Haplotype-based association between paternal DNMT1 variants and nonsyndromic cleft lip or without cleft palate in Chile.

Background: DNA methyltransferase 1 (DNMT1) is responsible for epigenetic remodeling of the genome during spermatogenesis and maintenance of DNA methylation. The current study aimed to assess the possible association between paternal polymorphic variants of the gene encoding DNMT1 enzyme and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) expression in offspring.

Methods: Nine DNMT1 polymorphic single nucleotide polymorphism (SNP) variants were analyzed in 101 fathers of NSCL/P Chilean cases and 187 fathers of controls. Single marker association for additive, dominant, and recessive models was performed using logistic regression analysis. The haplotype-based association was assessed using 3-SNPs sliding windows with a likelihood-ratio test. Multiple comparison corrections were applied using false discovery rates.

Results: None of the DNMT1 SNPs remained significant for any genetic models for single marker association. However, after false discovery rates correction, rs2228611-rs2228612-rs16999714 (q = 0.0042) and rs2228612-rs16999714-rs17291414 (q = 0.0014) haplotypes showed association with the phenotype, based on the dominant model.

Conclusions: Paternal haplotypes, sharing the rs2228612 and rs16999714 DNMT1 SNPs, are associated with NSCL/P expression in the Chilean population. The absence of in vitro/in vivo experimental evidence about the role of these variants on gene expression or protein function opens the opportunity for further investigations.