ESPE2021 ePoster Category 1 Thyroid B (10 abstracts)
DNA Methylation at a nutritionally sensitive region of the PAX8 gene is associated with thyroid volume and function in Gambian children
Toby Candler 1,2 , Noah Kessler 3 , Chathura Gunasekara 4 , Kate Ward 5 , Phil James 1 , Roger Dyer 6 , Rajavel Elango 6 , Robert Waterland 4 , Sophie Moore 7,1 , Marian Ludgate 8 , Andrew Prentice 1 & Matt Silver 1
1MRG The Gambia at LSHTM, London, United Kingdom; 2Bristol Royal Hospital for Chidlren, Bristol, United Kingdom; 3University of Cambridge, Cambridge, United Kingdom; 4Baylor College of Medicine, Houston, USA; 5University of Southampton, Southampton, United Kingdom; 6University of British Colombia, Vancouver, Canada; 7Kings College London, London, United Kingdom; 8University of Cardiff, Cardiff, United Kingdom
Background: Thyroid hormones contribute to a wide range of physiological processes and health outcomes. Epigenetic regulation of thyroid development and function has been little explored. PAX8 (Paired Box 8) is a thyroid transcription factor implicated in thyroid gland development and differentiation. PAX8 gene methylation appears to be sensitive to the environment in early pregnancy.
Methods and Findings: Using a recall-by-epigenotype design, 118 Gambian children were recruited from the top and bottom quintiles for PAX8 methylation measured in blood DNA taken at 2-years of age. Participants were assessed for thyroid volume, function, urinary iodine, and body composition and bone measures by whole body DXA scan at age 5-8 years. In multiple linear regression models adjusted for relevant covariates, the low PAX8 methylation group was associated with a 0.61cm3 [SE=0.15] or 21% increase in thyroid volume (P < 0.0001) and a 0.85 pmol/l [0.24] increase in free T4 (a change equivalent to 8.4% of the normal range, P < 0.001). Increased free T4 was associated with a decrease in all measures of overall body fat including log fat mass index (β=-0.04 [0.02], P = 0.033), log total fat mass (β=-0.05 [0.02], P = 0.041) and log fat lean ratio (β=-0.05 [0.02], P = 0.045), and with a decrease in log total-body-less-head bone mineral density (β= -0.008 [0.004], P = 0.044) after adjustment for relevant covariates. No fat or bone-related measures were independently associated with PAX8 methylation group. Infant PAX8 methylation measurements and nutritional biomarker data from maternal blood taken from early pregnancy were available for 303 children. Logit PAX8 methylation z-score was significantly lower in boys (β= -0.24[0.09], P = 0.005) and was nominally associated with 4 maternal one carbon metabolites: homocysteine (standardised β=-0.11[0.05], P = 0.05), cysteine (β=-0.16[0.05], P = 0.003), B12 (β=-0.1[0.05], P = 0.05) and the vitamin B6 vitamer, PLP (β=-0.12 [0.06], P = 0.03). The association with cysteine remained significant after correction for multiple testing. PAX8 methylation was shown to be stable from age 7 and 17 years (r = 0.76, P < 2.2x10-16). We observed a strong relationship between cis-genotype and PAX8 methylation variability suggesting sensitivity to environmental exposures may be under partial genetic control. An inverse relationship between PAX8 antisense expression and methylation at the analysed region was seen in non-malignant thyroid tissue from The Cancer Genome Atlas.
Conclusions: A maternal early nutrition-sensitive DNA methylation signature at the PAX8 gene was associated with thyroid function and volume in Gambian children. These findings may have significant implications for early embryonic programming of thyroid-related health and disease.
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