Sp1-activated FGFR2 is involved in early-life exposure to nickel-induced craniosynostosis by regulating the ERK1/2 signaling pathway.

Nickel, a common environmental hazard, is a risk factor for craniosynostosis. However, the underlying biological mechanism remains unclear. Here, we found that early-life nickel exposure induced craniosynostosis in mice. In vitro, nickel promoted the osteogenic differentiation of human mesenchymal stem cells (hMSCs), and its osteogenic ability in vivo was confirmed by an ectopic osteogenesis model. Further mRNA sequencing showed that ERK1/2 signaling and FGFR2 were aberrantly activated. FGFR2 was identified as a key regulator of ERK1/2 signaling. By promoter methylation prediction and methylation-specific PCR (MSP) assays, we found that nickel induced hypomethylation in the promoter of FGFR2, which increased its binding affinity to the transcription factor Sp1. During pregnancy and postnatal stages, AZD4547 rescued nickel-induced craniosynostosis by inhibiting FGFR2 and ERK1/2. Compared with normal individuals, nickel levels were increased in the serum of individuals with craniosynostosis. Further logistic and RCS analyses showed that nickel was an independent risk factor for craniosynostosis with a nonlinear correlation. Mediated analysis showed that FGFR2 mediated 30.13% of the association between nickel and craniosynostosis risk. Collectively, we demonstrate that early-life nickel exposure triggers the hypomethylation of FGFR2 and its binding to Sp1, thereby promoting the osteogenic differentiation of hMSCs by ERK1/2 signaling, leading to craniosynostosis.

PPARα Senses Bisphenol S to Trigger EP300-Mediated Autophagy Blockage and Hepatic Steatosis.

The internal exposure dose of bisphenol S (BPS) is increasing since its use as a substitute for BPA. The relationship between BPS and nonalcoholic liver disease (NAFLD) and the underlying mechanism remain unclarified. In this study, we evaluated the correlation of BPS with NAFLD in populations from the Jiangsu Survey and the 2013-2016 National Health Nutrition Examination Survey and unraveled the molecular pathway by which BPS blocked hepatic autophagy, contributing to lipid accumulation. The study found that serum and urine BPS were associated with NAFLD risks in both the Chinese and US populations. For each additional unit of the BPS level, the NAFLD risk increased by 3.163-fold (serum) and 3.979-fold (urine) in the Chinese population. In addition, after BPS exposure at a dose equivalent to human exposure for 20 weeks, mice developed liver lipid accumulation. BPS could trigger PPARα-mediated transcriptional activation of EP300 expression. BPS promoted the translocation of EP300 from the nucleus to the cytoplasm to regulate the acetylation of Raptor and the activation of mTORC1, which in turn induced autophagy blockage and interfered with lipid degradation in hepatocytes. Conversely, knockdown of EP300 reduced Raptor acetylation and ameliorated autophagy blockage. This study demonstrated that EP300 was a key enzyme for the development of BPS-related NAFLD and provided novel evidence that BPS causes NAFLD.

Association of air pollution exposure and increased coronary artery disease risk: the modifying effect of genetic susceptibility.

BACKGROUND: Both genetic factors and air pollution are risk factors for coronary artery disease (CAD), but their combined effects on CAD are uncertain. The study aimed to comprehensively investigate their separate, combined and interaction effects on the onset of CAD. METHODS: We utilized data from the UK Biobank with a recruitment of 487,507 participants who were free of CAD at baseline from 2006 to 2010. We explored the separate, combined effect or interaction association among genetic factors, air pollution and CAD with the polygenic risk score (PRS) and Cox proportional hazard models. RESULTS: The hazard ratios (HRs) [95% confidence interval (CI)] of CAD for 10-µg/m3 increases in PM2.5, NO2 and NOx concentrations were 1.25 (1.09, 1.44), 1.03 (1.01, 1.05) and 1.01 (1.00, 1.02), respectively. Participants with high PRS and air pollution exposure had a higher risk of CAD than those with the low genetic risk and low air pollution exposure, and the HRs (95% CI) of CAD in the PM2.5, PM10, NO2 and NOx high joint exposure groups were 1.56 (1.48, 1.64), 1.55(1.48, 1.63), 1.57 (1.49, 1.65), and 1.57 (1.49, 1.65), respectively. Air pollution and genetic factors exerted significant additive effects on the development of CAD (relative excess risk due to the interaction [RERI]: 0.12 (0.05, 0.19) for PM2.5, 0.17 (0.10, 0.24) for PM10, 0.14 (0.07, 0.21) for NO2, and 0.17 (0.10, 0.24) for NOx; attributable proportion due to the interaction [AP]: 0.09 (0.04, 0.14) for PM2.5, 0.12 (0.07, 0.18) for PM10, 0.11 (0.06, 0.16) for NO2, and 0.13 (0.08, 0.18) for NOx). CONCLUSION: Exposure to air pollution was significantly related to an increased CAD risk, which could be further strengthened by CAD gene susceptibility. Additionally, there were positive additive interactions between genetic factors and air pollution on the onset of CAD. This can provide a more comprehensive, precise and individualized scientific basis for the risk assessment, prevention and control of CAD.

Early-life exposure to lead changes cardiac development and compromises long-term cardiac function.

Lead (Pb) is widely used in industrial and daily-use consumer products. Early-life exposure may increase the risk of lead-related heart problems in childhood. However, the effects of early-life lead exposure on fetal heart development and long-term cardiac outcomes are unknown. In this study, pregnant ICR mice were exposed to lead acetate trihydrate (50 mg/kg/d) via oral gavage from gestation day 1.5 until offspring weaning. Thereafter, the second hit model was established, two groups of offspring (4 weeks old) were either administered sterile saline or Angiotensin II (Ang II) for 4 weeks until euthanasia. We investigated lead-induced offspring heart damage from embryonic period to adulthood by echocardiographic analysis, pathological H&E staining, and ultrastructural examination, as well as mitochondrial function detection. The results showed early-life lead exposure predisposed offspring mice to decreased ejection fraction, increased left ventricular volume, accompanied by hypertrophy and dilation, cardiomyocyte sarcomere dysplasia, abnormal mitochondrial structure, mitochondrial dysfunction, and decreased expression of key sarcomeric and mitochondrial genes, rendering them more susceptible to cardiac hypertrophy, vascular wall thickening, cardiac fibrosis, apoptosis, and heart failure induced by Ang II infusion. This study elucidates early-life low dose lead exposure compromises cardiac development and exacerbates second hit-induced cardiac pathological responses in adulthood, which furnishes crucial scientific evidence pertaining to the cardiac toxicity and risk evaluation associated with early-life exposure to lead.

The Association of Metabolomic Profiles of a Healthy Lifestyle with Heart Failure Risk in a Prospective Study.

Lifestyle has been linked to the incidence of heart failure, but the underlying biological mechanisms remain unclear. Using the metabolomic, lifestyle, and heart failure data of the UK Biobank, we identified and validated healthy lifestyle-related metabolites in a matched case-control and cohort study, respectively. We then evaluated the association of healthy lifestyle-related metabolites with heart failure (HF) risk and the added predictivity of these healthy lifestyle-associated metabolites for HF. Of 161 metabolites, 8 were identified to be significantly related to healthy lifestyle. Notably, omega-3 fatty acids and docosahexaenoic acid (DHA) positively associated with a healthy lifestyle score (HLS) and exhibited a negative association with heart failure risk. Conversely, creatinine negatively associated with a HLS, but was positively correlated with the risk of HF. Adding these three metabolites to the classical risk factor prediction model, the prediction accuracy of heart failure incidence can be improved as assessed by the C-statistic (increasing from 0.806 [95% CI, 0.796-0.816] to 0.844 [95% CI, 0.834-0.854], p-value < 0.001). A healthy lifestyle is associated with significant metabolic alterations, among which metabolites related to healthy lifestyle may be critical for the relationship between healthy lifestyle and HF. Healthy lifestyle-related metabolites might enhance HF prediction, but additional validation studies are necessary.

Association between NMR metabolomic signatures of healthy lifestyle and incident coronary artery disease.

AIMS: To identify metabolites associated with a healthy lifestyle and explore the possible mechanisms of lifestyle in coronary artery disease (CAD). METHODS AND RESULTS: The nuclear magnetic resonance metabolomics platform was applied to perform metabolomic profiling of baseline plasma samples from a randomly selected subset of 121 733 UK Biobank participants. Cox proportional hazards models with covariate adjustments were used to investigate the associations between validated lifestyle-associated metabolites and incident CAD and to estimate the accuracy of the inclusion of metabolites to predict CAD compared with traditional prediction models. The discriminatory ability of each model was evaluated using Harrell's C statistic, integrated discrimination improvement (IDI), and continuous net reclassification improvement (NRI) indexes. During a median of 8.6 years of follow-up, 5513 incident CAD cases were documented. Among the 111 lifestyle-associated metabolites, 65 were significantly associated with incident CAD after multivariate adjustment (Bonferroni P < 3.11 × 10-04). The addition of these metabolites to classic risk prediction models [Framingham Risk Score (FRS) using lipids; FRS using body mass index] improved CAD prediction accuracy as assessed by the C statistic (increasing to 0.739 [95% CI, 0.731-0.747] and 0.752 [95% CI, 0.746-0.758]), respectively; continuous NRI (0.274 [0.227-0.325] and 0.266 [0.223-0.317]) and IDI (0.003 [0.002-0.004] and 0.003 [0.002-0.004]). CONCLUSION: Healthy lifestyle-associated metabolites are associated with the incidence of CAD and may help improve the prediction of CAD risk. The use of metabolite information combined with the FRS model warrants further investigation before clinical implementation.

Interactions among maternal smoking, breastfeeding, and offspring genetic factors on the risk of adult-onset hypertension.

BACKGROUND: Previous studies have reported that maternal smoking during pregnancy and breastfeeding may affect the occurrence of hypertension, but whether early life factors modify the impact of the offspring's genetic risk on hypertension is still unknown. The aim of this study was to investigate the relationships among maternal smoking and breastfeeding with adult-onset hypertension and the modified impact of offspring genetic susceptibility. METHODS: This study included 437,185 participants from the UK Biobank who were initially free of hypertension and provided a prospective cohort of individuals aged 40 to 69 years. The association of maternal smoking during pregnancy and breastfeeding with hypertension was examined by using the Cox regression model. Then, a polygenic risk score (PRS) for hypertension was used to test the gene-environmental interaction on hypertension. RESULTS: During a median follow-up period of 8.7 years, a total of 68,148 cases of hypertension were identified in this study. The hazard ratios (HRs) and 95% confidence intervals (CIs) of hypertension for maternal smoking and breastfeeding were 1.11 (1.09, 1.13) and 0.96 (0.94, 0.98), respectively. However, no evidence of an interaction between maternal smoking and breastfeeding was observed. Across all levels of genetic risk, including high genetic risk, maternal smoking and nonbreastfeeding had higher hypertension hazards than nonmaternal smoking and breastfeeding, respectively. The adjusted HRs (95% CIs) of hypertension were 1.80 (1.73, 1.87) in those who had high genetic predisposition plus maternal smoking and 1.67 (1.60-1.74) in those with nonbreastfeeding and high genetic risk. There were significant additive interactions between maternal smoking or breastfeeding and genetic factors on the incidence of hypertension. CONCLUSIONS: Maternal smoking and nonbreastfeeding were associated with a higher risk of hypertension in adulthood and may attenuate the risk of hypertension related to genetic factors. These results suggested that adherence to nonmaternal smoking and breastfeeding was associated with a lower risk of hypertension among participants with all gradients of genetic risk.

Association of air pollutants and osteoporosis risk: The modifying effect of genetic predisposition.

BACKGROUND: Limited studies have examined the association between air pollutants and osteoporosis incidence; however, the results are conflicting. We aimed to quantify the effects of selected air pollutants on osteoporosis risk and explore the modifying effect of genetic predisposition. METHODS: A total of 422,955 subjects who did not have osteoporosis at baseline in the UK Biobank were included from 2006 to 2010. We conducted a Cox proportional hazards model with adjustment for covariates to examine the association between air pollutant scores and individual air pollutants and incident osteoporosis. Furthermore, a polygenic risk score (PRS) of osteoporosis was built and examined to determine whether genetic susceptibility modified the effect of air pollutants on osteoporosis. The relationship between air pollutants and osteoporosis was examined by using a restricted cubic spline (RCS) method. RESULTS: After confounder adjustment, the results showed a remarkable increase in the risk of osteoporosis with each 10 unit increase in exposure to air pollution (hazard ratio: 1.06, 95 % confidence interval: 1.03-1.08), PM2.5 (1.94, 1.52-2.48), NO2 (1.06, 1.02-1.10), and NOX (1.03, 1.01-1.04). However, no significant association was observed between PM10 or PM2.5-10 exposure and osteoporosis. Subjects with high air pollutant exposure levels and a high PRS had a noteworthy increase in osteoporosis risk compared to those with low air pollutant exposure levels and a low PRS. Air pollutants and genetic variants exerted additive effects on the risk of osteoporosis. Positive correlations were observed between osteoporosis and PM2.5 (P < 0.001), NO2 (P = 0.001), and NOx (P = 0.002) exposure. CONCLUSIONS: Exposure to PM2.5, NO2 and NOx was associated with an increase in osteoporosis risk, and this effect was more pronounced in populations with high genetic risk. The association between PM2.5, NO2 and NOx exposure and osteoporosis is modified by genetic variations.

Association of ambient air pollution exposure with low birth weight.

Increasing evidence has shown that exposure to air pollution is linked to adverse birth outcomes, but the results are not consistent. This study was performed on a subset of participants from the UK Biobank between 2006 and 2010. The land use regression (LUR) model was constructed to calculate the concentrations of particulate matter (PM2.5, PM2.5-10 and PM10), nitrogen oxides (NOx), and nitrogen dioxide (NO2). Binary logistic/multivariate linear regression models were applied to explore the potential linear relationships between air pollution exposure and newborn low birth weight (LBW) or BW. The Cochran-Armitage trend test was used to explore the possible association between the air pollution level and LBW. A restricted cubic spline (RCS) transformation of exposure variables was applied to visualize the relation of air pollutants to BW. Exposure to air pollutants, especially PM2.5 and PM10, was positively associated with LBW, and the odds ratios (ORs) and 95% confidence intervals (CIs) for each 10-µg/m3 increase in PM2.5 and PM10 were 1.25 ([1.03, 1.51], P = 0.025) and 1.12 ([1.02, 1.24], P = 0.021), respectively. A negative correlation was observed between the BW and PM2.5 (-0.05 [-0.08, -0.02], P = 0.001), PM10 (-0.03 [-0.05, -0.02], P < 0.001), PM2.5-10 (-0.04 [-0.07, -0.01], P < 0.001) and NOx (0.00 [0.00, 0.00], P = 0.021). Additionally, the BW changed dramatically up to a specific point (PM2.5 for 10.74 µg/m3, Pnonlinearity = 0.004; PM10 for 16.06 µg/m3, Pnonlinearity = 0.004; NO2 for 25.58 µg/m3, Pnonlinearity <0.001; and NOx for 39.88 µg/m3, Pnonlinearity <0.001), subsequently becoming relatively stable. PM2.5 and PM10 exposure were positively associated with LBW, and a negative correlation was observed between PM2.5, PM2.5-10, PM10 and NOx and BW.

Night Shift Work, Genetic Risk, and Hypertension.

OBJECTIVE: To perform a prospective cohort study to investigate whether night shift work is associated with incident hypertension and whether this association is modified by genetic susceptibility to hypertension because evidence on the association between night shift work and hypertension is insufficient. METHODS: A total of 232,665 participants of UK Biobank who were recruited from 2006 to 2010 and observed to January 31, 2018, were included in this study. A Cox proportional hazards model with covariate adjustment was performed to assess the association between night shift work exposure and hypertension risk. We constructed a polygenic risk score (PRS) for genetic susceptibility to hypertension, which was used to explore whether genetic susceptibility to hypertension modified the effect of night shift work. The robustness of the results was assessed by sensitivity analysis. RESULTS: Night shift workers had a higher hypertension risk than day shift workers, which increased with increasing frequency of night shift work (Ptrend<.001). The association was attenuated but still remained statistically significant in the fully adjusted model. We explored the joint effect of night shift work and genetic susceptibility on hypertension. Permanent night shift workers with higher hypertension PRSs had higher risk of hypertension than day workers with low PRSs. CONCLUSION: Night shift work exposure was associated with increased hypertension risk, which was modified by the genetic risk for hypertension, indicating that there is a joint effect of night shift work and genetic risk on hypertension.

Air pollution, genetic factors and the risk of depression.

Both genetics and ambient air pollutants contribute to depression, but the degree to which genetic susceptibility modifies the effect of air pollution on depression remains unknown. We aimed to investigate the effect of the modification of genetic susceptibility on depression. Notably, 490,780 participants who were free of depression at baseline in the UK Biobank study were recruited from 2006 to 2010. A land use regression (LUR) model was performed to estimate the concentrations of particulate matter with diameters ranging from ≤2.5-≤10 µm (PM2.5, PM2.5-10 and PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx). The International Classification of Diseases 10th Revision (ICD-10) code was used to identify depression cases. Cox proportional hazard models adjusted for covariates were used to investigate the association between ambient air pollutants and depression. Moreover, the polygenic risk score (PRS) was calculated to evaluate cumulative genetic effects, and additive interaction models were established to explore whether genetic susceptibility modified the effects of air pollutants on depression. PM2.5, PM10, NO2 and NOx exposure were significantly positively associated with the risk of depression, and the hazard ratios and 95 % confidence intervals for a 10-µg/m3 increase in PM2.5, PM10, NO2 and NOx concentrations were 2.12 (1.82, 2.47), 1.12 (1.03, 1.23), 1.07 (1.05, 1.10) and 1.04 (1.03, 1.05), respectively. Air pollutants and genetic variants exerted significant additive effects on the risk of depression (relative excess risk due to the interaction [RERI]: 0.15 for PM2.5, 0.12 for PM10, 0.10 for NO2, and 0.12 for NOx; attributable proportion due to the interaction [AP]: 0.12 for PM2.5, 0.10 for PM10, 0.08 for NO2, and 0.09 for NOx). Air pollution exposure was significantly associated with the risk of depression, and participants with a higher genetic risk were more likely to develop depression when exposed to high levels of air pollution.

Shift Work, Genetic Factors, and the Risk of Heart Failure: A Prospective Study of the UK Biobank.

OBJECTIVE: To quantify the association of combined shift work and genetic factors with the incidence of heart failure (HF). PARTICIPANTS AND METHODS: This study included 242,754 participants with complete shift work information in the UK Biobank. Participants were followed from baseline (2006 to 2010) through January 31, 2018. The association between shift work and HF incidence was investigated separately in males and females using a Cox proportional hazards model adjusted for covariates. In addition, we established a polygenic risk score and assessed whether shift work alters genetic susceptibility to HF. RESULTS: The results showed a significant association of permanent night shift work with incident HF among females (hazard ratio, 2.25; 95% CI, 1.34 to 3.76; P=.002) after adjusting for age, and the association was attenuated in the fully adjusted model. Among men, we did not detect an association between shift work and HF. In addition, we observed that the association between the risk of HF and shift work was strengthened by high genetic risk. Permanent night shift work paired with high genetic risk, compared with low genetic risk, was suggested to be associated with the risk of HF in females (hazard ratio, 2.89; 95% CI, 1.05 to 7.94) but not in males. CONCLUSION: Shift work, particularly permanent night shift work, may increase the risk of HF in females, especially in those with high genetic risk.

Associations of genetic risk factors and air pollution with incident hypertension among participants in the UK Biobank study.

The purposes of this study were to quantify the association of the combination of air pollution and genetic risk factors with hypertension and explore the interactions between air pollution and genetic risk. This study included 391,366 participants of European ancestry initially free from pre-existing hypertension in the UK Biobank. Exposure to ambient air pollutants, including particulate matter (PM2.5 PM2.5-10, and PM10), nitrogen dioxide (NO2) and nitrogen oxides (NOX), was estimated through land use regression modelling, and the associations between air pollutants and the incidence of hypertension were investigated using a Cox proportional hazards model adjusted for covariates. Furthermore, we established a polygenic risk score for hypertension and assessed the combined effect of genetic susceptibility and air pollution on incident hypertension. The results showed significant associations between the risk of hypertension and exposure to PM2.5 (hazard ratio [HR]: 1.41, 95% confidence interval [CI]: 1.29-1.53; per 10 µg/m3), PM10 (1.05, 1.00-1.09; per 10 µg/m3), and NOX (1.01, 1.01-1.02 per 10 µg/m3). Additive effects of PM2.5 and NOX exposure and genetic risk were observed. Compared to individuals with a low genetic risk and low air pollution exposure, participants with high air pollution exposure and a high genetic risk had a significantly increased risk of hypertension (PM2.5: 71% (66%-76%), PM10: 59% (55%-64%), NOX: 65% (60%-70%)). Our results indicate that long-term exposure to air pollution is associated with an increased risk of hypertension, especially in individuals with a high genetic risk.

Association between urinary cadmium concentrations and liver function in adolescents.

Evidence from previous studies has shown that exposure to cadmium (Cd) is associated with cardiovascular disease, kidney disease, and osteoporosis, but the effects of Cd on liver toxicity in adolescents are unclear. The data of 4411 adolescents who participated in the US The National Health and Nutrition Examination Survey (NHANES) during 1999-2016 was analyzed. Liver function was indicated by the levels of alanine aminotransferase (ALT) and aspartate amino transferase (AST). The associations between the levels of urinary Cd and liver function were evaluated using multivariate logistic regression models adjusted for covariates. The results showed that the odds ratios of ALT and AST in the highest quartiles of urinary Cd were 1.40 (95% confidence interval [CI], 1.07-1.82) and 1.64 (95% CI, 1.10-2.44), respectively, compared with the lowest quartiles, which were similar to using urinary creatinine as the covariate. We also found linear regression of associations of urinary Cd with elevated ALT and AST levels in boys. In addition, one augmented urinary Cd concentration unit (Log10) was associated with a 0.04-mg/dL increase in C-reactive protein and a 0.53-mg/dL decrease in HDL cholesterol in the fully adjusted model. Our results add novel evidence that exposure to Cd might be positively associated with indicators of liver injury, indicating the potential toxic effect of Cd exposure on the adolescent liver. Further confirmatory studies are needed.

Total cholesterol: a potential mediator of the association between exposure to acrylamide and hypertension risk in adolescent females.

Acrylamide (AA) exposure is associated with a range of adverse health effects. However, whether AA exposure is related to hypertension in adolescents remains unclear. The associations of blood hemoglobin biomarkers of AA (HbAA) and its metabolite glycidamide (HbGA) with hypertension risk, diastolic blood pressure (DBP), and systolic blood pressure (SBP) were evaluated by multivariate logistic regression and linear regression. We identified a potential positive association between blood HbGA and hypertension risk in adolescent females (OR 1.81, 95% CI 1.00-3.30; P for trend = 0.022); however, there was no correlation in the non-linear model (P = 0.831). In the sex-stratified linear models, blood HbGA level had a strong positive association with SBP in adolescent females (beta 0.84, 95% CI 0.13-1.55, P = 0.020). Mechanistically, a one-unit increase in blood HbGA (ln transformed) was associated with a 2.83 mg/dL increase in total cholesterol (TC) among females in the fully adjusted model. Mediation analysis showed that TC mediated 24.15% of the association between blood HbGA level and the prevalence of hypertension in females. The present results provide epidemiological evidence that exposure to AA, mainly its metabolite glycidamide, is positively associated with the prevalence of hypertension or increased SBP in adolescent females.

Single Cell RNA-Sequencing Reveals a Murine Gallbladder Cell Transcriptome Atlas During the Process of Cholesterol Gallstone Formation.

Gallstone disease is a worldwide common disease. However, the knowledge concerning the gallbladder in the pathogenesis of cholesterol gallstone formation remains limited. In this study, using single-cell RNA sequencing (scRNA-seq) to obtain the transcriptome of gallbladder cells, we showed cellular heterogeneity and transcriptomic dynamics in murine gallbladder cells during the process of lithogenesis. Our results indicated gallbladder walls were subjected to remodeling during the process of lithogenesis. The major molecular events that happened included proliferation of epithelial cells, infiltration of immune-cells, activation of angiogenesis, and extracellular matrix modulation. Furthermore, we observed partial reversal of gallbladder cell transcriptomes by ursodeoxycholic acid treatment. This work thus provides novel and integral knowledges on the cellular changes during lithogenesis, which is of great significance to the understanding of pathogenesis and treatment of cholesterol gallstone.

Maternal smoking during pregnancy is risk factor for gallbladder disease in offspring during adulthood: a prospective study from UK Biobank.

INTRODUCTION AND OBJECTIVES: Gallbladder disease is a common disease with high prevalence. Majority of gallbladder disease is due to gallstone. Though genetics are believed to play a role in its pathogenesis, the contribution of environmental pressures in early life to the development of this disease in adulthood has not been ever investigated. This study aimed to clarify the risk of maternal smoking exposure in association with gallbladder disease in adulthood. The interaction of maternal smoking and own smoking during adulthood on this association was studied as well. PATIENTS AND METHODS: A total of 286,731 eligible participants from the UK Biobank population-based cohort were included. Multivariable Cox regression analysis were used to examine the HR and 95% CI with adjustment for covariates. RESULT: During a median of 8.8 years follow-up, 7110 incident cases of gallbladder disease including 6800 (95.6%) gallstone were identified. Maternal smoking was associated with increased risk of incident total gallbladder disease (HR = 1.13; 95%CI: 1.06 - 1.21; P = 0.0002) as well as gallstones (HR = 1.13; 95%CI: 1.06 -1.21; P = 0.0003) in adulthood. Compared with those who were neither exposed to maternal smoking nor own smoking, subjects adherence to no smoking during adulthood but having maternal smoking exposure still had increased risk of total gallbladder disease (HR = 1.21; 95%CI: 1.1-1.34, P=0.0001) and gallstones (HR = 1.21; 95%CI: 1.1-1.35, P=0.0001). CONCLUSION: The present study using large prospective cohort data from UK Biobank, for the first time, demonstrated maternal smoking exposure bringing elevated risk of incident total gallbladder disease/gallstone in adulthood.

HDL cholesterol: A potential mediator of the association between serum levels of a mixture of metals and the risk of aortic dissection in a Chinese population.

Aortic dissection (AD) is a severe cardiovascular disease with a high mortality rate. However, the associations between the serum levels of metals and the risk of AD remain unclear. One hundred twenty-seven patients with AD (type A and B) identified from 2017 to 2019 at the Second Affiliated Hospital of Nanjing Medical University were included; 183 controls that were also included. A logistic regression analysis was performed to determine the associations between serum levels of metals and the risk of AD. Weighted Quantile Sum (WQS) regression and Bayesian Kernel Machine Regression (BKMR) analyses were performed to explore the effects of mixtures of metals on the risk of AD. A linear regression analysis was performed to evaluate the relationships between the serum levels of metals and the white blood cells (WBCs) count and serum lipid levels and blood glucose. We conducted a mediation analysis to explore the contribution rates of WBC counts or serum lipid levels and blood glucose to the association between metal levels and the risk of AD. Exposure to serum levels of Cu (coefficient = 6.33; 95 % CI = 2.52, 10.14; p trend < 0.001) were significantly and positively associated with the risk of AD. In the WQS analysis, Cu (50.3 %), Ni (32.7 %) and Mo (17.1 %) contributed to the AD risk. In the BKMR analysis, Cu and Mo were shown to play important roles in the association with the AD risk. Moreover, serum concentrations of Cu were significantly and inversely associated with HDL-cholesterol levels. HDL-cholesterol levels mediated 7.42 % of the association between serum Cu levels and the prevalence of AD. Our study provided the first evidence that serum levels of mixtures of metals are associated with the AD risk in a Chinese population. Increased concentrations of metals, particularly Cu, may increase the risk of AD by reducing HDL-cholesterol levels.

Birth Weight and Adult Obesity Index in Relation to the Risk of Hypertension: A Prospective Cohort Study in the UK Biobank.

Objectives: To investigate the association between birth weight and the risk of hypertension, and to examine the interaction between birth weight and the adult obesity index. Methods: We included 199,893 participants who had birth weight data and no history of hypertension at baseline (2006-2010) from the UK Biobank. A multivariate cubic regression spline was used to visually explore the dose-response relationship. Multivariate Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: We observed a nonlinear inverse association between birth weight and hypertension. The risk for hypertension decreased as birth weight increased up to approximately 3.80 kg. Compared with the participants with the fourth quintile of birth weight (3.43-3.80 kg), those with the first quartile of birth weight (<2.88 kg) were associated with a 25% higher risk of hypertension [HR 1.25; 95% CI (1.18-1.32)]. In addition, the participants with birth weight <2.88 kg and body mass index ≥30 kg/m2 had the highest risk [HR 3.54; 95% CI (3.16-3.97); p for interaction <0.0001], as compared with those with birth weight between 3.43-3.80 kg and body mass index between 18.5-25.0 kg/m2. These associations were largely consistent in the stratified and sensitivity analyses. Conclusion: Our findings indicate that lower birth weight is nonlinearly correlated with higher risk of hypertension, and birth weight between 3.43-3.80 kg might represent an intervention threshold. Moreover, lower birth weight may interact with adult obesity to significantly increase hypertension risk.

Association between birth weight and risk of cardiovascular disease: Evidence from UK Biobank.

BACKGROUND AND AIMS: Birth weight has been linked to cardiovascular disease (CVD) risk in adulthood, but no consensus has emerged on the threshold of birth weight for the lowest CVD risk and few studies have examined potential interaction between birth weight and adult adiposity. METHODS AND RESULTS: A total of 256,787 participants, who had birth weight data and were free of CVD at baseline, were included from UK Biobank. Multivariate restricted cubic splines and Cox regression models were used to assess the association between birth weight and CVD. We observed nonlinear inverse associations of birth weight with the risk of coronary heart disease (CHD), stroke, and heart failure. Participants with the first quintile of birth weight (≤2.85 kg) had higher risks for CHD (hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.15-1.32), stroke (HR = 1.19, 95% CI: 1.03-1.37), and heart failure (HR = 1.28, 95% CI: 1.11-1.48), as compared to the fourth quintile (3.41-3.79 kg). There was a significant interaction between birth weight and adult body mass index (BMI) on CHD and heart failure (both P for interaction <0.001), showing the highest risk for those who had birth weight ≤2.85 kg and BMI ≥30 kg/m2 (HR = 1.96, 95% CI: 1.70-2.25 and HR = 2.39, 95% CI: 1.77-3.22, respectively). CONCLUSIONS: Our findings indicate nonlinear inverse associations between birth weight and CVD risk, with a threshold of 3.41-3.79 kg for the lowest risk. Moreover, low birth weight may interact with adult obesity to increase the risk of CHD and heart failure.