title: Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood.
abstract: Obesity can increase the risk of complex metabolic diseases, including insulin resistance. Moreover, obesity can be caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are not well defined. Therefore, the identification of novel epigenetic biomarkers of obesity allows for a more complete understanding of the disease and its underlying insulin resistance. The aim of our study was to identify DNA methylation changes in whole-blood that were strongly associated with obesity and insulin resistance. Whole-blood was obtained from lean (n = 10; BMI = 23.6 ± 0.7 kg/m2) and obese (n = 10; BMI = 34.4 ± 1.3 kg/m2) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing on genomic DNA isolated from the blood. We identified 49 differentially methylated cytosines (DMCs; q < 0.05) that were altered in obese compared with lean participants. We identified 2 sites (Chr.21:46,957,981 and Chr.21:46,957,915) in the 5' untranslated region of solute carrier family 19 member 1 (SLC19A1) with decreased methylation in obese participants (lean 0.73 ± 0.11 vs. obese 0.09 ± 0.05; lean 0.68 ± 0.10 vs. obese 0.09 ± 0.05, respectively). These 2 DMCs identified by obesity were also significantly predicted by insulin sensitivity (r = 0.68, P = 0.003; r = 0.66; P = 0.004). In addition, we performed a differentially methylated region (DMR) analysis and demonstrated a decrease in methylation of Chr.21:46,957,915-46,958,001 in SLC19A1 of -34.9% (70.4% lean vs. 35.5% obese). The decrease in whole-blood SLC19A1 methylation in our obese participants was similar to the change observed in skeletal muscle (Chr.21:46,957,981, lean 0.70 ± 0.09 vs. obese 0.31 ± 0.11 and Chr.21:46,957,915, lean 0.72 ± 0.11 vs. obese 0.31 ± 0.13). Pyrosequencing analysis further demonstrated a decrease in methylation at Chr.21:46,957,915 in both whole-blood (lean 0.71 ± 0.10 vs. obese 0.18 ± 0.06) and skeletal muscle (lean 0.71 ± 0.10 vs. obese 0.30 ± 0.11). Our findings demonstrate a new potential epigenetic biomarker, SLC19A1, for obesity and its underlying insulin resistance.
authors.affiliation: a School of Life Sciences , Arizona State University , Tempe , AZ , USA.
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Day
authors.affiliation: b School for the Science of Health Care Delivery , Arizona State University , Phoenix , AZ , USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Coletta
authors.affiliation: c Division of Weight Management and Wellness , Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center , Pittsburgh , PA , USA.
authors.forename: Joon Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: b School for the Science of Health Care Delivery , Arizona State University , Phoenix , AZ , USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Garcia
authors.affiliation: a School of Life Sciences , Arizona State University , Tempe , AZ , USA.
authors.forename: Latoya E
authors.initials: LE
authors.lastname: Campbell
authors.affiliation: d Endocrinology Department , Mayo Clinic in Arizona , Scottsdale , AZ , USA.
authors.forename: Tonya R
authors.initials: TR
authors.lastname: Benjamin
authors.affiliation: d Endocrinology Department , Mayo Clinic in Arizona , Scottsdale , AZ , USA.
authors.forename: Lori R
authors.initials: LR
authors.lastname: Roust
authors.affiliation: d Endocrinology Department , Mayo Clinic in Arizona , Scottsdale , AZ , USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: De Filippis
authors.affiliation: e Department of Medicine , The University of Arizona College of Medicine , Tucson , AZ , USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Mandarino
authors.affiliation: e Department of Medicine , The University of Arizona College of Medicine , Tucson , AZ , USA.|f Department of Basic Medical Sciences , The University of Arizona College of Medicine , Phoenix , AZ , USA.
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Coletta
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D009765:Obesity / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers
keywords: Biomarker; DNA methylation; insulin resistance; obesity; whole-blood