Abstract 25: Long-Term Trends of BMI During Childhood and Adolescence Modify the Association of DNA Methylation Change at TXNIP With Glucose Change During Midlife

Abstract

Background: Thioredoxin-interacting protein (TXNIP) is a central master regulator of whole-body glucose homeostasis in humans; and DNA methylation (DNAm) at TXNIP has been identified to be related to diabetes. It remains unknown whether dynamic changes in DNAm at TXNIP are associated with glycemic changes; and whether early-life adiposity changes modify such association. Hypothesis: We hypothesized that dynamic changes in DNAm at TXNIP are associated with glycemic changes in midlife, and early-life adiposity changes may modify such association. Methods: A total of 594 Bogalusa Heart Study participants who had DNAm measurements at two time points in midlife were included in this study. Of them, 353 participants had at least 4 examinations of BMI during childhood and adolescence (aged 4–19 years). The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI during childhood and adolescence. Results: We found 25.3% of participants showed greater than 5% DNAm change at TXNIP during a mean of 6.2 years follow-up. Increase in DNAm at TXNIP was significantly associated with decrease in FPG independent of cell-type composition and other covariates ( P <0.001). Moreover, we found the increasing trend of BMI during childhood and adolescence significantly modified the above dynamic association. Each 1% increase in DNAm at TXNIP was associated with 2.90 (0.77) mg/dl decrease in FPG among participants with the highest tertile of incremental AUC of BMI, 0.96 (0.38) mg/dl decrease among those with middle tertile, whereas no significant association was observed among participants with the lowest tertile ( P -interaction=0.003). Conclusions: Our results indicate that changes in DNAm at TXNIP are significantly associated with dynamics in FPG in midlife, and such association is modified by BMI changes during childhood and adolescence.