Angiogenesis-related genes and thalidomide teratogenesis in humans: an approach on genetic variation and review of past in vitro studies.
Thalidomide embryopathy (TE) has affected more than 10,000 babies worldwide. The hypothesis of antiangiogenesis as the teratogenic mechanism of thalidomide has been investigated in several experimental models; but, in humans, it has only been accessed by in vitro studies. Here, we hypothesized the effect of thalidomide upon angiogenesis-related molecules or proteins, previously identified in human embryonic cells, through the in silico STRING-tool. We also investigated ten polymorphisms in angiogenesis-related genes in 38 Brazilian TE individuals and 136 non-affected Brazilians. NOS2, PTGS2, and VEGFA polymorphisms were chosen for genotyping. The STRING-tool suggested nitric oxide and β-catenin as the central angiogenesis-related molecules affected by thalidomide's antiangiogenic property. We did not identify a significant difference of allelic, genotypic or haplotypic frequencies between the groups. We could not predict a risk allele or a protective one for TE in NOS2, PTGS2, or VEGFA, although other genes should be analyzed in larger samples. The role of nitric oxide and β-catenin must be further evaluated, regarding thalidomide teratogenesis complex etiology.
INAGEMP-Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil; Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Thayne Woycinck
TW
Kowalski
INAGEMP-Instituto Nacional de Genética Médica Populacional, Porto Alegre, Brazil; Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Lucas Rosa
LR
Fraga
Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Post-Graduate Program of Epidemiology, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil.
Luciana
L
Tovo-Rodrigues
INAGEMP-Instituto Nacional de Genética Médica Populacional, 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.
Maria Teresa Vieira
MTV
Sanseverino
Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Mara Helena
MH
Hutz
INAGEMP-Instituto Nacional de Genética Médica Populacional, 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.
Lavínia
L
Schuler-Faccini
INAGEMP-Instituto Nacional de Genética Médica Populacional, 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; Service of Experimental Research, Genomics Medicine Laboratory, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil. Electronic address: fslvianna@gmail.com.
Fernanda Sales Luiz
FSL
Vianna
D000015:Abnormalities, Multiple / Q000139:chemically induced* / Q000235:genetics*; D001938:Brazil / Q000453:epidemiology; D051546:Cyclooxygenase 2 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009569:Nitric Oxide / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D064793:Teratogenesis / Q000235:genetics*; D013723:Teratogens / Q000633:toxicity*; D013792:Thalidomide / Q000633:toxicity*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
D013723:Teratogens; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D009569:Nitric Oxide; D013792:Thalidomide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
Embryopathy; Human embryonal cells; In-silico analyses; Nitric oxide