Background : Type-specific physical activity (PA) may be associated with different risks of ischemic heart disease (IHD), but few large studies have examined this. This study aimed to assess the incidence and dose–response relationships between total PA and 4 different types of PA and IHD risk in Chinese adults. Methods : The prospective China Kadoorie Biobank enrolled 35,508 adults from Qingdao from 2004 to 2008, including 33,342 IHD-free participants in this analysis. PA was collected through a self-report questionnaire, calculating metabolic equivalents of task-hours per day based on duration and frequency. Cox regression analysis was used to assess the association between PA and IHD risk. Results : During a median 9.2 years of follow-up, 2712 incident IHD cases were recorded. Total, occupational, commuting, and leisure-time PAs were inversely associated with IHD risk. Compared with the participants in the bottom quintiles of PA, the participants in the top quintiles of total PA, occupational PA, commuting PA, and leisure-time PA had 43% (hazard ratio [HR] = 0.57; 95% CI, 0.49–0.66), 38% (HR = 0.62; 95% CI, 0.50–0.75), 38% (HR = 0.62; 95% CI, 0.44–0.87), and 21% (HR = 0.79; 95% CI, 0.67–0.95) lower IHD risk, respectively. A negative association between household PA and IHD risk was found only in males (HR = 0.83; 95% CI, 0.70–0.98). The restricted cubic spline regression analysis revealed a linear relationship between total PA and IHD risk ( P for nonlinear = .5687). Conclusion : Among Chinese adults, higher total, occupational, commuting, and leisure-time PA was associated with significantly lower risks of IHD, and increased household PA could reduce IHD risk in males.

The reproducibility of obesity-related DNA methylation (DNAm) sites (CpGs) remains low across studies, and the underlying mechanisms involving genetic and environmental contributions require further investigation. In this study, we systematically searched PubMed, EMBASE, and EWAS catalogue for CpGs associated with BMI, waist circumference (WC), and waist-to-hip ratio (WHR) from previous publications, identifying 29 studies with 2,603/892/28 CpGs for BMI/WC/WHR, respectively. Then, based on 1,074 twins from Chinese National Twin Registry, 493/149/8 CpGs were validated for BMI/WC/WHR, controlling for genetic factors. Following this, within the full twin population and a subsample of 308 twins with longitudinal data collected over a 5-year period, structural equation models (SEMs) were used to assess the heritability of CpGs and how it changes over time. The overall heritability of these obesity-related CpGs was relatively high, averaging 0.34 in full twin population, which decreased from 0.38 at baseline to 0.31 at follow-up. Bivariate SEMs were employed to investigate the genetic/environmental effects behind the longitudinal stability of DNAm. Genetic correlations between baseline and follow-up DNAm levels were high (mean = 0.74), whereas environmental correlations were relatively low (mean = 0.19), suggesting the role of genetic influence on the stability of DNAm at these CpGs. For longitudinal cross-relationships between obesity indicators and DNAm, considerably higher genetic contributions from baseline obesity traits to follow-up DNAm (mean = 0.15) was observed, compared to the baseline DNAm’s genetic influences on follow-up obesity indices (mean = 0.09, P < 0.01). These findings provide genetic evidence for obesity-related DNAm and demonstrate that the genetic effects of obesity have a persistent longitudinal influence on DNAm.

AimTo 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.MethodsThis 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.ResultsThe 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.ConclusionsThis 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.

Dyslipidemia is one of the cardiometabolic risk factors that influences mortality globally. Unraveling the causality between blood lipids and metabolites and the complex networks connecting lipids, metabolites, and other cardiometabolic traits can help to more accurately reflect the body’s metabolic disorders and even cardiometabolic diseases. We conducted targeted metabolomics of 248 metabolites in 437 twins from the Chinese National Twin Registry. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) analysis was used for causal inference between metabolites and lipid parameters. Bidirectional mediation analysis was performed to explore the linkages between blood lipids, metabolites, and other seven cardiometabolic traits. We identified 44, 1, and 31 metabolites associated with triglyceride (TG), total cholesterol (TC), and high-density lipoprotein-cholesterol (HDL-C), most of which were gut microbiota-derived metabolites. There were 9, 1, and 14 metabolites that showed novel associations with TG, TC, and HDL-C, respectively. ICE FALCON analysis found that TG and HDL-C may have a predicted causal effect on 23 and six metabolites, respectively, and one metabolite may have a predicted causal effect on TG. Mediation analysis discovered 14 linkages connecting blood lipids, metabolites, and other cardiometabolic traits. Our study highlights the significance of gut microbiota-derived metabolites in lipid metabolism. Most of the identified cross-sectional associations may be due to the lipids having a predicted causal effect on metabolites, but not vice versa, nor are they due to family confounding. These findings shed new light on lipid metabolism and personalized management of cardiometabolic diseases.

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.

Epigenetic clocks were known as promising biomarkers of aging, including original clocks trained by individual CpG sites and principal component (PC) clocks trained by PCs of CpG sites. The effects of genetic and environmental factors on epigenetic clocks are still unclear, especially for PC clocks. We constructed univariate twin models in 477 same-sex twin pairs from the Chinese National Twin Registry (CNTR) to estimate the heritability of five epigenetic clocks (GrimAge, PhenoAge, DunedinPACE, PCGrimAge, and PCPhenoAge). Besides, we investigated the longitudinal changes of genetic and environmental influences on epigenetic clocks across 5 years in 134 same-sex twin pairs. Heritability of epigenetic clocks ranged from 0.45 to 0.70, and those for PC clocks were higher than those for original clocks. For five epigenetic clocks, the longitudinal stability was moderate to high and was largely due to genetic effects. The genetic correlations between baseline and follow-up epigenetic clocks were moderate to high. Special unique environmental factors emerged both at baseline and at follow-up. PC clocks showed higher longitudinal stability and unique environmental correlations than original clocks. For five epigenetic clocks, they have the potential to identify aging interventions. High longitudinal stability is mainly due to genetic factors, and changes of epigenetic clocks over time are primarily due to changes in unique environmental factors. Given the disparities in genetic and environmental factors as well as longitudinal stability between PC and original clocks, the results of studies with original clocks need to be further verified with PC clocks.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disorder with a growing global prevalence. Lipidomic and metabolomic analyses have been used to investigate the relationship between circulating metabolites and T2DM characteristics. However, few studies have explored this relationship specifically in twin populations.Methods: The data came from China's National Twin Registry (CNTR). 420 participants (210 twin pairs) were included. A mixed-effects model was applied to explore the relationship between individual metabolite/lipid levels and T2DM-related characteristics, such as homeostasis model assessment of T2DM, fasting insulin, fasting glucose, HbA1c, and insulin resistance (HOMA-IR). To compare metabolite/lipid levels in twins with inconsistent T2DM (one twin had T2DM while the other did not), the empirical Bayesian paired T-test was used. Lastly, bivariate structural equation models (SEM) were employed to investigate the genetic/environmental correlation between metabolite/lipid levels and T2DM. To ensure the statistical reliability of the results, all P values were corrected using the False Discovery Rate (FDR) method.Results: Mixed linear model results showed that a higher level of But-2-enoic (β=0.18, 95% confident interval [95% CI]: 0.14 to 0.22, adjusted P-value [Padj] = 0.002), a type of unsaturated fatty acid, And phosphatidylethanolamines (PE), including PE(39:6) (β=0.12, 95% CI: 0.09 to 0.15, Padj = 0.007), PE(40:7) (β=0.09, 95% CI: 0.07 to 0.11, Padj = 0.008), were found to be significantly associated with T2DM. In the empirical Bayesian paired T-test, a total of 71 metabolite levels associated with T2DM were identified, among which triglyceride (TG) (e.g., TG(53:3), TG(55:3), TG(55:5), etc.), L-Leucine (β=0.06, 95% CI: 0.01 to 0.12, Padj = 0.02), Deoxycholic acid 3-sulfate (β=0.23, 95% CI: 0.05 to 0.42, Padj = 0.02), PE(38:2) (β=0.08, 95% CI: 0.01 to 0.07, Padj = 0.04), and sphingomyelins [SM(d44:6)] (β=0.04, 95% CI: 0.01 to 0.06, Padj = 0.004) were found to be significantly elevated in affected twins as compared to their unaffected co-twins. The bivariate SEM analysis revealed that genetic correlations of 1 and 0.53 for D-Glucose and But-2-enoic acid, -0.04 and -0.37 for L-Lactic acid and phosphatidylcholines [PC(32:1p)], and 0.19 and 0.12 for PE(39:6) and PE(40:7). The environmental factors also contributed to the associations between T2DM and metabolite/lipid levels, with point estimates of 0.27 and 0.29 for D-Glucose and But-2-enoic acid, 0.4 and -0.14 for GM3(d41:1) and L-Lactic acid, and -0.33, -0.25, -0.44, and −0.18 for PC.Conclusion: In summary, our findings reveal regional aggregation of metabolite/lipid levels in T2DM, which highlights a potential pathway for future research. Furthermore, we demonstrate that PC and PE levels are partially subject to genetic control, while the association between metabolite/lipid levels and T2DM is partly explained by shared genes and environmental influences. The study sheds light on the complex relationship between metabolite/lipid levels and T2DM and provides a foundation for further research in this area.Funding: The CNTR wase supported from the National Natural Science Foundation of China (82173499, 82073633, 81973126, 81573223), the Special Fund for Health scientific research in public welfare (201502006, 201002007), and the Peking University Outstanding Discipline Construction Project of Epidemiology and Biostatistics.Declaration of Interest: The authors declare no conflict of interest.Ethical Approval: This study was approved by the Biomedical Ethics Committee at Peking University, Beijing, China (IRB00001052-13022, IRB00001052-14021, IRB00001052-22032). All enrolled subjects provided written informed consent.

Background: Studies investigating the relationship between egg consumption and the risk of cerebrovascular disease (CED) have yielded inconsistent results. This study evaluated the association between egg consumption and the risk of CED among Chinese adults. Methods: Data were obtained from China Kadoorie Biobank, Qingdao. A computerised questionnaire was used to collect information regarding egg consumption frequency. CED events were tracked through linkage with the Disease Surveillance Point System and the new national health insurance databases. Cox proportional hazards regression analyses were used to evaluate associations between egg consumption and CED risk controlling for potential confounders. Results: After a median follow-up of 9.2 years, 865 and 1083 CED events among men and women, respectively, were documented. More than 50% of participants consumed eggs daily with an average age of 52.0 (10.4) years at baseline. No association between egg consumption and CED were identified in the whole cohort and women. However, a 28% lower risk of CED was observed in those who consumed eggs at a higher frequency (HR = 0.72, 95% CI: 0.55–0.95) and a significant trend for the association (p for trend = 0.012) in a multivariable model in men. Conclusion: Higher frequency of egg consumption was associated with a lower risk of total CED events among men but not women in Chinese adults. The beneficial effect on women warrants further investigations.

Background and aims: The associations between genetic factors and waist circumference (WC) with stroke risk have been evaluated in Western studies. However, evidence of this association has rarely been reported in the Chinese population. This study aimed to evaluate the association between WC and family history of stroke (FHS) with ischemic stroke (IS) risk among Chinese adults and to further explore the potential interaction of these associations. Methods and results: The China Kadoorie Biobank (CKB) study recruited 35,508 participants aged 30-79 years from the Qingdao urban area during 2004-2008. A total of 33,355 participants were included in study. Cox regression analysis was used to estimate the multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the independent and interactional associations between FHS and WC and IS risk. Participants with FHS had a 29% (HR = 1.29, 95% CI: 1.12 -1.50) higher IS risk than those without FHS. Participants with excessive WC (85 cm for males and 80 cm for females) had a 78% (HR = 1.78, 95% CI: 1.51-2.10) higher IS risk than those with normal WC. The combined effect of FHS and excessive WC on IS was statistically significant (HR = 2.29, 95% CI: 1.84-2.86). The present study further found statistically significant multiplicative interactions of FHS and WC with IS risk (P interaction < 0.001). Conclusion: The present study indicated that FHS and WC were significantly associated with an increased risk of IS. The association between FHS and IS was associated with excessive WC.(c) 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

BACKGROUND AND AIMS:The relationship between seafood consumption and cardiovascular disease (CVD) is controversial, and studies have not considered competing risk events. Our study examined the association between a full range of seafood consumption and CVD incidence and mortality based on the Qingdao Diabetes Prevention Program. METHODS AND RESULTS:We followed up 5285 participants without CVD at baseline until December 31, 2021. CVD cases and deaths were identified through record linkage with the Qingdao CVD Surveillance System and the Qingdao Death Surveillance System, respectively. Information on seafood consumption was obtained using a food frequency questionnaire. We used the Cox proportional hazard model and the competing risk model to evaluate the association between all types of seafood consumption and CVD incidence and mortality. During a median follow-up of 11.4 years, 122 CVD cases and 75 deaths occurred. After adjustment for potential confounders, compared with nonconsumers, seafood consumption of 300-500 and > 500 g/week was associated with a lower risk of CVD incidence [hazards ratio and 95 % confidence interval (CI): 0.54 (0.29-0.99) and 0.49 (0.26-0.91), respectively]. However, seafood consumption of >500 g/week had a significantly lower risk of CVD mortality [subdistribution hazard ratio and 95 % CI: 0.40 (0.17-0.95)], but it was insignificant in other groups. CONCLUSION:Seafood consumption of 300-500 g/week and >500 g/week was associated with a lower CVD incidence and mortality. Our findings provide evidence of the recommendations of the 2022 Dietary Guidelines for Chinese residents and may guide the promotion of strategies for CVD prevention.

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.

BACKGROUND:Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population. METHODS:Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training ( n = 28,490) and testing sets ( n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21-I23 and fatal I20-I25) and soft CAD (all fatal or nonfatal I20-I25) were analyzed separately. RESULTS:In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19-1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell's C index by 0.001 (-0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4-6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model. CONCLUSIONS:In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.

BACKGROUND/OBJECTIVES:This study examined the relationship between famine exposure in early life and the risk of type 2 diabetes in adulthood during the 1959-1961 Chinese Famine.SUBJECTS/METHODS:A total of 3,418 individuals aged 35-74 years free of diabetes from two studies in 2006 and 2009 were followed up prospectively in 2009 and 2012, respectively. Famine exposure was classified as unexposed (individuals born in 1962-1978), fetal exposed (individuals born in 1959-1961), child exposed (individuals born in 1949-1958), and adolescent/adult exposed (born in 1931-1948). A logistic regression model was used to assess the relationship between famine exposure and diabetes after adjustment for potential covariates.RESULTS:During a three-year follow-up, the age-adjusted incidence rates of type 2 diabetes were 5.7%, 14.5%, 12.7%, and 17.8% in unexposed, fetal-exposed, child-exposed, and adolescent/adult-exposed groups, respectively (P < 0.01). Relative to the unexposed group, the relative risks (95% confidence interval) for diabetes were 2.15 (1.29-3.60), 1.53 (0.93-2.51), and 1.65 (0.75-3.63) in the fetal-exposed, child-exposed, and adolescent/adult-exposed groups, after controlling for potential covariates. The interactions between famine exposure and obesity, education level, and family history of diabetes were not observed, except for the urbanization type. Individuals living in rural areas with fetal and childhood famine exposure were at a higher risk of type 2 diabetes, with relative risks of 8.79 (1.82-42.54) and 2.33 (1.17-4.65), respectively.CONCLUSIONS:These findings indicate that famine exposure in early life is an independent predictor of type 2 diabetes, particularly in women. Early identification and intervention may help prevent diabetes in later life.Trial Registration:ClinicalTrials.gov Identifier: NCT01053195.

Aging plays a crucial role in the mechanisms of the impacts of genetic and environmental factors on blood pressure and serum lipids. However, to our knowledge, how the influence of genetic and environmental factors on the correlation between blood pressure and serum lipids changes with age remains to be determined. In this study, data from the Chinese National Twin Registry (CNTR) were used. Resting blood pressure, including systolic and diastolic blood pressure (SBP and DBP), and fasting serum lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) were measured in 2378 participants (1189 twin pairs). Univariate and bivariate structural equation models examined the genetic and environmental influences on blood pressure and serum lipids among three age groups. All phenotypes showed moderate to high heritability (0.37-0.59) and moderate unique environmental variance (0.30-0.44). The heritability of all phenotypes showed a decreasing trend with age. Among all phenotypes, SBP and DBP showed a significant monotonic decreasing trend. For phenotype-phenotype pairs, the phenotypic correlation (Rph) of each pair ranged from -0.04 to 0.23, and the additive genetic correlation (Ra) ranged from 0.00 to 0.36. For TC & SBP, TC & DBP, TG & SBP and TGs & DBP, both the Rph and Ra declined with age, and the Ra difference between the young group and the older adult group is statistically significant (p < .05). The unique environmental correlation (Re) of each pair did not follow any pattern with age and remained relatively stable with age. In summary, we observed that the heritability of blood pressure was affected by age. Moreover, blood pressure and serum lipids shared common genetic backgrounds, and age had an impact on the phenotypic correlation and genetic correlations.

Previous cross-sectional Epigenome-Wide Association Studies (EWASs) 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 EWASs have been inconsistent, and longitudinal observations of these associations are scarce. Furthermore, few studies have investigated whether DNAm could be modified by smoking, drinking and glycemic traits, which have broad impacts on genome-wide DNAm, and results in altering the risk of T2DM. Twin studies provide a valuable tool for epigenetic studies, as they are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and EMBASE for EWASs, 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 on 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. 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 was from the other cross-lagged direction, indicating 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 the potential role of DNAm of cg19693031, cg00574958 and cg04816311 in mediating the effect of altered glycemic traits on T2DM.

The aims of this study are to estimate the contributions of genetic factors to the variation of tea drinking and cigarette smoking, to examine the roles of genetic factors in their correlation and further to investigate underlying causation between them. We included 11 625 male twin pairs from the Chinese National Twin Registry (CNTR). Bivariate genetic modelling was fitted to explore the genetic influences on tea drinking, cigarette smoking and their correlation. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) was further used to explore the causal relationship between them. We found that genetic factors explained 17% and 23% of the variation in tea drinking and cigarette smoking, respectively. A low phenotypic association between them was reported (rph  = 0.21, 95% confidence interval [CI]: [0.19, 0.24]), which was partly attributed to common genetic factors (rA  = 0.45, 95% CI [0.19, 1.00]). In the ICE FALCON analysis with current smoking as the exposure, tea drinking was associated with his own (βself = 0.39, 95% CI [0.23, 0.55]) and his co-twin's smoking status (βco-twin = 0.25, 95% CI [0.10, 0.41]). Their association attenuated with borderline significance conditioning on his own smoking status (p = 0.045), indicating a suggestive causal effect of smoking status on tea drinking. On the contrary, when we used tea drinking as the predictor, we found familial confounding between them only. In conclusion, both tea drinking and cigarette smoking were influenced by genetic factors, and their correlation was partly explained by common genetic factors. In addition, our finding suggests that familial confounders account for the relationship between tea drinking and cigarette smoking. And current smoking might have a causal effect on weekly tea drinking, but not vice versa.

Objectives: : This study aimed to estimate the association between overweight and type 2 diabetes mellitus (T2DM) in twins, and further to explore whether genetic and early-life environmental factors account for this association. Methods: : This study included 31,197 twin individuals from the Chinese National Twin Registry (CNTR). Generalized estimating equation (GEE) models were applied for unmatched case-control analysis. Conditional logistic regressions were used in co-twin matched case-control analysis. Logistic regressions were fitted to examine the differences in odds ratios (ORs) from the GEE models and conditional logistic regressions. Bivariate genetic model was used to explore the genetic and environmental correlation between body mass index (BMI) and T2DM. Results: : In the GEE model, overweight was associated with a higher T2DM risk (OR=2.71, 95% confidence interval (CI): 1.96-3.73), compared with participants with normal BMI. In the multi-adjusted conditional logistic regression, the association was still significant (OR=2.60, 95% CI: 1.15-5.87). The ORs from the unmatched and matched analyses were different (P = 0.042). Particularly, overweight could increase T2DM risk in monozygotic (MZ) twins, and the difference in ORs between the unmatched and matched designs was significant (P = 0.014). After controlling for age and sex, the positive BMI-T2DM association was partly due to a significant genetic correlation (rA= 0.31, 95% CI: 0.20-0.41). Conclusions: : Our findings suggest that genetics and early-life environments might account for the observed overweight-T2DM association. Genetic correlation between BMI and T2DM further provides evidence for the influence of overlap genes on their association. ?? 2021 Elsevier Masson SAS. All rights reserved.

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.

It is crucial to understand the genetic mechanisms and biological pathways underlying the relationship between obesity and serum lipid levels. Structural equation models (SEMs) were constructed to calculate heritability for body mass index (BMI), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and the genetic connections between BMI and the four classes of lipids using 1197 pairs of twins from the Chinese National Twin Registry (CNTR). Bivariate genomewide association studies (GWAS) were performed to identify genetic variants associated with BMI and lipids using the records of 457 individuals, and the results were further validated in 289 individuals. The genetic background affecting BMI may differ by gender, and the heritability of males and females was 71% (95% CI [.66, .75]) and 39% (95% CI [.15, .71]) respectively. BMI was positively correlated with TC, TG and LDL-C in phenotypic and genetic correlation, while negatively correlated with HDL-C. There were gender differences in the correlation between BMI and lipids. Bivariate GWAS analysis and validation stage found 7 genes (LOC105378740, LINC02506, CSMD1, MELK, FAM81A, ERAL1 and MIR144) that were possibly related to BMI and lipid levels. The significant biological pathways were the regulation of cholesterol reverse transport and the regulation of high-density lipoprotein particle clearance (p < .001). BMI and blood lipid levels were affected by genetic factors, and they were genetically correlated. There might be gender differences in their genetic correlation. Bivariate GWAS analysis found MIR144 gene and its related biological pathways may influence obesity and lipid levels.