京都大学 / 新制・課程博士 / 博士(理学) / 甲第25151号 / 理博第5058号 / 新制||理||1721(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 村山 美穂, 教授 平田 聡, 教授 三谷 曜子 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

Objective: Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects on blood DNA methylation in participants of the LIFE-Adult study, a well-characterised population-based cohort from Germany. Research design and methods: Lifestyle scores (LS) based on diet, physical activity, smoking and alcohol intake were calculated in 4107 participants of the LIFE-Adult study. Fifty subjects with an extremely healthy lifestyle and 50 with an extremely unhealthy lifestyle (5th and 95th percentiles LS) were selected for genome-wide DNA methylation analysis in blood samples employing Illumina Infinium⃝R Methylation EPIC BeadChip system technology. Results: Differences in DNA methylation patterns between body mass index groups (<25 vs. >30 kg/m2) were rather marginal compared to inter-lifestyle dif- ferences (0 vs. 145 differentially methylated positions [DMPs]), which identified 4682 differentially methylated regions (DMRs; false discovery rate [FDR <5%) annotated to 4426 unique genes. A DMR annotated to the glutamine-fructose-6- phosphate transaminase 2 (GFPT2) locus showed the strongest hypomethylation (∼6.9%), and one annotated to glutamate rich 1 (ERICH1) showed the strongest hypermethylation (∼5.4%) in healthy compared to unhealthy lifestyle individu- als. Intersection analysis showed that diet, physical activity, smoking and alcohol intake equally contributed to the observed differences, which affected, among others, pathways related to glutamatergic synapses (adj. p < .01) and axon guid- ance (adj. p < .05). We showed that methylation age correlates with chronological age and waist-to-hip ratio with lower DNA methylation age (DNAmAge) acceler- ation distances in participants with healthy lifestyles. Finally, two identified top DMPs for the alanyl aminopeptidase (ANPEP) locus also showed the strongest expression quantitative trait methylation in blood. Conclusions: DNA methylation patterns help discriminate individuals with a healthy versus unhealthy lifestyle, which may mask subtle methylation differ- ences derived from obesity.