title: 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.
authors.affiliation: INAGEMP, National Institute of Medical Population Genetics, Porto Alegre, Brazil.|Post-graduate program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Thayne Woycinck
authors.initials: TW
authors.lastname: Kowalski
authors.affiliation: INAGEMP, National Institute of Medical Population Genetics, Porto Alegre, Brazil.|Post-graduate program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Lucas Rosa
authors.initials: LR
authors.lastname: Fraga
authors.affiliation: Post-graduate program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Post-graduate program in Epidemiology, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Tovo-Rodrigues
authors.affiliation: INAGEMP, National Institute of Medical Population Genetics, Porto Alegre, Brazil.|Post-graduate program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Teratogen Information Service, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil.
authors.forename: Maria Teresa Vieira
authors.initials: MT
authors.lastname: Sanseverino
authors.affiliation: Post-graduate program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Mara Helena
authors.initials: MH
authors.lastname: Hutz
authors.affiliation: INAGEMP, National Institute of Medical Population Genetics, Porto Alegre, Brazil.|Post-graduate program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Teratogen Information Service, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil.
authors.forename: Lavínia
authors.initials: L
authors.lastname: Schuler-Faccini
authors.affiliation: INAGEMP, National Institute of Medical Population Genetics, Porto Alegre, Brazil.|Post-graduate program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Teratogen Information Service, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil.|Post-Graduate program in Epidemiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
authors.forename: Fernanda Sales Luiz
authors.initials: FS
authors.lastname: Vianna
mesh_terms: D000293:Adolescent; D000328:Adult; D001938:Brazil; D002648:Child; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic; D013792:Thalidomide / Q000009:adverse effects*; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D013792:Thalidomide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III