PEMT Variants are Associated with Nonsyndromic Cleft Lip with or without Cleft Palate in Chile

Abstract

Aim: To assess the association between PEMT variants and nonsyndromic cleft lip with or without cleft palate in Chile and the effects of these variants on global DNA methylation. Subjects & methods: The authors obtained genotypes for nine variants from 247 cases and 453 controls for genotype–phenotype associations. The effect of significant polymorphisms on global DNA methylation (percentage of long interspersed element-1 methylation) was evaluated in a subsample of 95 controls. Results: After multiple comparison corrections, variants rs7649 and rs4646409 were associated with nonsyndromic cleft lip with or without cleft palate. Carriers of risk alleles presented lower DNA methylation levels than noncarriers. Conclusion: According to functional analysis for risk variants from previous reports, the authors infer that a decrease of methyl group availability is occurring in affected subjects.

Plain language summary

This study evaluated if variants in the gene named PEMT confers an increased risk for nonsyndromic cleft lip with or without cleft palate in Chile and its possible effects on methylation of DNA, a variable linked to gene expression modulation. The study found that the variants recognized as rs7649 and rs4646409 increase the risk of nonsyndromic cleft lip with or without cleft palate in the Chilean population and decrease DNA methylation. The authors conclude that this gene may be involved in this birth defect. New studies are needed to confirm the relation between this condition and DNA methylation mediated by these genetic variants.

Keywords::

• association
• choline
• genetic variants
• orofacial clefts
• PEMT

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0180

Author contributions

J Suazo: conception and design of the work; acquisition, analysis, and interpretation of data; drafting of the work and critical revision of it for important intellectual content; final approval of the version to be published and agreement to be accountable for all aspects of the work. C Salamanca: data analysis, drafting of the work, final approval of the version to be published and agreement to be accountable for all aspects of the work. P González-Hormazabal: data analysis, drafting of the work, final approval of the version to be published and agreement to be accountable for all aspects of the work. G Cáceres-Rojas: study design; data acquisition, analysis, and interpretation; drafting of the work; final approval of the version to be published and agreement to be accountable for all aspects of the work. R Pantoja: data acquisition, drafting of the work, final approval of the version to be published and agreement to be accountable for all aspects of the work. N Leiva: data acquisition, drafting of the work, final approval of the version to be published and agreement to be accountable for all aspects of the work. R Pardo: data interpretation, drafting of the work, final approval of the version to be published and agreement to be accountable for all aspects of the work.

Acknowledgments

The authors wish to thank the patients, their families and healthy individuals who voluntarily cooperated with the authors, as well as the staff members of all cleft children rehabilitation centers, blood banks and the University of Chile BioBank.

Financial & competing interests disclosure

This study was supported by the FONDECYT grant 1170805 (ANID Chile). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

For cases and control samples, the proper informed written consent was obtained from all subjects or from their parents/legal representatives. The study was approved by the Review Board of the Faculty of Dentistry, Universidad de Chile (Protocol #2017/07), following the principles outlined in the Declaration of Helsinki for human investigation. The database from which the single nucleotide polymorphisms were extracted is composed by genotype of more than 600,000 single nucleotide polymorphisms for each subject. Our financial grant consider only one-carbon metabolism genes. Thus, the authors have ethical restrictions for the use of other genes and to make public this database.

Additional information

Funding

This study was supported by the FONDECYT grant 1170805 (ANID Chile). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.