Body mass index associated with genome-wide methylation in breast tissue

Abstract

Gene expression studies indicate that body mass index (BMI) is associated with molecular pathways involved in inflammation, insulin-like growth factor activation, and other carcinogenic processes in breast tissue. The goal of this study was to determine whether BMI is associated with gene methylation in breast tissue and to identify pathways that are commonly methylated in association with high BMI. Epigenome-wide methylation profiles were determined using the Illumina HumanMethylation450 BeadChip array in the non-diseased breast tissue of 81 women undergoing breast surgery between 2009 and 2013 at the University of North Carolina Hospitals. Multivariable, robust linear regression was performed to identify methylation sites associated with BMI at a false discovery rate q value <0.05. Gene expression microarray data was used to identify which of the BMI-associated methylation sites also showed correlation with gene expression. Gene set enrichment analysis was conducted to assess which pathways were enriched among the BMI-associated methylation sites. Of the 431,568 methylation sites analyzed, 2573 were associated with BMI (q value <0.05), 57 % of which showed an inverse correlation with BMI. Pathways enriched among the 2573 probe sites included those involved in inflammation, insulin receptor signaling, and leptin signaling. We were able to map 1251 of the BMI-associated methylation sites to gene expression data, and, of these, 226 (18 %) showed substantial correlations with gene expression. Our results suggest that BMI is associated with genome-wide methylation in non-diseased breast tissue and may influence epigenetic pathways involved in inflammatory and other carcinogenic processes.

Obesity-Associated Alterations in Inflammation, Epigenetics, and Mammary Tumor Growth Persist in Formerly Obese Mice

“…Selection criteria for the Normal Breast Study included having an invasive ductal carcinoma with a tissue specimen sampled ≥4 cm from tumor margins, undergoing reduction mammoplasty, or undergoing prophylactic surgery (21). There were 150 participants with invasive breast cancer had tissue collected that was >4 cm from the tumor.…”

Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study

“…Normal breast tissue samples used in this study come from women enrolled in the NBS [40]. NBS contacted 526 women above 18 y of age who were undergoing breast surgery at the University of North Carolina Hospitals.…”

Association Between BMI and DNA Methylation in Blood or Normal Adult Breast Tissue: A Systematic Review

“…Three studies had mixed breast cancer patients and breast cancer-free Discovery sample column: *n not obese/n obese; # Data from meta-analysis are combined; ˚Mean between women's data and men's data; NW stands for normal weight, OW for overweight, OB for obese and V for visit. LDA column: 1 Leukocyte distribution adjustment; 2 The influence of leukocyte composition was adjusted using the algorithm described by Houseman et al (80); 3 The influence of leukocyte composition was adjusted by subtype cell count; 4 The influence of leukocyte composition was adjusted using SVA function; 5 CD4 + T-cell purity was estimated using the methods described participants: one was a meta-analysis of four studies (EPIC-Italy, EnviroGenoMarkers, NOWAC, EPIC-Netherlands) that included both men and women (43), another was derived from the Sister Study cohort which included only healthy women at enrollment with a sister with breast cancer (44), and finally, one that included only women (45). Our study included only female patients with breast cancer.…”

“…The mean age of included participants varied. Two studies reported mean age under 30 years (24,32), eight included participants with a mean age of 30-50 years (25,29,30,33,34,36,37,39), nine others included participants with a mean age of 50-60 years [ (13,27,35,38,41,(43)(44)(45) and the present study], and the last five had participants with a mean age above 60 years (26,28,31,40,42). The forty study participants from our study ranged in age from 33 to 69 years, with a mean age of 51.0 (standard deviation [SD] ±8.2) years.…”

“…In total, 21 of the 24 epigenome-wide studies used the HumanMethylation 450K BeadChip (Illumina) [ (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(41)(42)(43)(44)(45) and the present study]. The other three used the Illumina 27K (13) (450K predecessor), the Illumina GoldenGate Assay for Methylation (39) and the CHARM technique (40).…”