Abstract
Environmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to IA in 92 IA cases and 91 controls from the Diabetes Autoimmunity Study in the Young (DAISY). Causal mediation models were used to identify seven DNAm probe-metabolite pairs in which the metabolite measured at IA mediated the protective effect of the DNAm probe measured prior to IA against IA risk. These pairs included five DNAm probes mediated by histidine (a metabolite known to affect T1D risk), one probe (cg01604946) mediated by phostidyl choline p-32:0 or o-32:1, and one probe (cg00390143) mediated by sphingomyelin d34:2. The top 100 DNAm probes were over-represented in six reactome pathways at the FDR <0.1 level (q = 0.071), including transport of small molecules and inositol phosphate metabolism. While the causal pathways in our mediation models require further investigation to better understand the biological mechanisms, we identified seven methylation sites that may improve our understanding of epigenetic protection against T1D as mediated by the metabolome.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease characterized by the production of antibodies which target pancreatic β-cells
Candidate pairs were significantly associated at the p < 0.01 level, and both DNA methylation (DNAm) prMoebtaeboalniteds 2m02e1t,a1b1,o5l4it2e were associated with development of islet autoimmunity (IA) at the p < 0.01 level. (b) We examined airs with DNAm measured pre-seroconversion (PSV) and metabolite measured at seroconversion (SV). (c) We examined pairs with metabolite measured at PSV and DNAm measured at SV in separate analyses
The metabolite histidine mediated the effect of the five methylation sites associated with the CYP26B1, Human leukocyte antigen (HLA)-DQB2, KIF26A, and COL18A1 genes, while a phosphatidyl choline (PC) identified as PC (p-32:0) or PC (o-32:1) mediated the effect of cg01604946, and a sphingomyelin (SM) we identified as SM (d34:2) mediated the effect of cg00390143 (GALNT9 gene)
Summary
Type 1 diabetes (T1D) is an autoimmune disease characterized by the production of antibodies which target pancreatic β-cells. DAISY’s study design allows us to include exposure and mediator variables that are temporally separated in our mediation models because methylation was measured prior to seroconversion (PSV), defined as the autoantibody-negative visit preceding the visit at which the child first tested autoantibody positive (SV), and metabolite was measured at SV and vice versa. This aids in interpretation of the results and in theory does not violate the assumptions of a mediation analysis. FiFgiugrue r1e. (1a.) (Aa)floAwcflhoawrtcdheapritctdinegppicrtoingrgespsiroongfrreosmsiobnirtfhrotomislbeitrathutotoimimsluetniatyut(IoAim) amndunthiteyD(iIaAbe) teasnAdutthoeimDmiuanbiettyes StAuduytoinimthme uYonuitnygS(DtuAdIySYin) vtihseitsY. oTounregdu(DceAcIoSmYp)uvtiastiitosn. tTimo er,ewdue cpeercfoomrmpeudtsaitmiopnletilimneea,rwreegpreesrsfioonrmweitdhosuimt cpolvealriinateear adrjeugstrmesesnitotno iwdeinthtiofyupt aicrosvoaf rDiaNteA madetjuhystlamtieonnt(DtNo Aimde)nptriofbyespaanidrsmoetfabDolNiteAs fomr emtehdyilaattioionnan(aDlyNsiAs. mCa)ndpirdoabteespaairnsd wmereetsaigbnoilfiicteanstfloyramssoecdiaiatetidoant athneaply
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