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    • Limitations of this study relate

    2018-10-25

    Limitations of this study relate to the lack of cord, blood and adipose tissue from the same individuals, so we cannot extrapolate how CDKN2A methylation in cord tissue may relate to the methylation of CDKN2A in adipose or blood in the same individual, and/or whether such epigenetic alterations are causally involved in the development of fat mass. CDKN2A methylation was also measured in the 4 cohorts at different ages making exact comparisons between the cohorts more difficult, but the fact that a consistent negative association between CDKN2A methylation and measures of adiposity was seen across tissues types and ages suggest that differential methylation of CDKN2A may be a robust marker of adiposity. Interactions of genotype and in utero environment best explain the majority of inter-individual differences in umbilical cord DNA methylation (Teh et al., 2014). Therefore CDKN2A methylation levels may be specified by an interaction of infant genotype with in utero environment or genotype alone (known as a methylation quantitative trait loci (methQTL). MethQTLs are overwhelmingly found in cis and the peak enrichment for SNP to CpG distance is within 45bp (Gibbs et al., 2010). We excluded all known SNPs within the CDKN2A DMR (encompassing>45nt) by direct sequencing; without genome-wide sequencing it is not possible to exclude effects or epistatic interactions of distant SNPs, but the inter-individual variations in CDKN2A methylation are most likely to be a product of differential in utero environments, perhaps in interaction with individual genotype. Genome wide association studies (GWAS) have shown that SNPs in the CDKN2A locus (typified by rs10757274) and encompassed by ANRIL, but 94KB downstream of the DMR discussed in this paper, were associated with increased susceptibility to frailty, coronary artery disease, myocardial infarction, type 2 diabetes and late onset Alzheimer disease (Melzer et al., 2007; Cunnington et al., 2010; Grarup et al., 2007; Zhuang et al., 2012; Zeggini et al., 2007; Scott et al., 2007; Broadbent et al., 2008; Congrains et al., 2012). Interestingly the genetic associations seem independent of obesity (Broadbent et al., 2008). Disease associated genotype is also associated with ANRIL met inhibitor levels, and ANRIL expression also differs relative to disease (Zhao et al., 2015; Shanker et al., 2014; Bochenek et al., 2013). Previously Zhuang et al. (2012) found that methylation in blood at a locus overlapping with the DMR discussed here, was higher in coronary artery disease compared to controls but methylation was not associated with genotype at rs10757274 (Zhuang et al., 2012). This leads us to speculate that both rs10757274 risk genotype and prenatal environment mediated by differential methylation independently affect ANRIL expression to mediate disease risk. The finding of a consistent association between CDKN2A methylation at birth and later adiposity in Caucasian and Asian cohorts at loci relevant to gene function provides substantial support for a role for epigenetics in mediating the long-term consequences of the early life environment on health, and suggests that altered methylation of CpG loci within the CDKN2A locus provide a robust prognostic marker of adiposity trajectory. Moreover these findings suggest a role for the long non-coding RNA ANRIL in the developmental origins of obesity, and identify estrogen as a novel regulator of ANRIL expression.
    Funding Sources This work was supported by funding from the Medical Research Council (MC_UU_12011/4, MC_U147585827 and MC_ST_U12055) British Heart Foundation (RG/15/17/3174 and RG/07/009), Nestec (BIDG/2013/00456), NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme administered by the Singapore Ministry of Health\'s National Medical Research Council (NMRC) (NMRC/TCN/012-NUHS/2014), Singapore- NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. The BIOCLAIMS study was supported by the European Commission Seventh Framework Programme (Grant agreement no. 244995). Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore. KMG is supported by the European Union Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement no. 289346. The RAINE study was supported by The Australian National Health and Medical Research Council (NHMRC) (1059711).