A Composite Epigenetic Biomarker of FOXP3 / TIGIT Correlates With Regulatory T Cell Numbers in Cord Blood and Is Associated With Subsequent Food Allergy

Background Flow cytometry studies have reported an association between lower regulatory T cells (Treg) in cord blood and subsequent food allergy. Flow cytometry, however, is a resource‐intensive technique. We therefore aimed to develop an epigenetic biomarker (nTreg epi ) that correlates with the proportion of naïve regulatory T cells (nTreg) in cord blood white cells (CBWCs) measured by flow cytometry. We then investigated the association between nTreg epi and subsequent food allergy. Methods The Barwon Infant Study (BIS) is a prebirth cohort study ( n = 1074 infants). Illumina Infinium MethylationEPIC v1.0 BeadChips were used to assess DNA methylation in cord whole blood ( n = 936). In a subgroup, flow cytometry was used to measure the proportion of nTregs (CD4 + CD45RA + FOXP3+) in CBWCs ( n = 450). In a training set ( n = 338), we assessed the correlation between methylation at 78 probes in the FOXP3 and TIGIT genes and the proportion of nTregs in CBWCs. LASSO regression was then used to develop a linear methylation predictor of nTregs as a proportion of CBWCs, denoted ‘nTreg epi ’, which was then tested in a validation set ( n = 112). The association between nTreg epi and subsequent IgE‐mediated food allergy was evaluated using logistic regression. Results Methylation levels of 23/78 sites in FOXP3 and TIGIT were associated with the proportion of nTregs in CBWCs ( q < 0.05 for each). LASSO regression of methylation levels for these 21 probes was used to derive a linear predictor (nTreg epi ) which correlated with the log proportion of nTregs in the validation set ( R 2 = 0.22, p < 0.001). In the complete cohort with relevant data available ( n = 693), a higher nTreg epi was associated with decreased odds of food allergy (odds ratio 0.65 (95% CI 0.48–0.88, p = 0.005)). Conclusions A composite epigenetic biomarker in cord whole blood correlates with the proportion of nTreg in CBWCs and is strongly associated with the absence of subsequent food allergy.