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

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.
(© 2018 Wiley Periodicals, Inc.)