New Findings in ENOS Gene and Thalidomide Embryopathy Suggest Pre-transcriptional Effect Variants As Susceptibility Factors

Overview

Journal Sci Rep

Specialty Science

Date 2016 Mar 24

PMID 27004986

Citations 4

Authors

Thayne Woycinck Kowalski

Lucas Rosa Fraga

Luciana Tovo-Rodrigues

Maria Teresa Vieira Sanseverino

Mara Helena Hutz

Lavinia Schuler-Faccini

Fernanda Sales Luiz Vianna

Affiliations

Soon will be listed here.

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.

Citing Articles

Association between nitric oxide synthase T-786C genetic polymorphism and chronic kidney disease: Meta-analysis incorporating trial sequential analysis.

Hsiao P, Chiu C, Tsai D, Ko P, Chen Y, Cheng H PLoS One. 2021; 16(10):e0258789.

PMID: 34662360 PMC: 8523046. DOI: 10.1371/journal.pone.0258789.

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy.

Kowalski T, Caldas-Garcia G, Gomes J, Fraga L, Schuler-Faccini L, Recamonde-Mendoza M Front Genet. 2021; 12:680217.

PMID: 34249098 PMC: 8262662. DOI: 10.3389/fgene.2021.680217.

Genetic Susceptibility to Drug Teratogenicity: A Systematic Literature Review.

Gomes J, Olstad E, Kowalski T, Gervin K, Vianna F, Schuler-Faccini L Front Genet. 2021; 12:645555.

PMID: 33981330 PMC: 8107476. DOI: 10.3389/fgene.2021.645555.

The role of ESCO2, SALL4 and TBX5 genes in the susceptibility to thalidomide teratogenesis.

Gomes J, Kowalski T, Fraga L, Macedo G, Vieira Sanseverino M, Schuler-Faccini L Sci Rep. 2019; 9(1):11413.

PMID: 31388035 PMC: 6684595. DOI: 10.1038/s41598-019-47739-8.

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