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.

Investigation of TGFßR2 SNP rs4522809, Osteopontin, TGF ß1 and their association with dilatative pathology of ascending thoracic aorta.

BACKGROUND: Dilatative pathology of the ascending thoracic aorta (DPATA) is characterized by the aortic wall expansion more than 1.5 and could be accompanied by aortic wall rupture. Mutations of TGFBR2 gene demonstrated an association with syndromic DPATA and altered pathway of transforming growth factor beta (TGF-ß). Elevated TGF-ß1 level has been found in blood samples in DPATA group. Moreover, elevated osteopontin (OPN) level was associated with mutations of TGFBR2 gene. Based on recently published findings, we aimed to evaluate genotyping results of TGFBR2 rs4522809 and the association with circulating OPN and TGF-ß1 concentrations within DPATA patients. METHODS AND FINDINGS: TGFBR2 SNP genotyping assay was performed by quantitative real-time PCR, TGF-ß1 and OPN concentrations were measured using enzyme-linked immunosorbent assay. Genotyping results showed G allele to be associated with DPATA (p = .01), the presence of G allele significantly increased the possibility of DPATA by 1.67 times (OR = 1.67, 95%, CI = 1.12-2.47). TGF-ß1 concentration was significantly higher in DPATA subjects compared with Reference group (p = 0,001). Finally, we found moderate inverse correlation (r = -0,524) between circulating TGF-ß1 and OPN levels within DPATA subjects (p = 0,002), as increasing levels of TGF-ß1 cytokine significantly decrease concentration of OPN. CONCLUSIONS: This is the first report on the association between previously defined TGFßR2 SNP rs4522809 linked with dilatation of ascending thoracic aorta. Also, for the first time we report the inversed correlation between circulating TGF-ß1 and OPN concentrations in DPATA subjects indicating the possible biomarkers for DPATA.

Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a novel TGFBR2 mutation.

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients.

TGFBR2 mutation and MTHFR-C677T polymorphism in a Mexican mestizo population with cervico-cerebral artery dissection.

Spontaneous cervico-cerebral artery dissection (CCAD) is a common condition found among young patients with ischemic stroke. We examined the possible association between the polymorphism of methylenetetrahydrofolate reductase (MTHFR)-C677T and the gene mutation in transforming growth factor beta receptor II (TGFBR2) in a cohort of CCAD patients. One-hundred CCAD cases (65 males; mean age: 38.08 ± 10.68 years) and 100 matching controls were included. Ancestry informative markers (AIMs) were used to increase internal validity of the genetic analysis. Genotypes of the C677T polymorphism in the MTHFR gene were determined by polymerase chain reaction and restriction fragment length polymorphism; direct sequencing was used for a mutation analysis of the TGFBR2 gene. Associations were evaluated using a multivariate statistics, and Hardy-Weinberg equilibrium was analyzed. We also incorporated our data into a meta-analysis of the MTHFR-C677T. Sixty-three patients presented with vertebral and 37 with carotid artery dissection. Ancestry markers found a call rate on each over 95 %. All AIMs did not deviate from Hardy-Weinberg equilibrium (p > 0.05). The homozygous TT genotype was more frequent in cases (OR 2.04, CI 95 % 1.53-2.72, p = 0.005), whereas no significant difference was found on heterozygous CT genotype. TGFBR2 mutation was not present in our samples. In the meta-analysis of MTHFR/C677T variant, a total 613 cases and 1547 controls were analyzed; we found a moderate association for the recessive model genotype (OR 2.04, CI 95 % 1.53-2.72; p = 0.342; Z = 4.83; I (2) = 11.3). This study supports a positive association between the MTHFR-C677T polymorphism and genetically confirmed Mexican mestizo CCAD patients.