Association between epigenetic age and type 2 diabetes mellitus or glycemic traits: A longitudinal twin study.

Epigenetic clocks based on DNA methylation have been known as biomarkers of aging, including principal component (PC) clocks representing the degree of aging and DunedinPACE representing the pace of aging. Prior studies have shown the associations between epigenetic aging and T2DM, but the results vary by epigenetic age metrics and people. This study explored the associations between epigenetic age metrics and T2DM or glycemic traits, based on 1070 twins (535 twin pairs) from the Chinese National Twin Registry. It also explored the temporal relationships of epigenetic age metrics and glycemic traits in 314 twins (157 twin pairs) who participated in baseline and follow-up visits after a mean of 4.6 years. DNA methylation data were used to calculate epigenetic age metrics, including PCGrimAge acceleration (PCGrimAA), PCPhenoAge acceleration (PCPhenoAA), DunedinPACE, and the longitudinal change rate of PCGrimAge/PCPhenoAge. Mixed-effects and cross-lagged modelling assessed the cross-sectional and temporal relationships between epigenetic age metrics and T2DM or glycemic traits, respectively. In the cross-sectional analysis, positive associations were identified between DunedinPACE and glycemic traits, as well as between PCPhenoAA and fasting plasma glucose, which may be not confounded by shared genetic factors. Cross-lagged models revealed that glycemic traits (fasting plasma glucose, HbA1c, and TyG index) preceded DunedinPACE increases, and TyG index preceded PCGrimAA increases. Glycemic traits are positively associated with epigenetic age metrics, especially DunedinPACE. Glycemic traits preceded the increases in DunedinPACE and PCGrimAA. Lowering the levels of glycemic traits may reduce DunedinPACE and PCGrimAA, thereby mitigating age-related comorbidities.

Association of psychological distress and DNA methylation: A 5-year longitudinal population-based twin study.

AIM: To identify the psychological distress (PD)-associated 5'-cytosine-phosphate-guanine-3' sites (CpGs), and investigate the temporal relationship between dynamic changes in DNA methylation (DNAm) and PD. METHODS: This study included 1084 twins from the Chinese National Twin Register (CNTR). The CNTR conducted epidemiological investigations and blood withdrawal twice in 2013 and 2018. These included twins were used to perform epigenome-wide association studies (EWASs) and to validate the previously reported PD-associated CpGs selected from previous EWASs in PubMed, Embase, and the EWAS catalog. Next, a cross-lagged study was performed to examine the temporality between changes in DNAm and PD in 308 twins who completed both 2013 and 2018 surveys. RESULTS: The EWAS analysis of our study identified 25 CpGs. In the validation analysis, 741 CpGs from 29 previous EWASs on PD were selected for validation, and 101 CpGs were validated to be significant at a false discovery rate <0.05. The cross-lagged analysis found a unidirectional path from PD to DNAm at 14 CpGs, while no sites showed significance from DNAm to PD. CONCLUSIONS: This study identified and validated PD-related CpGs in a Chinese twin population, and suggested that PD may be the cause of changes in DNAm over time. The findings provide new insights into the molecular mechanisms underlying PD pathophysiology.

Association Between DNA Methylation and Blood Pressure: A 5-Year Longitudinal Twin Study.

BACKGROUND: Previous EWASs (Epigenome-Wide Association Studies) have reported hundreds of blood pressure (BP) associated 5'-cytosine-phosphate-guanine-3' (CpG) sites. However, their results were inconsistent. Longitudinal observations on the temporal relationship between DNA methylation and BP are lacking. METHODS: A candidate CpG site association study for BP was conducted on 1072 twins in the Chinese National Twin Registry. PubMed and EMBASE were searched for candidate CpG sites. Cross-lagged models were used to assess the temporal relationship between BP and DNA methylation in 308 twins who completed 2 surveys in 2013 and 2018. Then, the significant cross-lagged associations were validated by adopting the Inference About Causation From Examination of Familial Confounding approach. Finally, to evaluate the cumulative effects of DNA methylation on the progression of hypertension, we established methylation risk scores based on BP-associated CpG sites and performed Markov multistate models. RESULTS: 16 and 20 CpG sites were validated to be associated with systolic BP and diastolic BP, respectively. In the cross-lagged analysis, we detected that methylation of 2 CpG sites could predict subsequent systolic BP, and systolic BP predicted methylation at another 3 CpG sites. For diastolic BP, methylation at 3 CpG sites had significant cross-lagged effects for predicting diastolic BP levels, while the prediction from the opposite direction was observed at one site. Among these, 3 associations were validated in the Inference About Causation From Examination of Familial Confounding analysis. Using the Markov multistate model, we observed that methylation risk scores were associated with the development of hypertension. CONCLUSIONS: Our findings suggest the significance of DNA methylation in the development of hypertension.

Temporal associations between leukocytes DNA methylation and blood lipids: a longitudinal study.

BACKGROUND: The associations between blood lipids and DNA methylation have been investigated in epigenome-wide association studies mainly among European ancestry populations. Several studies have explored the direction of the association using cross-sectional data, while evidence of longitudinal data is still lacking. RESULTS: We tested the associations between peripheral blood leukocytes DNA methylation and four lipid measures from Illumina 450 K or EPIC arrays in 1084 participants from the Chinese National Twin Registry and replicated the result in 988 participants from the China Kadoorie Biobank. A total of 23 associations of 19 CpG sites were identified, with 4 CpG sites located in or adjacent to 3 genes (TMEM49, SNX5/SNORD17 and CCDC7) being novel. Among the validated associations, we conducted a cross-lagged analysis to explore the temporal sequence and found temporal associations of methylation levels of 2 CpG sites with triglyceride and 2 CpG sites with high-density lipoprotein-cholesterol (HDL-C) in all twins. In addition, methylation levels of cg11024682 located in SREBF1 at baseline were temporally associated with triglyceride at follow-up in only monozygotic twins. We then performed a mediation analysis with the longitudinal data and the result showed that the association between body mass index and HDL-C was partially mediated by the methylation level of cg06500161 (ABCG1), with a mediation proportion of 10.1%. CONCLUSIONS: Our study indicated that the DNA methylation levels of ABCG1, AKAP1 and SREBF1 may be involved in lipid metabolism and provided evidence for elucidating the regulatory mechanism of lipid homeostasis.

Longitudinal Association of DNA Methylation With Type 2 Diabetes and Glycemic Traits: A 5-Year Cross-Lagged Twin Study.

Investigators of previous cross-sectional epigenome-wide association studies (EWAS) in adults have reported hundreds of 5'-cytosine-phosphate-guanine-3' (CpG) sites associated with type 2 diabetes mellitus (T2DM) and glycemic traits. However, the results from EWAS have been inconsistent, and longitudinal observations of these associations are scarce. Furthermore, few studies have investigated whether DNA methylation (DNAm) could be modified by smoking, drinking, and glycemic traits, which have broad impacts on genome-wide DNAm and result in altering the risk of T2DM. Twin studies provide a valuable tool for epigenetic studies, as twins are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and Embase for EWAS, and 214, 33, and 117 candidate CpG sites were selected for T2DM, HbA1c, and fasting blood glucose (FBG). Based on 1,070 twins from the Chinese National Twin Registry, 67, 17, and 16 CpG sites from previous studies were validated for T2DM, HbA1c, and FBG. Longitudinal review and blood sampling for phenotypic information and DNAm were conducted twice in 2013 and 2018 for 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. A total of 11 significant paths from T2DM to subsequent DNAm and 15 paths from DNAm to subsequent T2DM were detected, suggesting both directions of associations. For glycemic traits, we detected 17 cross-lagged associations from baseline glycemic traits to subsequent DNAm, and none were from the other cross-lagged direction, indicating that CpG sites may be the consequences, not the causes, of glycemic traits. Finally, a longitudinal mediation analysis was performed to explore the mediation effects of DNAm on the associations of smoking, drinking, and glycemic traits with T2DM. No significant mediations of DNAm in the associations linking smoking and drinking with T2DM were found. In contrast, our study suggested a potential role of DNAm of cg19693031, cg00574958, and cg04816311 in mediating the effect of altered glycemic traits on T2DM.

Cardiometabolic Traits in Adult Twins: Heritability and BMI Impact with Age.

Background: The prevalence of obesity and cardiometabolic diseases continues to rise globally and obesity is a significant risk factor for cardiometabolic diseases. However, to our knowledge, evidence of the relative roles of genes and the environment underlying obesity and cardiometabolic disease traits and the correlations between them are still lacking, as is how they change with age. Method: Data were obtained from the Chinese National Twin Registry (CNTR). A total of 1421 twin pairs were included. Univariate structural equation models (SEMs) were performed to evaluate the heritability of BMI and cardiometabolic traits, which included blood hemoglobin A1c (HbA1c), fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Bivariate SEMs were used to assess the genetic/environmental correlations between them. The study population was divided into three groups for analysis: ≤50, 51−60, and >60 years old to assess the changes in heritability and genetic/environmental correlations with ageing. Results: Univariate SEMs showed a high heritability of BMI (72%) and cardiometabolic traits, which ranged from 30% (HbA1c) to 69% (HDL-C). With age increasing, the heritability of all phenotypes has different degrees of declining trends. Among these, BMI, SBP, and DBP presented significant monotonous declining trends. The bivariate SEMs indicated that BMI correlated with all cardiometabolic traits. The genetic correlations were estimated to range from 0.14 (BMI and LDL-C) to 0.39 (BMI and DBP), while the environmental correlations ranged from 0.13 (BMI and TC/LDL-C) to 0.31 (BMI and TG). The genetic contributions underlying the correlations between BMI and SBP and DBP, TC, TG, and HDL-C showed a progressive decrease as age groups increased. In contrast, environmental correlations displayed a significant increasing trend for HbA1c, SBP, and DBP. Conclusions: The findings suggest that genetic and environmental factors have essential effects on BMI and all cardiometabolic traits. However, as age groups increased, genetic influences presented varying degrees of decrement for BMI and most cardiometabolic traits, suggesting the increasing importance of environments. Genetic factors played a consistently larger role than environmental factors in the phenotypic correlations between BMI and cardiometabolic traits. Nevertheless, the relative magnitudes of genetic and environmental factors may change over time.

A Comparison of Preterm Birth Rate and Growth from Birth to 18 Years Old between in Vitro Fertilization and Spontaneous Conception of Twins.

The aim of the present study was to compare the rate of preterm birth (PTB) and growth from birth to 18 years between twins conceived by in vitro fertilization (IVF) and twins conceived by spontaneous conception (SC) in mainland China. The retrospective cohort study included 1164 twins resulting from IVF and 25,654 twins conceived spontaneously, of which 494 from IVF and 6338 from SC were opposite-sex twins. PTB and low birth weight (LBW), and growth, including length/height and weight, were compared between the two groups at five stages: infancy (0 year), toddler period (1-2 years), preschool (3-5 years), primary or elementary school (6-11 years), and adolescence (10-18 years). Few statistically significant differences were found for LBW and growth between the two groups after adjusting for PTB and other confounders. Twins born by IVF faced an increased risk of PTB compared with those born by SC (adjusted odds ratio [aOR] 8.21, 95% confidence interval [CI] [3.19, 21.13], p < .001 in all twins and aOR 10.12, 95% CI [2.32, 44.04], p = .002 in opposite-sex twins). Twins born by IVF experienced a similar growth at five stages (0-18 years old) when compared with those born by SC. PTB risk, however, is significantly higher for twins conceived by IVF than those conceived by SC.