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DNA methylation plays an important role in the development and etiology of type 2 diabetes; however, few epigenomic studies have been conducted on twins. Herein, a two-stage study was performed to explore the associations between DNA methylation and type 2 diabetes, fasting plasma glucose, and HbA1c. DNA methylation in 316 twin pairs from the Chinese National Twin Registry (CNTR) was measured using Illumina Infinium BeadChips. In the discovery sample, the results revealed that 63 CpG sites and 6 CpG sites were significantly associated with fasting plasma glucose and HbA1c, respectively. In the replication sample, cg19690313 in TXNIP was associated with both fasting plasma glucose (P = 1.23 × 10-17, FDR < 0.001) and HbA1c (P = 2.29 × 10-18, FDR < 0.001). Furthermore, cg04816311, cg08309687, and cg09249494 may provide new insight in the metabolic mechanism of HbA1c. Our study provides solid evidence that cg19690313 on TXNIP correlates with HbA1c and fasting plasma glucose levels.

Aims The potential difference in the impacts of lifestyle factors (LFs) on progression from healthy to first cardiometabolic disease (FCMD), subsequently to cardiometabolic multimorbidity (CMM), and further to death is unclear. Methods and results We used data from the China Kadoorie Biobank of 461 047 adults aged 30–79 free of heart disease, stroke, and diabetes at baseline. Cardiometabolic multimorbidity was defined as the coexistence of two or three CMDs, including ischaemic heart disease (IHD), stroke, and type 2 diabetes (T2D). We used multi-state model to analyse the impacts of high-risk LFs (current smoking or quitting because of illness, current excessive alcohol drinking or quitting, poor diet, physical inactivity, and unhealthy body shape) on the progression of CMD. During a median follow-up of 11.2 years, 87 687 participants developed at least one CMD, 14 164 developed CMM, and 17 541 died afterwards. Five high-risk LFs played crucial but different roles in all transitions from healthy to FCMD, to CMM, and then to death. The hazard ratios (95% confidence intervals) per one-factor increase were 1.20 (1.19, 1.21) and 1.14 (1.11, 1.16) for transitions from healthy to FCMD, and from FCMD to CMM, and 1.21 (1.19, 1.23), 1.12 (1.10, 1.15), and 1.10 (1.06, 1.15) for mortality risk from healthy, FCMD, and CMM, respectively. When we further divided FCMDs into IHD, ischaemic stroke, haemorrhagic stroke, and T2D, we found that LFs played different roles in disease-specific transitions even within the same transition stage. Conclusion Assuming causality exists, our findings emphasize the significance of integrating comprehensive lifestyle interventions into both health management and CMD management.

BACKGROUND AND AIMS: Little is known about the associations between perinatal exposure to maternal smoking and cardiovascular disease (CVD) incidence in offspring, and whether such associations are modified by adulthood and genetically determined smoking behaviors. METHODS: A total of 414,588 participants without CVD at baseline were included from the UK Biobank in 2006–2010 and followed up through 2018. Cox-proportional hazard models were used to examine the association of perinatal maternal smoking with CVD, and both multiplicative and additive interaction analyses were performed to investigate the modification effects of own smoking behaviors. RESULTS: During a median follow-up of 8.93 years, we observed 10,860 incident CVD events, including 7006 myocardial infarction (MI) and 4147 stroke. We found that perinatal exposure to maternal smoking was associated with increased risks of CVD (HR: 1.10; 95% CI: 1.05–1.14), MI (1.10; 1.05–1.16) and stroke (1.10; 1.03–1.18). In addition, we observed significant interactions between perinatal exposure to maternal smoking and adulthood exposure to own smoking on CVD and MI on both the multiplicative and additive scales (all p

Background SCFAs are involved in regulation of body weight and bone health. Objectives We aimed to examine whether genetic variations related to butyrate modified the relation between dietary fiber intake and changes in bone mineral density (BMD) in response to weight-loss dietary interventions. Methods In the 2-y Preventing Overweight Using Novel Dietary Strategies trial, 424 participants with BMD measured by DXA scan were randomly assigned to 1 of 4 diets varying in macronutrient intakes. A polygenic score (PGS) was calculated based on 7 genetic variants related to the production of butyrate for 370 of the 424 participants. Results SCFA PGS significantly modified the association between baseline dietary fiber intake and sex on 2-y changes in whole-body BMD (P-interaction = 0.049 and 0.008). In participants with the highest tertile of SCFA PGS, higher dietary fiber intake was related to a greater increase in BMD (β: 0.0022; 95% CI: 0.0009, 0.0035; P = 0.002), whereas no such association was found for participants in the lower tertiles. In the lowest tertiles of SCFA PGS, men showed a significant increase in whole-body BMD (β: 0.0280; 95% CI: 0.0112, 0.0447; P = 0.002) compared with women. In the highest tertile, no significant difference was found for the change in BMD between men and women. Conclusions Our data indicate that genetic variants related to butyrate modify the relations of dietary fiber intake and sex with long-term changes in BMD in response to weight-loss diet interventions.

Background Acute respiratory infections have been associated with a transient increase in cardiovascular risk. However, whether such an association persists beyond 1 month and the potential modifying effect of cardiovascular risk factors on such an association are less well established. Methods The China Kadoorie Biobank enrolled 512 726 participants aged 30–79 years from 10 areas across China during 2004–2008. By the end of 2017, a total of 5444 participants with new-onset ischaemic heart disease (IHD) and 4846 with ischaemic stroke (IS) who also had at least a record of hospitalization for pneumonia during follow-up were included. We used a self-controlled case-series method and calculated the age- and season-adjusted relative incidences (RIs) and 95% confidence intervals (CIs) for ischaemic cardiovascular disease (CVD) after pneumonia. Results The risk of ischaemic CVD increased during days 1–3 after pneumonia hospitalization, with an RI (95% CI) of 4.24 (2.92–6.15) for IHD and 1.85 (1.02–3.35) for IS. The risk gradually reduced with longer duration since pneumonia hospitalization but remained elevated until days 92–365 for IHD (1.23, 1.12–1.35) and days 29–91 for IS (1.25, 1.05–1.48). Pre-existing cardiovascular risk factors amplified the associations between pneumonia and ischaemic CVD risks, such as chronic obstructive pulmonary disease for both IHD and IS, and diabetes and smoking for IHD (all Pinteraction Conclusion Among middle-aged and older Chinese adults, pneumonia hospitalization was associated with both short- and long-term increases in ischaemic CVD risk for ≤1 year.

BACKGROUND: Plant-based dietary patterns may be related to better cardiovascular profiles. Whether a healthy plant-based dietary index is predictive of future cardiovascular disease (CVD) across people with different genetic susceptibility remains uncertain. OBJECTIVE: We investigated associations of adherence to healthy plant-based diets with the incidence of CVD considering the genetic susceptibility. METHODS: This prospective cohort study included a total of 156,148 adults initially free of CVD and cancer. We calculated a healthful plant-based diet index (healthful-PDI) in which healthy plant foods received positive scores, and less healthy plant foods and animal foods received reverse scores. Genetic risk scores (GRSs) for myocardial infarction (MI) and stroke were calculated to assess interactions between healthful-PDI and GRSs. RESULTS: During 5 y of follow-up, we observed 1812 incident cases of CVD. Higher healthful-PDI was associated with a lower CVD risk [HR per 10-unit increment: 0.87 (95% CI: 0.81, 0.93) after adjusting for demographic, lifestyle, and other dietary factors (model 1); HR 0.90 (0.84, 0.97) after further adjusting for obesity and metabolic factors (model 2)]. The risk of CVD was gradually decreased in association with higher adherence to healthful-PDI, regardless of genetic susceptibility. The inverse associations of healthful-PDI with CVD were consistently observed in people with low GRS-MI [HR 0.85 (95% CI: 0.76, 0.94) in model 1; HR 0.88 (0.79, 0.97) in model 2] and those with high GRS-MI [HR 0.91 (0.82, 0.99) in model 1; HR 0.94 (0.86, 1.04) in model 2], without significant interactions (P(interaction) = 0.59 in model 1; P(interaction) = 0.66 in model 2). Similarly, higher healthful-PDI was related to a lower risk of CVD, regardless of low/high GRS-stroke. CONCLUSION: Adherence to healthy plant-based diets may be associated with a decreased incidence of CVD in the entire population, suggesting that plant-based dietary patterns may modify the risk of CVD, regardless of genetic susceptibility.

Context Recent evidence has related circulating branch-chained amino acids (BCAAs) to ectopic fat distribution. Objective To investigate the associations of changes in plasma BCAAs induced by weight-loss diet interventions with hepatic fat and abdominal fat, and potential modification by different diets. Design, Setting, and Participants The current study included 184 participants from the 2-year Preventing Overweight and Using Novel Dietary Strategies (POUNDS Lost) trial with repeated measurements on plasma BCAAs, hepatic fat, and abdominal fat over 2 years. Main Outcome Measures Repeated measurements of hepatic fat, abdominal fat distribution, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT). Results Over 2 years, a decrease in total plasma BCAAs was significantly associated with improvement in hepatic density (a marker for hepatic fat; P = 0.02) and reductions in abdominal fat, including VAT, SAT, and TAT (all P < 0.05) in the main analyses. Additionally, we observed that decreases in BCAAs were associated with decreased insulin, homeostasis model assessment of insulin resistance, and triglycerides, independent of weight loss (all P < 0.05). Moreover, we found that dietary protein intake significantly modified the relation between changes in total plasma BCAAs and hepatic density at 6 months (Pinteraction = 0.01). Participants with a larger decrease in total BCAAs showed a greater increase in hepatic density when consuming a high-protein diet, compared with those with a smaller decrease or increase in total BCAAs. Conclusions Our findings indicate that weight-loss diet-induced decrease in plasma BCAAs is associated with reductions of hepatic and abdominal fat. In addition, dietary protein intake may modify these associations.

PURPOSE: Obesity is a heterogeneous condition, and distinct adiposity subtypes may differentially affect type 2 diabetes risk. We assessed relations between genetically determined subtypes of adiposity and changes in glycemic traits in a dietary intervention trial. METHODS: The four genetic subtypes of adiposity including waist hip ratio-increase only (WHRonly+), body mass index-increase only (BMIonly+), WHR-increase and BMI-increase (BMI+WHR+), and WHR-decrease and BMI-increase (BMI+WHR−), were assessed by polygenetic scores (PGSs), calculated based on 159 single nucleotide polymorphisms related to BMI and/or WHR. We examined the associations between the four PGSs and changes in fasting glucose, insulin, β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in 692 overweight participants (84% white Americans) who were randomly assigned to one of four weight-loss diets in a 2-year intervention trial. RESULTS: Higher BMI+WHR− PGS was associated with greater decrease on 2-year changes in waist circumference in white participants (P=0.002). We also found significant interactions between WHRonly+ PGS and dietary protein on 2-year changes in fasting glucose and HOMA-B (P=0.0007 and

Submandibular gland (SMG) transplantation improves the tear film and other ocular-surface features for patients with severe dry eye disease (DED). Using the dry eye-related quality of life (QOL) questionnaire, we aimed to evaluate whether DED patients' QOL would benefit from SMG transplantation and determine whether preoperative ophthalmologic and QOL measurements could predict which patients would be most satisfied with this surgery.This prospective study included DED patients with successful SMG transplantation. Using the Chinese version of the Dry Eye Related Quality of Life (CDERQOL) instrument, QOL was measured before and 1-year after surgery.The QOL data of 51 consecutive patients were analyzed. Before surgery, all the patients had a poor QOL. One year after surgery, all five QOL domains (Dry Eye Symptom Bother, Impact on Daily Activities, Emotional Impact, Impact on Work, and Satisfaction with Treatment) showed significant improvement (P 0.01). Unsuccessful treatment experience with cyclosporin eyedrops as well as pre-surgical low scores of visual acuity and all five QOL domains (except for "Satisfaction with Treatment") were found to significantly increase the post-surgical QOL scores (P 0.01); however, pre-surgical Schirmer's test, break-up times of tear-film, and corneal fluorescein staining measurements showed no effects or contradictory correlations with post-surgical QOL scores.The life quality and satisfaction of DED patients showed significant improvement after SMG transplantation. Patients with severe and refractory DED could reap the benefits of surgery. A subjective QOL questionnaire is very valuable for predicting and evaluating the treatment effect.

OBJECTIVE Type 2 diabetes is related to obesity and altered bone health, and both are affected by gut microbiota. We examined associations of weight loss diet–induced changes in a gut microbiota–related metabolite trimethylamine N-oxide (TMAO), and its precursors (choline and l-carnitine), with changes in bone mineral density (BMD) considering diabetes-related factors. RESEARCH DESIGN AND METHODS In the 2-year Preventing Overweight Using Novel Dietary Strategies trial (POUNDS Lost), 264 overweight and obese participants with measurement of BMD by DXA scan were included in the present analysis. The participants were randomly assigned to one of four diets varying in macronutrient intake. Association analysis was performed in pooled participants and different diet groups. Changes in blood levels of TMAO, choline, and l-carnitine from baseline to 6 months after the dietary intervention were calculated. RESULTS We found that a greater reduction in plasma levels of TMAO from baseline to 6 months was associated with a greater loss in whole-body BMD at 6 months and 2 years (P = 0.03 and P = 0.02). The greater reduction in TMAO was also associated with a greater loss in spine BMD (P = 0.005) at 2 years, independent of body weight changes. The associations were not modified by baseline diabetes status and glycemic levels. Changes in l-carnitine, a precursor of TMAO, showed interactions with dietary fat intake in regard to changes of spine BMD and hip BMD at 6 months (all P < 0.05). Participants with the smallest decrease in l-carnitine showed less bone loss in the low-fat diet group than the high-fat diet group (Pspine = 0.03 and Phip = 0.02). CONCLUSIONS TMAO might protect against BMD reduction during weight loss, independent of diet interventions varying in macronutrient content and baseline diabetes risk factors. Dietary fat may modify the relation between change in plasma l-carnitine level and changes in BMD. Our findings highlight the importance of investigating the relation between TMAO and bone health in patients with diabetes.

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.

Background:Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population.Methods:We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10 year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module.Results:After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR < 0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47 % decrease to a 118 % increase. Mediation analyses revealed 28.5 % of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region of ANKS1A gene (P for mediation effect = 0.036). Methylation level at the promoter region of SNX30 was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7 % (P = 0.003) via systolic blood pressure and 6.4 % (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD.Conclusions:We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and blood pressure-related pathways to CHD risk.Funding:This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).

This study assessed the temporal relationship of elevated blood pressure (BP) with left ventricular hypertrophy (LVH) and geometric changes in a longitudinal cohort of adults. Left ventricular mass index (LVMI), relative wall thickness (RWT), and BP were measured at 2 time points 4.1 to 14.9 years apart between 2000 and 2016 among 984 adults (677 White and 307 Black people; 41.1% men; age range, 24.2–56.7 years) in the Bogalusa Heart Study cohort. Cross-lagged path analysis models were used to examine the temporal relationship of BP with LVMI and RWT in subjects who did not take antihypertensive medications (n=693). The cross-lagged path coefficients did not differ significantly between race and sex groups. In the combined sample, the path coefficients from baseline systolic BP to follow-up LVMI/RWT were significantly greater than the path coefficients from baseline LVMI/RWT to follow-up systolic BP (0.111 versus −0.005 for LVMI, P =0.010 for difference; 0.146 versus 0.004 for RWT, P =0.002 for difference). Hypertensive subjects at baseline had a significantly higher incidence rate of concentric LVH at follow-up compared with normotensive subjects (19.4% versus 9.7%, P P =0.503 for difference). Diastolic BP showed similar results to those of systolic BP. In conclusion, the findings on these one-directional paths provide strong and fresh evidence that elevated BP precedes the development of LVH, especially concentric LVH, during the young-to-midlife adult age period.

Background Little is known about the effects of lifestyle modification on biological aging in population-based studies of middle-aged and older adults. Method We examined the individual and joint associations of multiple lifestyle factors with accelerated biological aging measured by change in frailty index (FI) over 8 years in a prospective study of Chinese adults. Data were obtained on 24 813 participants in the China Kadoorie Biobank on lifestyle factors and frailty status at baseline and at 8 years after baseline. Adherence to healthy lifestyle factors included nonsmoking or quitting smoking for reasons other than illness, avoidance of heavy alcohol consumption, daily intake of fruit and vegetables, being physically active, body mass index of 18.5–23.9 kg/m2, and waist-to-hip ratio of Results Overall, 8 760 (35.3%) individuals had a worsening frailty status. In multivariable-adjusted logistic regression analyses, adherence to healthy lifestyle was associated with a lower risk of worsening frailty status. Compared with robust participants maintaining 0–1 healthy lifestyle factors, the corresponding odds ratios (95% CIs) were 0.93 (0.83–1.03), 0.75 (0.67–0.84), 0.68 (0.60–0.77), and 0.55 (0.46–0.65) for robust participants with 2, 3, 4, and 5–6 healthy lifestyle factors. The decreased risk of frailty status worsening by adherence to healthy lifestyle factors was similar in both middle-aged and older adults, and in both robust and prefrail participants at baseline. Conclusions Adherence to a healthy lifestyle may attenuate the rate of change in biological aging in middle-aged and older Chinese adults.

Objective . The strongest locus which associated with type 2 diabetes (T2D) by the common variant rs7903146 is the transcription factor 7-like 2 gene ( TCF7L2 ). We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits, body weight, or waist circumference in overweight or obese adults in several randomized controlled trials (RCTs). Methods . From October 2016 to May 2018, a large collaborative analysis was performed by pooling individual-participant data from 7 RCTs. These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults. Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies. Results . In the joint analysis, a total of 7 eligible RCTs were included ( n = 4,114 ). Importantly, we observed a significant effect modification of diet/lifestyle-related interventions on the TCF7L2 variant rs7903146 and changes in fasting glucose. Compared with the control group, diet/lifestyle interventions were related to lower fasting glucose by -3.06 (95% CI, -5.77 to -0.36) mg/dL (test for heterogeneity and overall effect: I 2 = 45.1 % , p < 0.05 ; z = 2.20 , p = 0.028 ) per one copy of the TCF7L2 T risk allele. Furthermore, regardless of genetic risk, diet/lifestyle interventions were associated with lower waist circumference. However, there was no significant change for diet/lifestyle interventions in other glycemic control and adiposity traits per one copy of TCF7L2 risk allele. Conclusions . Our findings suggest that carrying the TCF7L2 T risk allele may have a modestly greater benefit for specific diet/lifestyle interventions to improve the control of fasting glucose in overweight or obese adults.

Objective: Insulin resistance and hyperuricemia, established risk factors of type 2 diabetes (T2DM), are highly correlated, but their complex relationships are not well understood. This study aims to examine the temporal relationship between uric acid (UA) and insulin and their joint impact on T2DM in middle-aged adults. Research Design and Methods: The longitudinal cohort consisted of 1351 non-diabetic adults (979 whites and 372 blacks; 41.2% males, mean age=36.1 years at follow-up) who had serum UA and insulin measured twice at baseline and follow-up over 7.7 years on average. The cross-lagged analysis model was used to examine the temporal relationship between UA and insulin. The general mediation analysis models were constructed to examine the mediating effects of UA and insulin on incident T2DM identified in the outcome survey 12.2 years after the follow-up survey. Results: After adjusting for age, race, sex, body mass index, smoking, alcohol drinking and follow-up years, the path coefficient from baseline UA to follow-up insulin was 0.082 (p

Background Systemic studies of association of genome-wide DNA methylated sites with cardiovascular disease (CVD) in prospective cohorts are lacking. Our aim was to identify DNA methylation sites associated with the risk of CVD and further investigate their potential predictive value in CVD development for high-risk subjects. Methods We performed an epigenome-wide association study (EWAS) to identify CpGs related to CVD development in a Chinese population.We adopted a nested case–control design based on data from China PEACE Million Persons Project. A total of 83 cases who developed CVD events during follow-up and 83 controls who were matched with cases by age, sex, BMI, ethnicity, medications treatment and behavior risk factors were included in the discovery stage. Genome-wide DNA methylation from whole blood was detected using Infinium Human Methylation EPIC Beadchip (850 K). For significant CpGs [FDR(false discovery rate) Results In discovery set, we identified 8 significant CpGs (FDR UACA) were replicated in another independent set (p p = 9.716E-15]. Conclusions Our study identified the novel CpGs associated with CVD development and revealed their additional predictive power in the risk of CVD for high-risk subjects.

Rationale: In observational studies, type 2 diabetes mellitus (T2D) has been associated with an increased risk of hypertension, and vice versa; however, the causality between these conditions remains to be determined. Objectives: This population-based prospective cohort study sought to investigate the bidirectional causal relations of T2D with hypertension, systolic and diastolic blood pressure (BP) using Mendelian randomization (MR) analysis. Methods and Results: After exclusion of participants free of a history of heart failure, cardiovascular disease, cardiac procedures, and non-T2D diabetes mellitus, a total of 318 664 unrelated individuals with qualified genotyping data of European descent aged 37 to 73 from UK Biobank were included. The genetically instrumented T2D and hypertension were constructed using 134 and 233 single nucleotide polymorphisms, respectively. Seven complementary MR methods were applied, including inverse-variance weighted method, 2 median-based methods (simple and weighted), MR-Egger, MR-robust adjusted profile scores, MR-Pleiotropy Residual Sum and Outlier, and multivariate MR. The genetically instrumented T2D was associated with risk of hypertension (odds ratio, 1.07 [95% CI, 1.04–1.10], P =3.4×10 −7 ), whereas the genetically determined hypertension showed no relationship with T2D (odds ratio, 0.96 [0.88–1.04], P =0.34). Our MR estimates from T2D to BP showed that the genetically instrumented T2D was associated with a 0.67 mm Hg higher systolic BP (95% CI, 0.41–0.93, P =5.75×10 –7 ) but not with a higher diastolic BP. There was no clear evidence showing a causal effect of elevated systolic BP or diastolic BP on T2D risk. Positive pleiotropic bias was indicated in the hypertension→T2D relation (odds ratio, of MR-Egger intercept 1.010 [1.004–1.016], P =0.001) but not from T2D to hypertension (1.001 [0.998–1.004], P =0.556). Conclusions: T2D may causally affect hypertension, whereas the relationship from hypertension to T2D is unlikely to be causal. These findings suggest the importance of keeping an optimal glycemic profile in general populations, and BP screening and monitoring, especially systolic BP, in patients with T2D.

ObjectiveAlterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention.DesignWe included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes (Δ) in TMAO, choline and L-carnitine levels after the intervention were calculated.ResultsGreater decreases in choline and L-carnitine were significantly (pinteraction ConclusionOur findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism.Trial registration numberNCT00072995.

BACKGROUND AND AIM Gallstone disease has been related to a higher prevalence and incidence of chronic conditions, such as dyslipidemia, obesity, and cardiovascular disease (CVD). However, limited data are available regarding whether gallstone disease is related to mortality. METHODS We examined the relationship of a history of gallstone disease and risk of death, using Cox proportional hazards regression analysis, among 86 030 women from the Nurses' Health Study and 43 949 men from the Health Professionals Follow-up Study. RESULTS During the up-to 32 years of follow-up, 34 011 all-cause deaths were confirmed, of which 8138 were CVD deaths and 12 173 were cancer deaths. For the participants with a history of gallstone disease compared with those without, the hazard ratio of total mortality was 1.16 (95% confidence interval 1.13, 1.20), of CVD mortality 1.11 (1.05, 1.17), of cancer mortality 1.15 (1.09, 1.20), and of other mortality 1.19 (1.14, 1.25) from a pooled-analysis of women and men (all P

BACKGROUND: Growing evidence has implicated DNA methylation (DNAm) in the regulation of body adiposity; a recent epigenome-wide association study (EWAS) identified a genetic variant determining DNAm at the SREBF1 gene that affected body mass index (BMI). OBJECTIVE: In the present study, we tested interactions between DNAm variant rs752579 and methylation metabolism-related B-vitamins (folate, vitamin B(2), vitamin B(6), and vitamin B(12)) on longitudinal change in BMI in the Women’s Health Initiative Memory Study (WHIMS). DESIGN: A total of 5687 white women aged 65–79 from WHIMS with genotyping data on SNP rs752579 were included in the analysis. B-vitamins intakes were estimated by a self-report semi-quantitative food frequency questionnaire. BMI was measured at baseline and 6-year follow-up. RESULT: We found significant interactions between the SREBF1 rs752579 genotype and intake of food source B-vitamins on 6-year change in BMI (p interaction

Asthma is related to various cardiovascular risk. Whether a history of asthma from childhood contributes to arterial stiffness in adulthood, a noninvasive surrogate for cardiovascular events, is unknown. Prospective analyses were performed among 1746 Bogalusa Heart Study participants aged 20 to 51 years with data on self-report asthma collected since childhood. Aorta–femoral pulse wave velocity (af-PWV, m/s) was repeatedly assessed among adults ≥aged 18 years. Generalized linear mixed models and generalized linear models were fitted for the repeated measurements of af-PWV and its changes between the last and the first measurements, respectively. After a median follow-up of 11.1 years, participants with a history of asthma from childhood had a higher af-PWV (6.78 versus 6.13; P =0.048) and a greater increase in af-PWV (8.99 versus 2.95; P =0.043) than those without asthma, adjusted for age, sex, race, smoking status, heart rate, body mass index, systolic blood pressure, lipids, and glycemia. In addition, we found significant interactions of asthma with body mass index and systolic blood pressure on af-PWV and its changes ( P for interaction 2 ) or with prehypertension and hypertension (systolic blood pressure ≥120 mm Hg) compared with those with a normal body mass index or systolic blood pressure. Our findings indicate that a history of asthma from childhood is associated with higher af-PWV and greater increases in af-PWV, and such associations are stronger among young adults who are overweight or with elevated blood pressure.

Aim To determine whether weight-loss diets varying in macronutrients modulate the genetic effect of hepatocyte nuclear factor 1α (HNF1A) rs7957197 on weight loss and improvement of insulin resistance. Materials and methods We analysed the interaction between HNF1A rs7957197 and weight-loss diets with regard to weight loss and insulin resistance improvement among 722 overweight/obese adults from a 2-year randomized weight-loss trial, the POUNDS Lost trial. The findings were replicated in another independent 2-year weight-loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT), in 280 overweight/obese adults. Results In the POUNDS Lost trial, we found that a high-fat diet significantly modified the genetic effect of HNF1A on weight loss and reduction in waist circumference (P for interaction = .006 and .005, respectively). Borderline significant interactions for fasting insulin and insulin resistance (P for interaction = .07 and .06, respectively) were observed. We replicated the results in DIRECT. Pooled results showed similar significant interactions with weight loss, waist circumference reduction, and improvement in fasting insulin and insulin resistance (P values for interaction = .001, .005, .02 and .03, respectively). Greater decreases in weight, waist circumference, fasting insulin level and insulin resistance were observed in participants with the T allele compared to those without the T allele in the high-fat diet group (P = .04, .03 and .01, respectively). Conclusions Our replicable findings provide strong evidence that individuals with the HNF1A rs7957197 T allele might obtain more benefits in weight loss and improvement of insulin resistance by choosing a hypocaloric and high-fat diet.

Whether change in physical activity over time modifies the genetic susceptibility to long-term weight gain is unknown. We calculated a BMI–genetic risk score (GRS) based on 77 BMI-associated single nucleotide polymorphisms (SNPs) and a body fat percentage (BF%)-GRS based on 12 BF%-associated SNPs in 9,390 women from the Nurses’ Health Study (NHS) and 5,291 men from the Health Professionals Follow-Up Study (HPFS). We analyzed the interactions between each GRS and change in physical activity on BMI/body weight change within five 4-year intervals from 1986 to 2006 using multivariable generalized linear models with repeated-measures analyses. Both the BMI-GRS and the BF%-GRS were associated with long-term increases in BMI/weight, and change in physical activity consistently interacted with the BF%-GRS on BMI change in the NHS (P for interaction = 0.025) and HPFS (P for interaction = 0.001). In the combined cohorts, 4-year BMI change per 10-risk allele increment was −0.02 kg/m2 among participants with greatest increase in physical activity and 0.24 kg/m2 among those with greatest decrease in physical activity (P for interaction < 0.001), corresponding to 0.01 kg versus 0.63 kg weight changes every 4 years (P for interaction = 0.001). Similar but marginal interactions were observed for the BMI-GRS (P for interaction = 0.045). Our data indicate that the genetic susceptibility to weight gain may be diminished by increasing physical activity.

Objectives This study aimed to examine whether a history of asthma from childhood is associated with left ventricular (LV) mass in adulthood. Background Asthma has been related to various cardiovascular risk factors affecting LV hypertrophy. The authors saw a need for a prospective study to analyze the relationship between a history of asthma from childhood and markers of LV mass among asymptomatic young adults. Methods Prospective analyses were performed among 1,118 Bogalusa Heart Study participants (average age at follow-up 36.7 ± 5.1 years), with a baseline history of self-reported asthma collected since childhood (average age at baseline 26.8 ± 10.1 years). LV mass (g) was assessed using 2-dimensional guided M-mode echocardiography and was indexed for body height (m2.7) as LV mass index (LVMI; g/m2.7). A multivariate linear mixed model was fitted for the repeated measures. Results After an average of 10.4 ± 7.5 years of follow-up, participants with a history of asthma from childhood had a greater LV mass (167.6 vs. 156.9; p = 0.01) and LVMI (40.7 vs. 37.7; p Conclusions The findings of this study indicate that a history of asthma is associated with higher LVMI, and this association is stronger among participants with pre-hypertension and hypertension.

Salivary and pancreatic amylases (encoded by AMY1 and AMY2 genes, respectively) are responsible for digesting starchy foods. AMY1 and AMY2 show copy number variations that affect differences in amylase amount and activity, and AMY1 copies have been associated with adiposity. We investigated whether genetic variants determining amylase gene copies are associated with 2-year changes in adiposity among 692 overweight and obese individuals who were randomly assigned to diets varying in macronutrient content. We found that changes in body weight (BW) and waist circumference (WC) were significantly different according to the AMY1-AMY2 rs11185098 genotype. Individuals carrying the A allele (indicating higher amylase amount and activity) showed a greater reduction in BW and WC at 6, 12, 18, and 24 months than those without the A allele (P < 0.05 for all). The association was stronger for long-term changes compared with short-term changes of these outcomes. The genetic effects on these outcomes did not significantly differ across diet groups. In conclusion, the genetic variant determining starch metabolism influences the response to weight-loss dietary intervention. Overweight and obese individuals carrying the AMY1-AMY2 rs11185098 genotype associated with higher amylase activity may have greater loss of adiposity during low-calorie diet interventions.

Background: Previous studies have indicated that the cardioprotective effects of long-chain (LC) n-3 (ω-3) polyunsaturated fatty acids (PUFAs) may vary across various ethnic populations. Emerging evidence has suggested that the gene-environment interaction may partly explain such variations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was shown to have a mutually regulating relation with LC n-3 PUFAs and also to reduce the risk of cardiovascular diseases (CVDs). Therefore, we hypothesized that certain PCSK9 genetic variants may modify the association between LC n-3 PUFA intake and CVD risk.Objective: We determined whether a PCSK9 variant (rs11206510), which has been identified for early onset myocardial infarction (MI), modified the association of LC n-3 PUFAs with nonfatal MI risk in Costa Rican Hispanics.Design: We analyzed cross-sectional data from 1932 case subjects with a first nonfatal MI and 2055 population-based control subjects who were living in Costa Rica to examine potential gene-environment interactions. Two-sided P values

OBJECTIVE: The purpose of this study was to estimate the associations of genetically determined maternal blood glucose levels with obesity-related outcomes among children from pregnancies with and without gestational diabetes mellitus (GDM). METHODS: A total of 1,114 mothers with (N = 560) and without (N = 554) GDM and their children were included in the present study. A maternal genetic risk score (GRS) for blood glucose was constructed on the basis of 17 single-nucleotide polymorphisms identified from a recent genome-wide association study. RESULTS: It was found that maternal GRS for blood glucose showed different associations with offspring risk of overweight and obesity, as well as adiposity measures (all P (for interaction) < 0.05). Among mothers without GDM, genetically determined maternal blood glucose levels were associated with an 89% higher risk of overweight in their children (95% CI: 42%−152% per SD increase in GRS, P = 1.40 × 10(−5)) and a 120% higher risk of obesity (44%−235%, P = 2.61 × 10(−4)) after adjustment for covariates. In addition, higher maternal GRS for blood glucose was associated with children’s increased obesity-related traits (all P < 0.05). However, no significant associations were observed among children of mothers with GDM. CONCLUSIONS: This study indicates that GDM status may modify the relation between genetically determined glucose levels and obesity risk among children.

Introduction: Lower educational attainment is one of the major socioeconomic factors contributing to cardiovascular diseases (CVD); higher education tends to be associated with healthier behaviors and lower risk of CVD. However, whether education plays a causal role in adherence to a healthy lifestyle, and if there is causality, how much of the education-CVD association is mediated by the lifestyle factors, has not been established. Methods: A healthy lifestyle score was constructed on body mass index, smoking status, physical activity, and diet. The causal relations between educational attainment and adherence to a healthy lifestyle was assessed by two-sample Mendelian Randomization analyses using summary statistics for single nucleotide polymorphisms (SNPs) identified from a genome-wide association study (GWAS) of educational attainment (N=1,131,881) and the UK Biobank cohort (N=425,770). We further performed mediation analyses to quantify the effect of educational attainment on the risk of CVD through healthy lifestyle among 386,442 participants in UK Biobank. Results: We found a significant positive causal relationship between years of education and adherence to a healthy lifestyle, independent of age, sex, alcohol intake, and person’s socioeconomic status. In addition, we found that adherence to favorable lifestyle mediated a 42.1%, 40.3%, and 33.5% reduction in the incidence of coronary heart disease (CHD), CVD events, and CVD mortality, respectively (all p Conclusions: Our results indicate that educational attainment is causally associated with adherence to a healthy lifestyle, which in turn, mediates a significant proportion of the effect of educational attainment on cardiovascular events.

Aims To quantify the association of combined sleep behaviours and genetic susceptibility with the incidence of cardiovascular disease (CVD). Methods and results This study included 385 292 participants initially free of CVD from UK Biobank. We newly created a healthy sleep score according to five sleep factors and defined the low-risk groups as follows: early chronotype, sleep 7–8 h per day, never/rarely insomnia, no snoring, and no frequent excessive daytime sleepiness. Weighted genetic risk scores of coronary heart disease (CHD) or stroke were calculated. During a median of 8.5 years of follow-up, we documented 7280 incident CVD cases including 4667 CHD and 2650 stroke cases. Compared to those with a sleep score of 0–1, participants with a score of 5 had a 35% (19–48%), 34% (22–44%), and 34% (25–42%) reduced risk of CVD, CHD, and stroke, respectively. Nearly 10% of cardiovascular events in this cohort could be attributed to poor sleep pattern. Participants with poor sleep pattern and high genetic risk showed the highest risk of CHD and stroke. Conclusion In this large prospective study, a healthy sleep pattern was associated with reduced risks of CVD, CHD, and stroke among participants with low, intermediate, or high genetic risk.

BackgroundChemerin is highly expressed in the serum, placenta tissue, and umbilical cord blood of diabetic mother; however, the impact of chemerin on cognitive disorders of offspring from mothers with diabetes in pregnancy remains unclear.MethodsA diabetic phenotype in pregnant mice dams was induced by streptozocin (STZ) injection or intraperitoneal injection of chemerin. Behavioral changes in offspring of diabetic dams and nondiabetic controls were assessed, and changes in chemerin, two receptors of chemerin [chemerin receptor 23 (ChemR23) and chemokine (C-C motif) receptor-like 2 (CCRL2)], macrophages, and neurons in the brain tissue were studied to reveal the underlying mechanism of the behavioral changes.ResultsChemerin treatment mimicked the STZ-induced symptom of maternal diabetes in mice along with the altered behavior of offspring in the open field test (OFT) assay. In the exploring process for potential mechanism, the brain tissues of offspring from chemerin-treated dams were observed with an increase level of macrophage infiltration and a decrease number of neuron cells. Moreover, an increased level of NOD-like receptor family pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like (Asc) protein as well as pyroptosis [characterized by increased active caspase-1 content and secretion of cytokines such as interleukin (IL) 1 beta (IL-1β) and IL-18] more activated in macrophages is also observed in the brain of these diabetic dam’s offspring, in the presence of ChemR23. In vitro, it was found that pyroptosis activation was increased in macrophages separated from the abdominal cavity of normal mice, after chemerin treatment. However, depletion of CCRL2 decreased the level of chemerin in the brain tissues of diabetic dams’ offspring; depletion of ChemR23 decreased macrophage pyroptosis, and depletion of either receptor reversed chemerin-mediated neurodevelopmental deficits and cognitive impairment of offspring of diabetic pregnant dams.ConclusionsChemerin induced diabetic pregnant disease and CCRL2 were required to enrich chemerin in the brain of offspring. Aggregation of chemerin could lead to macrophage recruitment, activation of pyroptosis, the release of inflammatory cytokines, a decrease in the number of neurons, and cognitive impairment in offspring in a ChemR23-dependent manner. Targeting CCRL2 and/or ChemR23 could be useful for treating neuropsychological deficits in offspring of dams with diabetes in pregnancy.

OBJECTIVE Glucosamine is a widely used supplement typically taken for osteoarthritis and joint pain. Emerging evidence suggests potential links of glucosamine with glucose metabolism, inflammation, and cardiometabolic risk. We prospectively analyzed the association of habitual glucosamine use with risk of type 2 diabetes (T2D) and assessed whether genetic susceptibility and inflammation status might modify the association. RESEARCH DESIGN AND METHODS This study analyzed 404,508 participants from the UK Biobank who were free of diabetes, cancer, or cardiovascular disease at baseline and completed the questionnaire on supplement use. Cox proportional hazards models were used to evaluate the association between habitual use of glucosamine and risk of incident T2D. RESULTS During a median of 8.1 years of follow-up, 7,228 incident cases of T2D were documented. Glucosamine use was associated with a significantly lower risk of T2D (hazard ratio 0.83, 95% CI 0.78–0.89) after adjustment for age, sex, BMI, race, center, Townsend deprivation index, lifestyle factors, history of disease, and other supplement use. This inverse association was more pronounced in participants with a higher blood level of baseline C-reactive protein than in those with a lower level of this inflammation marker (P-interaction = 0.02). A genetic risk score for T2D did not modify this association (P-interaction = 0.99). CONCLUSIONS Our findings indicate that glucosamine use is associated with a lower risk of incident T2D.

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.

Objective To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes. Design Individual participant data meta-analysis. Data sources Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. Review methods Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. Results Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I 2 =7.1%, τ 2 =0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I 2 =18.0%, τ 2 =0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I 2 =58.8%, τ 2 =0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I 2 =25.9%, τ 2 =0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. Conclusions These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.

Background: Recent evidence has related high levels of plasma branch-chained amino acids (BCAAs) with liver and visceral fat. We examined the associations of plasma BCAAs with liver fat and abdominal fat distribution and assessed the potential modification of weight-loss diet interventions on these relations. Methods: The current study included 184 participants with available data on plasma BCAAs, hepatic fat and abdominal fat distribution over 2 years, who were randomly assigned to 1 of 4 diets varying in macronutrient components. Results: Decrease in plasma BCAAs after weight loss was significantly associated with improvement in hepatic density (a marker for hepatic fat; p=0.03) and reduction in visceral fat (p=0.01). We also found that a decrease in BCAAs was associated with decreased insulin, HOMA-IR, and triglycerides (p Conclusion: Our findings indicate that weight-loss diets decrease BCAAs, which are in turn associated with the reduction of hepatic and visceral fat. Finally, dietary protein modifies the direction of these associations. Disclosure X. Li: None. D. Sun: None. T. Zhou: None. G. Bray: Advisory Panel; Self; Herbalife International of America, Inc., Medifast. F. Sacks: None. L. Qi: None. Funding National Heart, Lung, and Blood Institute (HL0791981, HL034594, HL126024); National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, DK100383, DK078616); Boston Nutrition Obesity Research Center (DK46300); United States-Israel Binational Science Foundation (2011036); American Heart Association (0730094N to L.Q.)

Prenatal exposure to maternal smoking (MS) and genetic predisposition to obesity have been related to an increased risk of developing type 2 diabetes (T2D), individually; however, little is known about whether these risk factors may interact with each other. This study included 394867 European participants in UK Biobank. Three types of adiposity polygenetic score (PGS) were created based on 97, 66, and 12 genetic loci associated with BMI, waist-to-hip ratio adjusted for BMI (WHRadjBMI), and percentage of body fat (PBF). The adjusted odds ratio (OR) of MS for T2D was 1.25 (95% CI: 1.21-1.28), and ORs for T2D were 1.09 (1.08-1.11), 1.07 (1.05-1.08), and 1.02 (1.01-1.04) per one SD increment of BMI-, WHRadjBMI-, and PBF- PGS. The joint associations of MS and a higher adiposity genetic susceptibility for T2D were 1.52 (1.45-1.60), 1.43 (1.36-1.50), and 1.35 (1.28-1.41), respectively. The estimated proportions of the joint association were 45.1% for MS alone, 28.4% for genetic susceptibility to obesity alone, and 26.5% for their additive interaction. Our results indicate that the increased risk of T2D due to the joint association of MS and adiposity genetic predisposition was greater than each factor. Our findings extend our knowledge on the synergistic contribution of prenatal factors and genetic make-up to adiposity on T2D risk, and re-emphasize the importance of smoking cessation around pregnancy in women. Disclosure D. Sun: None. T. Zhou: None. X. Li: None. Y. Heianza: None. L. Qi: None. Funding National Heart, Lung, and Blood Institute (HL0791981, HL034594, HL126024); National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK078616); Boston Nutrition Obesity Research Center (DK46200); United States-Israel Binational Science Foundation (2011036)

Objective To prospectively assess the association of habitual glucosamine use with risk of cardiovascular disease (CVD) events. Design Prospective cohort study. Setting UK Biobank. Participants 466 039 participants without CVD at baseline who completed a questionnaire on supplement use, which included glucosamine. These participants were enrolled from 2006 to 2010 and were followed up to 2016. Main outcome measures Incident CVD events, including CVD death, coronary heart disease, and stroke. Results During a median follow-up of seven years, there were 10 204 incident CVD events, 3060 CVD deaths, 5745 coronary heart disease events, and 3263 stroke events. After adjustment for age, sex, body mass index, race, lifestyle factors, dietary intakes, drug use, and other supplement use, glucosamine use was associated with a significantly lower risk of total CVD events (hazard ratio 0.85, 95% confidence interval 0.80 to 0.90), CVD death (0.78, 0.70 to 0.87), coronary heart disease (0.82, 0.76 to 0.88), and stroke (0.91, 0.83 to 1.00). Conclusion Habitual use of glucosamine supplement to relieve osteoarthritis pain might also be related to lower risks of CVD events.

Zinc transporter 8 genetic variant SLC30A8 has been associated with postpartum risk of type 2 diabetes among women with gestational diabetes mellitus (GDM). Gestational weight gain is one of the strongest risk factors for postpartum hyperglycemia. We assessed the interaction between type 2 diabetes–associated SLC30A8 rs13266634 and gestational weight gain on 1–5 years of postpartum glycemic changes in 1,071 women with prior GDM in a longitudinal study. Compared with gestation of 26–30 weeks, postpartum levels of fasting glucose, oral glucose tolerance test 2-h glucose, and hemoglobin A1c (HbA1c) increased across rs13266634 TT, CT, and CC genotypes in women with excessive gestational weight gain, whereas opposite genetic associations were found in women with inadequate or adequate gestational weight gain. Postpartum changes in fasting glucose per additional copy of the C allele were −0.18, −0.04, and 0.12 mmol/L in women with inadequate, adequate, and excessive gestational weight gain, respectively (P for interaction = 0.002). We also found similar interactions for changes in 2-h glucose and HbA1c (P for interaction = 0.003 and 0.005, respectively). Our data indicate that gestational weight gain may modify SLC30A8 variant on long-term glycemic changes, highlighting the importance of gestational weight control in the prevention of postpartum hyperglycemia in women with GDM.

Although obesity and insulin resistance are closely correlated, their temporal sequences in early life and influence on adult hypertension are largely unknown. This study aims to delineate the temporal relationship patterns between body mass index (BMI) and insulin in childhood and their impact on adult hypertension. The longitudinal cohort consisted of 990 adults (630 whites and 360 blacks) who had BMI and fasting insulin measured twice 5.4 years apart in childhood (mean age, 10.5 years at baseline and 15.9 years at follow-up) and blood pressure measured 14.7 years later in adulthood (mean age, 30.5 years). Cross-lagged panel and mediation analysis models were used to examine the temporal relationship between childhood BMI and insulin and its impact on adult hypertension. After adjusting for age, race, sex, and follow-up years, the cross-lagged path coefficient (β=0.33; P P >0.05) from baseline insulin to follow-up BMI in childhood with P P P P P

Adiponectin has a pivotal role in linking fat distribution with cardiometabolic disorders. We investigated the associations of long-term changes in circulating adiponectin with body composition and fat distribution at different abdominal depots in response to weight-loss dietary interventions, as well as the modification effect of sex.In the 2-year Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial, 811 overweight or obese adults were randomly assigned to one of four diets varying in macronutrient intakes. Circulating concentrations of adiponectin were repeatedly measured at baseline, 6 months and 2 years. Body composition and fat distribution were repeatedly measured by dual-energy X-ray absorptiometry scan (n=424) and computed tomography (n=195).Over the 2-year intervention, after adjustment for age, sex, ethnicity, follow-up time, diet group, baseline body mass index and baseline level of respective outcome trait, increase of adiponectin was significantly associated with reduction of total fat mass (FM), total fat-free mass (FFM), whole body total percentage of fat mass (FM%), percentage of trunk fat (TF%), total adipose tissue (TAT), and adipose tissue mass at different depots including visceral (VAT), deep subcutaneous (DSAT) and superficial subcutaneous (SSAT; P0.03 for each). The relations with FM, FM%, TF%, VAT and DSAT were significantly modified by sex (P for interaction=0.02, 0.005 and0.001, 0.002, 0.03, respectively) with greater reductions associated with increase of adiponectin in men than in women.Long-term changes in circulating adiponectin were differentially associated with improvement of body composition and abdominal fat distribution in men and women.

BACKGROUND Pregnancy-induced hypertension (PIH) causes increased risk of maternal, fetal, and neonatal morbidity and mortality. Identification of risk factors for PIH in early life is central to the development of prevention strategies. METHODS A cohort of 703 women aged 25.5-51.3 years from the Bogalusa Heart Study were included. PIH were defined as self-reported hypertension during pregnancy and a blood pressure level

Importance: Obesity has been related to sedentary lifestyle, and an increased risk of coronary heart disease (CHD); however, no study has assessed the causal link between obesity, sedentary lifestyle, and CHD. Objective: To examine whether BMI is causally associated with sedentary lifestyle, and quantify the mediation effects of sedentary lifestyle in the relation between BMI and CHD. Method: Sedentary lifestyle was quantified by hours spent on sedentary behaviors including TV watching, using computer (not at work) and driving. We tested the causality between BMI and sedentary lifestyle by Mendelian randomization (MR) analysis using 77 BMI related single-nucleotide polymorphisms (SNP) as the instrumental variable, among 401,876 white British participants (enrolled from 2006 to 2010) from the UK Biobank. A further mediation analysis was performed to assess the relations between BMI, sedentary lifestyle, and CHD risk among 366,370 participants with 3,816 incident CHD cases (followed up to 2016). Result: The MR analysis showed that there was a causal relation between BMI and sedentary lifestyle. One standard deviation increment in BMI causally resulted in 0.38 increase in the sedentary hour (p Conclusion: Our results indicate that high BMI is causally associated with increased hours of sedentary lifestyle, which mediate a significant proportion of the CHD risk associated with high BMI.

Introduction: Plant-based diets include beneficial nutrients for the prevention of obesity and cardiovascular disease (CVD). No study has assessed interactions between a new healthful plant-based diet index (hPDI) and genetic predisposition to obesity in relation to adiposity and its related metabolic abnormalities. Hypothesis: We assessed the hypothesis that adherence to healthy plant-based diets would modify the genetic risk of obesity, and people at genetically higher risk of obesity would be more susceptible to the healthy diets for improving obesity and cardiovascular health. Methods: This study included 160184 participants initially free of CVD (myocardial infarction or stroke), diabetes, and cancer. We calculated the hPDI in which healthy plant foods received positive scores and the other foods received negative scores based on previous studies. A genetic risk score (GRS) of obesity was created based on 75 SNPs for BMI. Outcome measures included differences in BMI and mean arterial blood pressure (MAB), untreated hypertension (systolic blood pressure ≥130 mmHg, diastolic blood pressure ≥80 mmHg without antihypertensive medication use), and the 5-year incidence of CVD. Results: Higher hPDI was related to lower risks of obesity and untreated hypertension among the total study participants. We found a significant interaction between GRS and hPDI for BMI (Pinteraction Conclusions: Adherence to the healthy plant-based dietary pattern significantly attenuated genetic association with obesity. People at genetically higher risk of obesity may be more susceptible to benefits of healthy plant-based diets in improving adiposity and cardiovascular health.

Introduction: Being obese has been related to changes in physical fitness, such as pace-speed declination, which was recently associated with increased coronary heart disease (CHD) risk. The causal link between obesity, walking pace declination, and CHD remains to be established. Hypothesis: High BMI is causally related to slower walking pace, and the relationship between high BMI and CHD that is mediated by altered walking pace. Methods: Data form UK biobank including 408,836 white British participants (enrolled from 2006 to 2010) was used in this study. The usual walking pace was self-reported as slow, steady/average, and brisk, among 352,663 participants with 3,634 CHD cases (enrolled from 2006 to 2010 and followed up to 2016). The causal relation between BMI and walking pace was assessed by Mendelian randomization analysis using 97 BMI related single-nucleotide polymorphisms. A further mediation analysis was performed to assess the association between BMI, walking pace, and incident CHD. Results and Conclusions: In Mendelian randomization analysis performed among 408,836 individuals in the UK Biobank (baseline mean [SD] age, 56.8 [8.0] years; 54.1% (221,196 of 408,836) women), we found a significant causal relationship between genetically instrumented higher BMI and slower walking pace (odds ratio: 1.58, 95% CI: 1.45-1.71, per 1 SD increase in BMI), independent of age, sex, socioeconomic status, alcohol intake, and smoking. In mediation analysis, we found that slow and average walking pace was estimated to mediate 29% and 19% of the association between BMI and incident CHD, respectively, compared with brisk walking pace (p

Ligustrum robustum (LR) shows antiobesity effects in animal studies. However, little is known about the effect on human. The present study aimed to investigate the effect of LR intake on weight change in obese women and the role of gut microbiota. Thirty overweight and obese female participants (BMI ≥24 kg/m2) were recruited in the current study. The participants drank LR 10g/d for 12 wks. Their body composition and related biomarkers were assessed. Alterations of the gut microbiota were analyzed using 16S rRNA sequencing. The primary outcome was the change in body weight. LR intake resulted in 2.5% weight loss over 12 wks (P Bacteroidaceae, Bacteroides, Bacilli, and Lactobacillales were higher while Ruminococcaceae, Enterobacteriaceae, Enterobacteriales, Lachnospiraceae, Clostridia, and Clostridiales were lower at 12 wk. Moreover, LR intervention decreased fasting glucose (Pβ (P LR intervention moderately decreased the body weight in overweight and obese women and such effect might be due to modulation of gut microbiota.

Background: The associations of age-related changes in body weight and waist circumferences with cardiovascular disease (CVD) and mortality remain unclear. Methods: We assessed changes in weight and waist circumference from baseline survey and resurvey among 27 964 participants in the China Kadoorie Biobank (CKB, 2004-2008) and Dongfeng-Tongji Cohort (DF-TJ, 2008-2013). We used Cox proportional hazards models to evaluate the associations between adiposity changes and the subsequent risks of incident CVD, CVD mortality and all-cause mortality. Findings: On average, during a median of 3·4 years from baseline to resurvey, participants experienced a weight loss of 0·6 kg, accompanied by a 2·1 cm increase in waist circumference. We identified 3589 incident CVD cases, 485 CVD deaths, and 1283 all-cause deaths during the follow-up in the CKB (2008-2016) and DF-TJ (2013-2016). Weight loss and waist gain were associated with increased risks of those outcomes in the two cohorts. In particular, compared with participants who had stable waist (waist change -2·0 to 7·0 cm) and weight (weight change -2·5 to 2·5 kg), those who gained waist but lost weight (waist circumference change >7·0 cm, weight change ≤ -2·5 kg) had the highest risk of incident CVD, CVD mortality and all-cause mortality, with the pooled multivariate hazard ratios (HRs) of 1·41 (95% CI, 1·13 to 1·75), 2·48 (1·40 to 4·37), and 1·71 (1·16 to 2·51), respectively. Among the weight-stable participants, waist circumference was linearly associated with CVD risk, with 17% higher risk (HR 1·17, 1·04 to 1·32) for those gained waist while 13% lower risk (HR 0·87, 0·77 to 0·99) for those lost waist compared to waist-stable participants. Interpretation: Increased waist circumference with concurrent weight loss is significantly associated with increased risks of CVD morbidity, CVD mortality, and all-cause mortality among Chinese middle-aged and elderly adults. Funding Statement: This work was partly supported by grants from the Foundation of National Key Programs of Research and Development of China (2016YFC0900800, 2016YFC0900500, 2017YFC0907501 and 2017YFC0907504), the National Natural Science Foundation of China (91643202 and 81390540), the 111 Project and the Program for Changjiang Scholars and Innovative Research Team in University. The China Kadoorie Biobank baseline survey and the first resurvey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up has been supported by the UK Wellcome Trust (grants 088158/Z/09/Z, 104085/Z/14/Z), and the Chinese Ministry of Science and Technology (2011BAI09B01). The British Heart Foundation, UK Medical Research Council, and Cancer Research provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The CKB study was approved by the ethics committees or institutional review boards at the University of Oxford, the Chinese Center for Disease Control and Prevention (China CDC), the Chinese Academy of Medical Sciences. The DF-TJ cohort was approved by the ethics committees of Tongji Medical College and the Sinopharm Dongfeng General Hospital. All participants provided written informed consents.

Gut microbiota alterations may be related to insulin resistance, diabetes, and the impaired amino acid metabolism. We investigated whether changes in gut microbiota metabolite of trimethylamine N-oxide (TMAO) and its precursors (choline and L-carnitine) were associated with improvements of diabetes-related traits and diabetes-risk-related amino acids in a weight-loss diet intervention. This study included 504 obese adults who were randomly assigned to 1 of 4 energy-reduced diets varying in the macronutrient composition. We calculated changes (Δ) in TMAO, choline, and L-carnitine from baseline to 6 months after the diet intervention. Greater decreases in choline and L-carnitine were significantly (p In conclusion, weight-loss-diet-induced changes in TMAO, choline, and L-carnitine were significantly associated with the improvements in glycemia and insulin sensitivity, regardless concurrent changes in diabetes-risk related amino acids. Dietary fat intake may modify the associations of changes in TMAO with the improvements of diabetes-related traits. Disclosure Y. Heianza: None. D. Sun: None. G. Bray: Advisory Panel; Self; Herbalife International of America, Inc., Novo Nordisk A/S. L. Qi: None.

Type 2 diabetes is one of the most common chronic diseases in the U.S.; however, few studies have comprehensively assessed the relations between its comorbidities and premature death. Prospective analyses were performed linking data from National Health Interview Surveys (1997 to 2009) to National Death Index records (2011) among 366,971 adults. Cox models were used to test the relations of diabetes and eleven comorbidities with all-cause, CVD, or cancer mortality. After a median follow-up of 8.0 years (2.9 million person-years), a total of 38,687 participants had died. Compared with common-conditions-free subjects, we ranked hazard ratios (HR[95% CI]) of eleven diabetic comorbidities, and the top three were chronic kidney disease (CKD: 5.3[4.9-5.7]), liver cirrhosis (5.1[4.6-5.8]), and blindness (4.4[3.8-5.1]) for all-cause mortality. Diabetics with CKD (5.9[5.0-6.9]) and blindness (5.0[3.8-6.5]) were at the highest risk for CVD deaths. Comorbid cancer (4.1[3.6-4.6]), liver cirrhosis (4.1[3.2-5.2]), and hepatitis (2.7[2.1-3.5]) ranked top three for cancer mortality. Diabetes comorbidities may substantially increase the risk of all-cause, CVD, or cancer mortality. Liver disease is more strongly related to cancer mortality, whereas CKD and blindness with CVD. Recognition of these associations may assist with more appropriate and effective screening programs that may help decrease associated mortality. Disclosure D. Sun: None. T. Zhou: None. X. Li: None. Y. Heianza: None. X. Shang: None. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis. L. Qi: None.

Diabetes affected over 30 million U.S. adults in 2015, and its comorbidities remained among the leading causes of premature death and reduced quality of life. However, little is known about the secular trend of diabetes comorbidities in the last 20 years. Sample-weighted prevalence of twelve common comorbidities of diabetes was estimated using data from 52,842 adults aged ≥18 years who had diabetes in the National Health Interview Survey from 1997 through 2016, with age-standardized to the 2000 U.S. population. We ranked the prevalence [% (SE)] of twelve diabetes comorbidities, and the top five were hypertension [53.7(3.1)], arthritis [33.2(3.1)], asthma [17.2(2.9)], coronary heart disease [CHD: 14.4(2.3)]), and chronic obstructive pulmonary disease [COPD: 9.1(2.3)]. From 1997 to 2016, the estimated prevalence (%) of diabetes comorbidities including hypertension (47.8 to 59.7), asthma (13.2 to 21.0), cancer (7.6 to 10.4), and liver cirrhosis (3.0 to 4.1) continuingly increased (P Disclosure D. Sun: None. T. Zhou: None. X. Li: None. Y. Heianza: None. X. Shang: None. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis. L. Qi: None.

In this issue of the Journal, Chen et al. (Am J Epidemiol. 2016;183(7):599–608) present repeated measures of aorto-femoral pulse wave velocity, capacitive compliance (C1), and oscillatory compliance (C2) in the Bogalusa Heart Study, with the purpose of addressing which comes first: blood pressure elevation or arterial stiffening. After an average follow-up period of 7 years (2000–2010), the authors found that blood pressure at a mean age of 36 years predicted change in arterial stiffening by a mean age of 43 years, but not the reverse. Essential hypertension results from a mosaic of pathological mechanisms. It has been theorized that biological pathways involving increased sympathetic tone, insulin resistance, renin-angiotensin-aldosterone activation, and inflammation lead to hyperkinetic circulation, volume overload, and vascular remodeling. The resultant accelerated vascular aging may be assessed by determining the degree of arterial stiffness. The findings of Chen et al. add important empirical information to the literature but do not solve the dilemma regarding the origins of essential hypertension, partly because there are many techniques for estimating the many aspects of arterial stiffness which are not fully understood. Mathematical features of estimates might not be uniform across the age range. There is a need for tracking blood pressure and different aspects of arterial stiffness from childhood onward, with an aim of preventing hypertension in adult life.