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.
['Viena|Camila Sane|CS|', 'Machado|Renato Assis|RA|', 'Persuhn|Darlene Camati|DC|', 'Martelli-Júnior|Hercílio|H|', 'Medrado|Alena Peixoto|AP|', 'Coletta|Ricardo D|RD|0000-0001-5285-3046', 'Reis|Silvia R A|SRA|0000-0003-1195-0485']
D000328:Adult D000483:Alleles D001921:Brain D001938:Brazil D016022:Case-Control Studies D002971:Cleft Lip D002972:Cleft Palate D005190:Family D005260:Female D005787:Gene Frequency D020022:Genetic Predisposition to Disease D055106:Genome-Wide Association Study D005838:Genotype D006801:Humans D040582:Inheritance Patterns D036341:Intercellular Signaling Peptides and Proteins D008297:Male D000075388:Netrin-1 D020641:Polymorphism, Single Nucleotide D012307:Risk Factors
GREM1 nonsyndromic cleft lip with or without cleft palate SNP-SNP interaction NTN1 gene-environmental factor interaction