Genetic Modulation of the Erythrocyte Phenotype Associated with Retinopathy of Prematurity-A Multicenter Portuguese Cohort Study

Int J Mol Sci. 2023 Jul 23;24(14):11817. doi: 10.3390/ijms241411817.

Abstract

The development of retinopathy of prematurity (ROP) may be influenced by anemia or a low fetal/adult hemoglobin ratio. We aimed to analyze the association between DNA methyltransferase 3 β (DNMT3B) (rs2424913), methylenetetrahydrofolate reductase (MTHFR) (rs1801133), and lysine-specific histone demethylase 1A (KDM1A) (rs7548692) polymorphisms, erythrocyte parameters during the first week of life, and ROP. In total, 396 infants (gestational age < 32 weeks or birth weight < 1500 g) were evaluated clinically and hematologically. Genotyping was performed using a MicroChip DNA on a platform employing iPlex MassARRAY®. Multivariate regression was performed after determining risk factors for ROP using univariate regression. In the group of infants who developed ROP red blood cell distribution width (RDW), erythroblasts, and mean corpuscular volume (MCV) were higher, while mean hemoglobin and mean corpuscular hemoglobin concentration (MCHC) were lower; higher RDW was associated with KDM1A (AA), MTHFR (CC and CC + TT), KDM1A (AA) + MTHFR (CC), and KDM1A (AA) + DNMT3B (allele C); KDM1A (AA) + MTHFR (CC) were associated with higher RDW, erythroblasts, MCV, and mean corpuscular hemoglobin (MCH); higher MCV and MCH were also associated with KDM1A (AA) + MTHFR (CC) + DNMT3B (allele C). We concluded that the polymorphisms studied may influence susceptibility to ROP by modulating erythropoiesis and gene expression of the fetal/adult hemoglobin ratio.

Keywords: DNA methylation; DNA polymorphism; biomarker; epigenetics; gene expression; histone modifications; pathophysiology; preterm infant; retina; retinopathy of prematurity.

Publication types

  • Multicenter Study

MeSH terms

  • Cohort Studies
  • DNA
  • Erythrocytes
  • Fetal Hemoglobin / genetics
  • Gestational Age
  • Hemoglobins / genetics
  • Histone Demethylases / genetics
  • Humans
  • Infant, Newborn
  • Infant, Very Low Birth Weight
  • Phenotype
  • Portugal
  • Retinopathy of Prematurity* / genetics
  • Risk Factors

Substances

  • Hemoglobins
  • Fetal Hemoglobin
  • DNA
  • KDM1A protein, human
  • Histone Demethylases

Grants and funding

This work was supported by the Genetics Laboratory, Environmental Health Institute (ISAMB), Associate Laboratory TERRA, Faculty of Medicine of the University of Lisbon, the Institute for Scientific Research Bento Rocha Cabral, and the company HeartGenetics, Genetics and Biotechnology SA. The writing of the manuscript was also supported by funds from the Foundation for Science and Technology to ISAMB (ref. UIDB/04295/2020 and UIDP/04295/2020), Ph.D. scholarship in medicine from the company CUF and the Portuguese Society of Ophthalmology.