Title : Hydroxymethylation in the SOCS3 gene-related DNA region mediates the longitudinal positive association of eating speed with the onset of type 2 diabetes in fraternal rather than identical male twins
Abstract:
Background: Eating speed is thought to be a novel risk factor for the development of diabetes. Our previous study reported that the DNA region related to the SOCS3 gene, which encodes suppressor of cytokine signaling 3 (SOCS3), was a primary candidate region differentially hydroxymethylated towards type 2 diabetes. However, it is unknown if hydroxymethylation in the SOCS3 gene-related DNA region is a novel pathophysiological pathway that links eating speed to the onset of type 2 diabetes.
Objectives: We aim to test this pathway using traditional epidemiological mediation analysis.
Method: Thirty-six white, male twin pairs [16 identical (MZ) and 20 fraternal (DZ) twin pairs] developed incident type 2 diabetes discordantly after exam 3 (1986-1987) through 2017 in the U.S. National Heart, Lung, and Blood Institute (NHLBI) Twin Study initiated in 1969-1973 (exam 1). These discordant twins were enrolled in this study if their DNA samples at exam 3 were available, and none of them had diabetes from exams 1 to 3. Subjects rated their response to the question “I eat rapidly even when there is plenty of time” on a 5-point reverse Likert scale (1=definitely true, 5= definitely false) at exam 2 (1981-1982). Buffy coat DNA samples were collected at exam 3. Incident type 2 diabetes was identified at exams 4, 5, and 6, or from the underlying cause of death through 2017. The SOCS3 gene-related DNA region was selected based on our previously published study. Hydroxymethylation was measured with the hMe-Seal-seq. Normalized reads as counts per million reads in the region were used. Exact conditional logistic regression was conducted to evaluate the association at a statistical significance level of 0.20 due to the limited sample size.
Results: The hazard ratio (HR) was 1.76 (80% CI 1.21-2.66, p=0.035) in the combined MZ and DZ sample, 1.38 (80% CI 0.80-2.52, p=0.53) in MZ that naturally controlled for 100% genetic factors and environmental factor shared between twins of a pair (aka common environment), and 2.37 (80% CI 1.24-5.67, p=0.046) in DZ pairs that naturally controlled for 50% genetic factors on average and common environment. Adding hydroxymethylation into the model reduced the regression coefficient by 54% in MZ and 11% in DZ pairs, and contributed 11% and 7% additional information, respectively.
Conclusion: Genetic factors modify and enhance the longitudinal positive association of eating speed with incident type 2 diabetes developed over 3 decades. Hydroxymethylation in the SOCS3 gene-related DNA region mediates the association in a temporal order.
