Assessment of global long interspersed nucleotide element‐1 ( LINE ‐1) DNA methylation in a longitudinal cohort of type 2 diabetes mellitus (T2 DM ) individuals

Abstract

Introduction Recent studies have indicated that methylation of the LINE‐1 elements is associated with an increased risk of worsening carbohydrate metabolism. It has been shown that overall DNA methylation of LINE‐1 elements could be considered as a risk factor for T2DM and its complications, independent of other established risk factors. Methods A total of 794 T2DM individuals from Salford, UK were included in this study (60% men n = 470). All patients had clinical and metabolic variables measured in 2002 (baseline outcomes) and annually through to 2016. Global LINE‐1 DNA methylation was measured at four CpG sites. The QIAGEN PyroMark Q96 MD pyrosequencer was used to quantify methylation. Results The overall mean ± SD global LINE‐1 methylation was 75.81 ± 3.25%. Cross‐sectional linear regression analysis at baseline year 2002 showed that LINE‐1 methylation was a significant predictor of diastolic BP (adjusted beta coefficient β = −0.25), estimated glomerular filtration rate (eGFR) (β = −0.48) and cholesterol HDL ratio (β = −0.04). A 10% increase in LINE‐1 methylation was associated with a lower diastolic BP by 2.5 mm Hg, a lower eGFR by 4.8 ml/min/1.73 m2 and decreased cholesterol/HDL ratio by 0.4 mmol/L. Longitudinal analysis over the 14‐year‐follow‐up periods showed that global LINE‐1 methylation at baseline was associated with lower BMI in women [β = −0.25] and lower cholesterol: HDL ratio [β = −0.07]. A 10% increase in LINE‐1 methylation was associated with reduction in BMI by 2.5 kg/m2 in women and reduction in cholesterol:HDL ratio by 0.7 mmol/L. Conclusion In a 14‐year longitudinal cohort of T2DM individuals, relations between global LINE‐1 DNA methylation status and specific metabolic markers were seen. Also, a higher degree of DNA methylation was predictive of less weight gain over time in women.

Sexually dimorphic DNA-methylation in cardiometabolic health: A systematic review

“…Malipatil et al, in their study reported that an increase of 10 % in LINE-1 methylation was associated with decreased cholesterol/HDL ratio by 0.4 mmol/L in the overall sample of men and women. However, when stratifying by sex, the inverse association remained significant only in women [25]. In an EWAS performed by Garcia-Calzon et al, female samples displayed on average higher methylation in the X-chromosome, whereas males presented higher methylation in the autosomes.…”

“…Global DNA methylation is a frequent used marker for epigenetic screening since it captures the DNA methylation also at unknown genetic locations while the results of average DNA methylation correlate with the methylation of some trait-relevant genes [23,24]. Ten articles [14,[25][26][27][28][29][30][31][32][33] investigated sex-specific associations between DNAm and blood lipid concentrations applying global n = 2, epi-genome wide n = 1 and candidate gene n = 7 approaches. In total 2,443 non-overlapping participants 1,174 women and 1,269 men from USA, Canada, Finland, UK and China were included in these studies.…”

“…Two cross-sectional studies [14,25] investigating global DNAm and blood lipid levels reported sex differences. In the study conducted by Cash et al, LINE-1 methylation was significantly higher in men than in women, and among the entire sample, lower levels of LINE-1 methylation was associated with higher levels of fasting low-density lipoprotein-cholesterol (LDL) and lower levels of fasting high-density lipoprotein-cholesterol (HDL) [14].…”

“…Seven articles [25,[34][35][36][37][38][39] based on five unique studies reported associations between sex-specific DNAm and essential hypertension (EH), while one study investigated the cross-sectional association between DNAm and blood pressure [25]. Among these, five studies investigated candidate gene methylation [34][35][36]38], while another study investigated epi-genome wide methylation [40] in regard to hypertension.…”

Can Epigenetics of Endothelial Dysfunction Represent the Key to Precision Medicine in Type 2 Diabetes Mellitus?

“…LINE-1 sequences are highly repeated human DNA sequences that constitute about 17% of the human genome [84] and the degree of LINE-1 DNA methylation may provide a link between environmental exposure and development of cardiovascular complications of T2DM independently of other classical risk factors [85]. Indeed, higher levels of LINE1 methylation have been associated to a reduction in cholesterol/HDL cholesterol ratio and considered predictive of less weight gain over time and subsequent lower body mass index (BMI) in female patients [86].…”