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Epigenetic changes in womb may predict early-onset myopia

Tristan Manalac
21 May 2019

Epigenetic changes while inside the uterus may affect the likelihood of developing early-onset myopia in children, according to a recent Singapore study.

“To our knowledge, this is the first epigenome-wide association study of early-onset myopia among children. We have identified statistically significant differential methylation at five CpG sites that associate with early-onset myopia,” said researchers.

Performing genome-wide DNA methylation profiling in umbilical cord samples from 519 Singaporean infants (mean gestational age, 38.1 weeks; 261 females), researchers identified 160,418 CpG sites eligible for further analysis. Of the participants, 29 had spherical equivalent refraction values <–0.5 D and were determined to have myopia. The remaining 490 were set as controls. [PLoS One 2019;14:e0214791]

Five CpG probes were found to be significantly differently methylated in the myopia vs nonmyopia children (p<3.10x10–7). All five probes passed the false discovery date threshold of 5 percent; three remained after Bonferroni correction. In all five CpG sites, DNA methylation was found to be significantly reduced in myopia patients. These findings remained significant even after adjusting for parental refractive and smoking status.

Four putative genes-of-interest were located near the significant CpG sites: ARL1, FGB, PQLC1 and KRT12.

Subsequent gene expression experiments showed that ARL1 was expressed in the adult retina (p=1.0x10–15), sclera (p=0.0004), cornea (p=1.0x10–15), optic nerve (p=0.0002) and retinal pigment epithelium (RPE; p=0.0037). The gene was also expressed in foetal tissues: retina, choroid, sclera, optic nerve and cornea (p=1.0x10–15 for all).

In comparison, PCLQ1 was found in the adult RPE (p=0.0037) and in foetal RPE, sclera, choroid, optic nerve (p=1.0x10–15 for all) and cornea (p=0.0002) tissues. KRT12 was likewise expressed in adult and foetal corneas (p=1.0x10–15 for both). Notably, FGB was not expressed in any human eye tissues.

Of the three genes with detectable expression levels in human eye tissues, two – PQLC1 and KRT12 – also tested positive in a mouse model. This led to “the hypothesis that these CpG sites may be biologically relevant,” said researchers.

“All five CpG sites showed a reduction in methylation among myopic children versus nonmyopic children, which may correlate with gene expression alterations and lead to a higher likelihood of developing myopia in early childhood,” they continued.

Several important study limitations should be considered, researchers added, chief of which is the difficulty in obtaining the most optimal tissue samples. Eye tissue, for instance, would have been the most appropriate, but due to barriers of access, umbilical cord samples were used in the study.

Though researchers postulated that “the biological changes seen in early-onset myopia in very young children are already reflected in umbilical cord tissue at birth,” it is definitely possible that epigenetic patterns in the umbilical cord may not reflect that in more relevant tissues, such as the eye and brain.

“We understand that there is a need to construe the results with caution to prevent over-interpretation,” said researchers. “[H]ence further large-scale epigenetic studies to examine how these markers progress with time and correlate with myopia, as well as how umbilical cord tissue methylation correlates with human eye methylation are warranted,” said researchers.

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