Interactions between superoxide dismutase and paraoxonase polymorphic variants in nonsyndromic cleft lip with or without cleft palate in the Brazilian population

Abstract

During development, oxidative stress is hypothesized to mediate embryotoxicity, which may be intensified by exposition to environmental factors and by genetic variations in the enzymes involved in protecting cells from these damaging effects, including superoxide dismutase (SOD) and paraoxonase (PON). The aim of this study was to evaluate the influence of single‐nucleotide polymorphisms (SNP) in genes associated with the neutralization of oxidative stress (SOD and PON family members) in the risk of nonsyndromic oral cleft in the Brazilian population. Initially, we tested for association between 28 SNP in SOD1, SOD2, SOD3, PON1, PON2, and PON3 among 325 nonsyndromic cleft lip with or without cleft palate (NSCL±P) case‐parent trios. Multiple logistic regression analyses were used to explore gene, GxG and GxE, involving factors that induce oxidative stress accumulation during pregnancy. Signals still significant after both Bonferroni correction and in permutation test were subsequently confirmed in an ancestry‐structured case–control analysis with 722 NSCL±P and 866 controls from the same population. In the trio sample, transmission disequilibrium test (TDT) (allele and haplotype) and GxE analysis showed no significant associations, but multiple pairwise GxG interactions involving 10 SNP in PON1, PON2, and PON3 were detected and further examined in the case–control sample. The PON1 rs2237583 and PON2 rs17166879 yielded significant evidence of SNP‐SNP interactions after adjustment for multiple tests (both Bonferroni correction and 10,000 permutation test). The C allele and the CT genotype of PON1 rs2237583 were associated with significant protective effects against NSCL±P, while rs3917490 showed a significant association only in the sample composed of patients displaying high African ancestry. Our results reveal associations between rs2237583 and rs3917490 in PON1 and GxG interactions containing rs2237583 and rs17166879 with the susceptibility of NSCL±P in the Brazilian population. Furthermore, this study underlines the recent tendency of taking into account potential GxG interactions to clarify the underlying mechanisms associated with the etiology of this common malformation. Environ. Mol. Mutagen. 60: 185–196, 2019. © 2018 Wiley Periodicals, Inc.

Genetics and signaling mechanisms of orofacial clefts

“…Lipid metabolism plays important roles during craniofacial morphogenesis, and is regulated by Tgf‐β signaling during secondary palatogenesis in animal models (J. Iwata et al, 2014). Several genes involved in lipid metabolism have been implicated in nonsyndromic cleft studies, including the fatty acid hydrolase androgen‐dependent TFPI‐regulating protein ( ADTRP ) (Park et al, 2006), apolipoprotein C2 ( APOC2 ) (M. L. Marazita et al, 2002), and stearoyl‐CoA desaturase 5 ( SCD5 ) (Beiraghi et al, 2003), and a gene‐gene interaction between variants in the paraoxonases 1 and 2 ( PON1/2 ), which protect against damage due to low‐density lipoprotein oxidation, was determined to contribute to NSCL/P risk (Machado et al, 2019). Variants in genes that encode enzymes involved in metabolizing drug and environmental toxins may contribute to formation of OFCs, including aryl hydrocarbon receptor nuclear transporter ( ARNT ) (Kayano et al, 2004), alcohol dehydrogenase 1C ( ADH1C ) (Jugessur et al, 2009), and sulfotransferase 2A1 ( SULT2A1 ) (Butali et al, 2019).…”

Genetic and environmental contributions for the relationship between tooth loss and oral potentially malignant disorders and oral squamous cell carcinoma

“…In our study, there were no significant associations after Bonferroni correction regarding the association of each SNP and the occurrence of the outcome (OPMD/oral cancer) among those with and without tooth loss. It was found in the literature some similar results regarding the loss of association after Bonferroni correction in genetic studies 27,39,40 . One possible explanation is that the Bonferroni correction reduces statistical power, making it more challenging to detect true associations, especially in genetic studies, where the goal is often to identify subtle effects 38 …”

“…It was found in the literature some similar results regarding the loss of association after Bonferroni correction in genetic studies. 27,39,40 One possible explanation is that the Bonferroni correction reduces statistical power, making it more challenging to detect true associations, especially in genetic studies, where the goal is often to identify subtle effects. 38 The evidence regarding the relationship between tooth loss and oral cancer remains inconsistent.…”

Environmental factors in non‐syndromic orofacial clefts: A review based on meta‐analyses results

“…This is the case of Xuan et al, (2016) for casecontrol studies (1974 to 2011) and Kummet et al, (2016) for cohorts (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)). Tobacco's nicotine induces apoptosis of embryonic cells under oxidative stress, which relates to damage in nucleic acids (Zhao & Reece, 2005;Machado et al, 2019). In addition, when cells from the first branchial arch are exposed to cigarette smoke extract they show reduced DNA methylation (Mukhopadhyay et al, 2015).…”