Understanding the participation of GREM1 polymorphisms in nonsyndromic cleft lip with or without cleft palate in the Brazilian population

Abstract

Background GREM1, which encodes Gremlin 1, an antagonist of bone morphogenic proteins with effects on proliferation and apoptosis, has been considered a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCL±P). In this study, we investigated potential associations of single nucleotide polymorphisms (SNP) in GREM1 and NSCL±P risk in the Brazilian population. Additionally, SNP‐SNP interactions of GREM1 with previously reported rs1880646 variant in NTN1 (netrin 1), a gene also responsible for apoptotic phenotypes were verified. Methods Applying Taqman allelic discrimination assays, we evaluated the variants rs16969681, rs16969816, rs16969862, and rs1258763 in 325 case‐parent trios and in 1,588 isolated samples in a case‐control study. Allelic and genotypic analyses, as well as interaction tests assessing gene‐environmental factor (GxE) and SNP‐SNP interaction with rs1880646 variant in NTN1, were performed based on logistic regression analysis adjusted for the effects of gender and genomic ancestry proportions. Results The risk alleles of all SNP were undertransmitted in NSCL±P trios, though the case‐control analysis confirmed only the association with rs16969862 alleles (OR: 0.78, 95% CI: 0.63–0.96, p = .02). The GxE interaction analysis revealed a significant interaction between maternal environmental contact with agrotoxics and rs16969816 (OR: 0.25, 95% CI: 0.08–0.74, p = .01), and pairwise interaction test with NTN1 rs1880646 yielded significant p values in the 1,000 permutation test for rs16969681, rs16969816, and rs16969862. Conclusion The GREM1 is involved in the etiology of NSCL±P in the Brazilian population and reveal that the interaction between GREM1 and NTN1 may be related with the pathogenesis of this common craniofacial malformation.

Increased hypospadias risk by GREM1 rs3743104[G] in the southern Han Chinese population

“…Church et al [ 37 ] found that among GREM1 -knockout mice with a C57BL/6 background, most died in a short period of time after birth due to lung defects and kidney dysplasia. Wang [ 38 ] et al revealed a significant correlation between GREM1 polymorphism rs1258763 and the risk of nonsyndromic orofacial clefts, and Viena CS [ 39 ] found that interaction between NTN1 and GREM1 may be associated with the pathogenesis of nonsyndromic cleft lip with or without cleft palate. It was also reported that GREM1 inhibits BMP2-mediated differentiation of MSCs to osteoblasts [ 40 ].…”

Designing Effective small interfering RNA for Post-Transcriptional Silencing of Human GREM1: A Comprehensive Bioinformatics Approach

“…Improper regulation and expression of gremlin-1 resulted in several defects and disorders [33,34]. Gremlin-1 can induce angiogenic effects and fibrosis in organs, contributing to progression of cancer development of complex diseases [8].…”

Exploring the role of the WNT5A rs566926 polymorphism and its interactions in non-syndromic orofacial cleft: a multicenter study in Brazil

“… 10 , 13 Other SNPs were included due to their potential interactions with WNT5A , as determined by the STRING database (http:/string-db.org), and their involvement in signaling pathways related to orofacial cleft development. The SNPs included were BMP4 rs11623717, rs17563, rs2071047, and rs2761887; 25 FGFR1 rs7829058 ; 27 GREM1 rs16969681, rs16969816, rs16969862, and rs1258763 ; 23 MMP2 rs243836; 26 and WNT3 rs11653738. 27 …”