Abstract 4253: Genome-wide blood leukocyte DNA methylation in relation to visceral, subcutaneous, and hepatic adiposity in postmenopausal women.

Abstract

Abstract Obesity has a broad spectrum of health consequences and is responsible for 15-20% of cancer deaths. Yet, little is known about systemic epigenetic alterations that may mediate the detrimental metabolic effects of excess adiposity. We investigated differences in genome-wide blood leukocyte methylation associated with amounts of visceral, liver and abdominal subcutaneous fat in healthy women. Participants were drawn from a feasibility study conducted in Honolulu, Hawaii, where 60 women, aged 60-65 years and of Japanese or European descent, underwent dual energy X-ray absorptiometry assessing total and regional fat (kg) and abdominal magnetic resonance imaging at L4-L5 assessing visceral and subcutaneous fat areas (cm2) and percent liver fat. Forty six women with MRI data were analyzed for the study. Over 480K loci were determined by the Illumina HumanMethylation450K BeadChip. Data were normalized using GenomeStudio and transferred to Partek Genomics Suite for analysis. We performed analysis of covariance adjusted for age and ethnicity to determine loci that were differentially methylated (DM) by levels of visceral fat (VF), liver fat (LF) and abdominal subcutaneous fat (SF) (dichotomization at the median). DM genes were examined for their biological pathway. We found that 70 loci were DM for high vs. low levels of VF at p<5.0xE-03. 56 and 109 loci were DM for SF and LF, respectively. The top DM loci included hypo-CPLX1, FAM163A, ACLY and hyper-UCP3 for VF (p<6.0xE-05); hypo-BAI1, TNNT1, DAPK3, PRAME and hyper-CD81 for SF (p<5.0xE-05); and hyper-DIAPH2, RPA4, WT1, TBC1D3C and NRG1 for LF (p<3.0xE-05). Although none of these loci reached statistical significance after multiple test correction (Bonferroni p<1.0xE-07), their hyper- and hypo-methylation clearly segregated by high vs. low levels of VF, SF or LF in principal component analyses and heatmaps. We limited the pathway analysis to the CpGs in promoters because they are most likely to regulate gene expression. VF was associated with hypermethylation of cellular development and proliferation related genes (CDK6, FAM204A, GUSB, HLA-DMB, MAGED1, MATK, miR-10B, PPP1R13L, PPP1R14C, PPP2R2B, UCP3 and VAV3). SF was associated with hypomethylation of cellular growth and proliferation, tissue morphology and cell cycle related genes (DAPK3, EHMT2, MAFB, NHLRC1, PRAME, SMPD3 and TGOLN2). LF was associated with hypermethylation of genes related to neurological disease, organismal abnormalities, and cell-to-cell signaling (ADRB3, COMT, DNTTIP1, PLEC, RPA4 and SEPT6). There was little overlap among DM genes by different levels of the fat depots. Our findings provide further evidence that the various body fat depots are distinct metabolic entities and suggest that they are associated with specific DNA methylation profiles in blood leukocytes. Citation Format: Min-Ae Song, Unhee Lim, Thomas Ernst, Maarit Tiirikainen, Lynne R. Wilkens, Cheryl L. Albright, Rachel Novotny, Linda Chang, Laurence N. Kolonel, Loic Le Marchand. Genome-wide blood leukocyte DNA methylation in relation to visceral, subcutaneous, and hepatic adiposity in postmenopausal women. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4253. doi:10.1158/1538-7445.AM2013-4253