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Seang-Mei Saw, Cheryl Ngo, Pan Hong, Wei Jie Seow, Stuart W Tompson, Kristina N Whisenhunt, Eranga Nishanthie Vithana, Yap Seng Chong, Fabian Yap, Veluchamy A Barathi, Pirro G Hysi, Terri L Young, Neerja Karnani; Epigenetic markers for early-onset myopia in an epigenome-wide association study. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1224.
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To investigate epigenetic modifications in umbilical cords associated with early-onset myopia in Singapore preschool children.
Pregnant women from two major hospitals were recruited for the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort. We determined epigenome-wide DNA methylation profiles in umbilical cords using the Infinium HumanMethylation450 BeadChip at birth. Cycloplegic autorefraction was obtained in 3 year old children. Logistic regression models were used to identify the top epigenetic hits for myopia (spherical equivalent (SE) <-0.5) using methylation profiles from fetal cord cells (29 cases, 490 controls), controlling for gestational age, ethnicity, gender and estimated cell types. Expression data from fetal eyes at 12-weeks’ (n=8) and 24-weeks’ gestation (n=6) were compared with 6 cadaveric adult eyes. The RNA samples were labelled, amplified and hybridized to Illumina HumanHT-12 v4 Expression BeadChips. Mouse gene expression was determined using total RNA isolated from mouse retina (n=12), hybridized and scanned using a Genechip® Scanner 3000 7G.
We identified 5 epigenome-wide significant CpG sites and all 5 showed loss of DNA methylation in myopic cases compared to controls. The nearest genes for the top CpG sites included CLDN23 (p = 1.7 x 10-7) on chromosome 8, responsible for tight junction-specific obliteration of the intercellular space, ARL1 on chromosome 12 (p=2.5 x 10-7) regulating intracellular vesicular membrane trafficking and FGB on chromosome 4 (p=3.6 x 10-7) that encodes the beta component of fibrinogen. Two other genes were PQLC1 (p=8.9 x 10-7) and KRT12 (p = 1.2 x 10-6). CLDN23, ARL1 and PQLC1 were expressed in the sclera, choroid and retina of human and fetal tissues. CLDN23, FGB, PQLC1 and KRT12 were expressed in mouse myopia scleral tissue.
Young children with myopia had loss of DNA methylation for 5 CpG sites that map to genes on chromosomes 8, 12, 4, 18 and 17 which correlate with gene expression alterations. Intrauterine epigenetic mechanisms may play an important role in the development of early-onset myopia.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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