New findings in eNOS gene and thalidomide embryopathy suggest pre-transcriptional effect variants as susceptibility factors

• Autor(a) principal: Kowalski, Thayne Woycinck
• Data de Publicação: 2016
• Outros Autores: Fraga, Lucas Rosa, Rodrigues, Luciana Tovo, Sanseverino, Maria Teresa Vieira, Hutz, Mara Helena, Faccini, Lavinia Schuler, Vianna, Fernanda Sales Luiz
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/225508
• topic: Talidomida; Embriopatias

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.