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Menni, C.* ; Kastenmüller, G. ; Petersen, A.-K. ; Bell, J.T.* ; Psatha, M.* ; Tsai, P.C.* ; Gieger, C. ; Schulz, H. ; Erte, I.* ; John, S.* ; Brosnan, M.J.* ; Wilson, S.G.* ; Tsaprouni, L.* ; Lim, E.M.* ; Stuckey, B.* ; Deloukas, P.* ; Mohney, R.P.* ; Suhre, K. ; Spector, T.D.* ; Valdes, A.M.*

Metabolomic markers reveal novel pathways of ageing and early development in human populations.

Int. J. Epidemiol. 42, 1111-1119 (2013)

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BACKGROUND: Human ageing is a complex, multifactorial process and early developmental factors affect health outcomes in old age. METHODS: Metabolomic profiling on fasting blood was carried out in 6055 individuals from the UK. Stepwise regression was performed to identify a panel of independent metabolites which could be used as a surrogate for age. We also investigated the association with birthweight overall and within identical discordant twins and with genome-wide methylation levels. RESULTS: We identified a panel of 22 metabolites which combined are strongly correlated with age (R(2) = 59%) and with age-related clinical traits independently of age. One particular metabolite, C-glycosyl tryptophan (C-glyTrp), correlated strongly with age (beta = 0.03, SE = 0.001, P = 7.0 × 10(-157)) and lung function (FEV1 beta = -0.04, SE = 0.008, P = 1.8 × 10(-8) adjusted for age and confounders) and was replicated in an independent population (n = 887). C-glyTrp was also associated with bone mineral density (beta = -0.01, SE = 0.002, P = 1.9 × 10(-6)) and birthweight (beta = -0.06, SE = 0.01, P = 2.5 × 10(-9)). The difference in C-glyTrp levels explained 9.4% of the variance in the difference in birthweight between monozygotic twins. An epigenome-wide association study in 172 individuals identified three CpG-sites, associated with levels of C-glyTrp (P < 2 × 10(-6)). We replicated one CpG site in the promoter of the WDR85 gene in an independent sample of 350 individuals (beta = -0.20, SE = 0.04, P = 2.9 × 10(-8)). WDR85 is a regulator of translation elongation factor 2, essential for protein synthesis in eukaryotes. CONCLUSIONS: Our data illustrate how metabolomic profiling linked with epigenetic studies can identify some key molecular mechanisms potentially determined in early development that produce long-term physiological changes influencing human health and ageing.

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