-α serum levels was conducted by ELISA.Results: The genotype distribution in female patients showed a significantly elevated frequency of heterozygotes (AG) (23.5% vs. 12.8%, OR = 2.072, p = 0.029) in comparison with the healthy women. Substantially higher TNF-α serum levels were observed in females compared to males, in both patients and healthy controls (p < 0.05). According to the genotype, TNF-α levels in the RRMS group were calculated in the following order: for GA/AA genotypes (5.67pg/ml vs. 3.48pg/ml, p = 0.0031) and for GG genotypes (4.58pg/ml vs. 3.52pg/ml, p = 0.00043). Moreover, the carriers of at least one A-allele of -308G/A TNF-α polymorphism (GA+AA) are significantly associated with two fold increased risk for RRMS development (OR = 1.950; p = 0.042) in women in contrast to men as well as associated with early onset of the disease (OR = 2.400; p = 0.021).Conclusion: Our study showed that the level of TNF-α in the serum of patients with RRMS showed a significant association with the -308G/A TNF-α polymorphism and gender dependency.

A link between promoter polymorphisms of the transforming growth factor ß1 (TGFB1) and TGF-ß1 receptor II (TGFBR2) genes and relapsing-remitting multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic progressive autoimmune disease characterised by nerve demyelination, mediated by myelin-specific Th1 autoreactive cells. Transforming growth factor ï¢1 (TGF-1) is a regulatory cytokine involved in MS aetiology by maintaining CD4+ cell differentiation and preventing autoimmune responses. Because of the important role of the TGF-1 signalling pathway in MS aetiopathogenesis, we aimed to investigate the association of two DNA polymorphisms: TGFB1C[-509]T and TGFBR2G[-875]A and their combined genotypes with the risk of MS development in a cohort of Bulgarian patients. The effect of the two promoter polymorphisms on the disease onset was also assessed. MATERIAL AND METHODS: In the study, a cohort of 183 patients with relapsing-remitting multiple sclerosis (RRMS) and 307 sex- and age-matched healthy subjects were recruited. Genotyping of the TGFB1C[-509]T (rs1800469) and TGFBR2G[-875]A (rs3087465) polymorphisms was performed by PCR-RFLP and PIRA-PCR approaches. RESULTS: Frequencies of the TGFB1T[-509]T genotype and TGFB1[-509]*T-allele were lower in RRMS men than in control healthy men (15.7% vs. 26.9%, 37.3% vs. 50.7%, respectively). Among males, the TGFB1T[-509]T genotype was related to a significantly reduced risk of RRMS (OR = 0.360, 95% CI: 0.126-1.028, p = 0.05) in comparison to the TGFB1C[-509]C genotype. Also, TGFB1[-509]*T-allele was more common in men with RRMS than in healthy men relative to the TGFB1[-509]*C-allele and was associated with a statistically significant protective effect (OR = 0.576, 95% CI: 0.341-0.974, p = 0.039). The combination of TGFB1T[-509]T/TGFB1T[-509]C and TGFBR2G[-875]A genotypes among men was associated with a significant protective effect compared to the wild-type homozygous TGFB1C[-509]C and TGFBR2G[-875]G genotypes (OR = 0.268, 95% CI: 0.088-0.818, p = 0.018). No significant association between rs1800469 and rs3087465 was observed among females with and without (controls) RRMS. CONCLUSIONS: In summary, we suggest that in males, a higher TGF-1 level determined by TGFB1T[-509]T genotype in combination with the TGFBR2G[-875]A genotype might be a protective factor against RRMS development.