Gene-environment interaction in molar-incisor hypomineralization

PLoS One. 2021 Jan 6;16(1):e0241898. doi: 10.1371/journal.pone.0241898. eCollection 2021.


Molar incisor hypomineralization (MIH) is an enamel condition characterized by lesions ranging in color from white to brown which present rapid caries progression, and mainly affects permanent first molars and incisors. These enamel defects usually occur when there are disturbances during the mineralization or maturation stage of amelogenesis. Both genetic and environmental factors have been suggested to play roles in MIH's development, but no conclusive risk factors have shown the source of the disease. During head and neck development, the interferon regulatory factor 6 (IRF6) gene is involved in the structure formation of the oral and maxillofacial regions, and the transforming growth factor alpha (TGFA) is an essential cell regulator, acting during proliferation, differentiation, migration and apoptosis. In this present study, it was hypothesized that these genes interact and contribute to predisposition of MIH. Environmental factors affecting children that were 3 years of age or older were also hypothesized to play a role in the disease etiology. Those factors included respiratory issues, malnutrition, food intolerance, infection of any sort and medication intake. A total of 1,065 salivary samples from four different cohorts were obtained, and DNA was extracted from each sample and genotyped for nine different single nucleotide polymorphisms. Association tests and logistic regression implemented in PLINK were used for analyses. A potential interaction between TGFA rs930655 with all markers tested in the cohort from Turkey was identified. These interactions were not identified in the remaining cohorts. Associations (p<0.05) between the use of medication after three years of age and MIH were also found, suggesting that conditions acquired at the age children start to socialize might contribute to the development of MIH.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amelogenesis / genetics
  • Child
  • Dental Enamel Hypoplasia / genetics*
  • Female
  • Gene-Environment Interaction*
  • Genotype*
  • Humans
  • Incisor / growth & development*
  • Incisor / pathology
  • Male
  • Molar / growth & development*
  • Molar / pathology
  • Polymorphism, Single Nucleotide*
  • Transforming Growth Factor alpha / genetics*


  • TGFA protein, human
  • Transforming Growth Factor alpha

Grants and funding

F.M.F.S. was supported by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro– FAPERJ process E-26/201.745/2019 ( E.G.C. was supported by CAPES. A.R. was supported by the University of Pittsburgh School of Dental Medicine Dean’s Summer Research program. The work was supported in part by a grant from Araucária Foundation awarded to R.I.W ( This paper is based in part on a thesis submitted to the graduate faculty, Federal University of Rio de Janeiro, in partial fulfillment of the requirements for the PhD degree (for F.M.F.S.) and on a thesis submitted to the graduate faculty, Pontifical Catholic University of Paraná, in partial fulfillment of the requirements for the MS degree (for E.G.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.