Genetic and in silico analysis show a role of SMAD3 on recurrent pregnancy loss

Abstract

Recurrent pregnancy loss (RPL) is one of the most common reproductive failures affecting 1–5% of couples. Smad3 is an effector of signalling of the Transforming Growth Factors-β superfamily (TGF-β), regulating the transcription of several target genes of these cytokines. The objective of this study was to evaluate the influence of a variant on SMAD3 (rs17293443) in RPL. A case-control study was carried out with 149 women who experienced RPL and 159 controls, as well as bioinformatics tools to determine the role of this variant in this condition. Our study showed an allelic (p = 0.023) and genotypic (p < 0.01) association of this variant with the RPL. Our functional in silico predictions suggest that this variant causes a change in SMAD3 expression levels. Alterations in the expression of this gene can directly compromise the Smad3-dependent signalling pathway that is fundamental for key processes for gestation such as steroid hormone regulation and implantation, as demonstrated by ontologies analyses performed and the literature. Our findings regarding the involvement of Smad3 on RPL are a novelty in this field, and they seem to be promising to the clinical management of this condition.

Keywords:

• Pregnancy
• recurrent miscarriage
• hormone response
• TGF-β
• rs17293443
• Gene Expression Omnibus

Author contributions

João Bremm conceived of the study, performed the experiments and wrote the article; Marcus Michels contributed to design of the study, article preparation, editing and the final revision of the article; Bruna Rengel contributed to perform the bioinformatics analyses; Flávia Gobetti contributed to the design of the study; Lucas Fraga and Maria Sanseverino contributed to the design of the study, supervised the project and greatly assisted with data interpretation and reviewed the manuscript writing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The article recived support by the Hospital de Clínicas de Porto Alegre (HCPA) by project number 2018-0351. Also, JMB received funding support from Universidade Federal do Rio Grande do Sul and the brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).