2p24.2 (rs7552) is a susceptibility locus for nonsyndromic cleft lip with or without cleft palate in the Brazilian population

Abstract

The population of Brazil is highly admixed, with each individual showing variable levels of Amerindian, European and African ancestry, which may interfere in the genetic susceptibility of known risk loci to nonsyndromic cleft lip with or without cleft palate (NSCL±P). Here, we investigated 5 reported genome-wide loci for NSCL±P in an ancestry-structured case-control study containing 1697 Brazilian participants (831 NSCL±P and 866 healthy controls). SNPs rs7552 in 2q24.2, rs8049367 in 16p13.3, rs1880646, rs7406226, rs9891446 in 17p13, rs1588366 in 17q23.2 and rs73039426 in 19q13.11 were genotyped using TaqMan allelic discrimination assays and genomic ancestry was estimated using a panel of 40 biallelic short insertion/deletion polymorphic markers informative of the Brazilian population. Logistic regression analysis of the single-markers revealed rs7552 in 2p24.2 as a susceptibility risk marker for NSCL±P, yielding an odds ratio (OR) of 1.71 (95% confidence interval (CI): 1.31-2.24, P = 9 × 10 ) in the homozygous state. Several SNP-SNP interactions containing rs7552 reached significance after adjustment for multiple tests (both Bonferroni assumption and 1000 permutation test), with the most significant interaction involving the 3-loci among rs7552, rs9891446 and rs73039426 (P = 6.1 × 10 and p = 0.001). Our study is the first to support the association of rs7552 in 2p24.2 with NSCL±P in the highly admixed Brazilian population.

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

“…Recently, we demonstrated a protective association of variant rs1880646 in NTN1 at 17p13 with NSCL±P in this same case‐control sample (Machado et al, ). As rs1880646 in NTN1 and SNP in GREM1 showed similar protective effects and both genes are associated with apoptotic phenotypes (Broutier et al, ; Church et al, ; Costello et al, ; Michos et al, ), which are essentials for normal embryogenesis, we further performed pairwise SNP‐SNP interaction analysis.…”

“…Indeed, targeted deletion of Gremlin 1 in mice leads to a loss of kidneys due to complete elimination of the metanephric mesenchyme by apoptosis (Michos et al, ). Recently, we demonstrated protective effects of variant rs1880646, which is located in NTN1 (Netrin 1), a gene associated with apoptotic phenotypes (Broutier et al, ; Lahlali et al, ), with NSCL±P in this same Brazilian sample (Machado et al, ). Together GREM1 and NTN1 SNP may interact, reducing NSCL±P risk.…”

“…For the case‐control analysis, the multiple logistic regression analysis under unrestricted, dominant and recessive genetic models, considering gender and the proportion of genomic ancestry of each subject as potential confounders, was performed with SNPassoc and Haplo.stats packages in R software. Pairwise SNP‐SNP interactions between GREM1 variants and rs1880646 in NTN1 (Machado et al, ) were performed using the mbmdr package in R, using the 1,000 permutation test to eliminate the false‐positive interactions. The Bonferroni correction for multiple comparisons was applied, and the corrected p value of ≤.01 was considered statistically significant.…”

“…The global prevalence of NOC is approximately 1:700 live births (Dixon, Marazita, Beaty, & Murray, 2011), but in Brazil, with considerable geographic variation, the prevalence ranges from 1:650 to 1:2,700 live births (Martelli-Junior et al, 2007;Rodrigues, Sena, Roncalli, & Ferreira, 2009). NOC etiology is recognized as complex and heterogeneous, and though our understanding behind this malformation is evolving, the exact environmental and genetic risk factors associated remains not fully defined (Assis Machado et al, 2018;Beaty, Marazita, & Leslie, 2016). Many studies have supported the participation of maternal contact with agrotoxics, smoking, alcohol and some drugs, and folate supplementation during early pregnancy as the main environmental factors related to NOC etiology (Molina-Solana, Yáñez-Vico, Iglesias-Linares, Mendoza-Mendoza, & Solano-Reina, 2013;Spinder et al, 2017;Xiao, Liu, Liu, Zhang, & Xue, 2017;Xuan et al, 2016).…”

Investigação do padrão de metilação em genes ou regiões candidatas à fissura labial com ou sem palato não-sindrômica (FL/P NS)

“…Além da região 8q24.21, estudos de GWAS detectaram outras regiões associadas à FL/P NS como 1p22.1 e 20q12 nas populações europeia e asiática (Beaty et al, 2010) e 2p24.2, 4p16.2, 5p12, 8p11.23, 17q23, 19q13, entre outras, em estudos multi-étnicos (Leslie et al, 2016;Yu et al, 2017). Já foram confirmadas na população brasileira variantes comuns em 8q24.21, 2p24.2 e 1p22.1 (Brito et al, 2012a;Machado et al, 2018, Bagordakis et al, 2013.…”