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New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors.

ABSTRACT: Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (-786C?>?T) and rs1799983 (894T?>?G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p?=?0.007). Alleles -786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p?=?0.018; OR?=?2.57; IC?=?1.2-5.8). This association was not identified with polymorphism 894T?>?G (p?=?0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue.

SUBMITTER: Kowalski TW

PROVIDER: S-EPMC4804217 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors.

Kowalski Thayne Woycinck TW Fraga Lucas Rosa LR Tovo-Rodrigues Luciana L Sanseverino Maria Teresa Vieira MT Hutz Mara Helena MH Schuler-Faccini Lavínia L Vianna Fernanda Sales Luiz FS

Scientific reports 20160323

Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gen ...[more]

PMID: 27004986

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Project description:Background: IHD is determined by an inadequate coronary blood supply to the myocardium, and endothelial dysfunction may represent one of the main pathophysiological mechanisms involved. Genetic predisposition to endothelial dysfunction has been associated with IHD and its clinical manifestation. However, studies are often confounding and inconclusive for several reasons, such as interethnic differences. Validation of results in larger cohorts and new populations is needed. The aim of this study is to evaluate the associations between the allelic variants of the eNOS rs1799983 single-nucleotide polymorphism, IHD susceptibility and its clinical presentation. Methods: A total of 362 consecutive patients with suspected myocardial ischemia were enrolled. Patients were divided into three groups: G1, coronary artery disease (CAD); G2, coronary microvascular dysfunction (CMD); and G3, a control group with anatomically and functionally normal coronary arteries. Analysis of three allelic variants, GT, GG and TT, of rs1799983 for the NOS3 gene, encoding for eNOS, was performed. Results: rs1799983_GT was significantly more expressed by the ischemic groups (G1 and G2) compared to G3. The TT variant was significantly more expressed by the G1 group, compared to the G2 group. Among ischemic patients, GT was significantly more expressed in patients with acute coronary syndrome (ACS) presentation, compared to other clinical presentations. In the multivariate analysis, the allelic variant GT was found to potentially represent an independent predictor of IHD and ACS presentation. Conclusion: The presence of the SNP rs1799983_GT, encoding for eNOS, is an independent risk factor for IHD and, remarkably, for ACS presentation, independently of cardiovascular risk factors. These results may be useful for the prediction of IHD development, particularly with an acute clinical manifestation. They may allow the early identification of patients at high risk of developing IHD with an ACS, promoting a genetic-based prevention strategy against IHD.

Dataset Information

New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors.

Publications

New Findings in eNOS gene and Thalidomide Embryopathy Suggest pre-transcriptional effect variants as susceptibility factors.

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