The role of the immunoproteasome in cardiovascular disease.

The ubiquitinproteasome system (UPS) is the main mechanism responsible for the intracellular degradation of misfolded or damaged proteins. Under inflammatory conditions, the immunoproteasome, an isoform of the proteasome, can be induced, enhancing the antigen-presenting function of the UPS. Furthermore, the immunoproteasome also serves nonimmune functions, such as maintaining protein homeostasis and regulating signalling pathways, and is involved in the pathophysiological processes of various cardiovascular diseases (CVDs). This review aims to provide a comprehensive summary of the current research on the involvement of the immunoproteasome in cardiovascular diseases, with the ultimate goal of identifying novel strategies for the treatment of these conditions.

The impact of sunlight exposure on brain structural markers in the UK Biobank.

Sunlight is closely intertwined with daily life. It remains unclear whether there are associations between sunlight exposure and brain structural markers. General linear regression analysis was used to compare the differences in brain structural markers among different sunlight exposure time groups. Stratification analyses were performed based on sex, age, and diseases (hypertension, stroke, diabetes). Restricted cubic spline was performed to examine the dose-response relationship between natural sunlight exposure and brain structural markers, with further stratification by season. A negative association of sunlight exposure time with brain structural markers was found in the upper tertile compared to the lower tertile. Prolonged natural sunlight exposure was associated with the volumes of total brain (ß: - 0.051, P < 0.001), white matter (ß: - 0.031, P = 0.023), gray matter (ß: - 0.067, P < 0.001), and white matter hyperintensities (ß: 0.059, P < 0.001). These associations were more pronounced in males and individuals under the age of 60. The results of the restricted cubic spline analysis showed a nonlinear relationship between sunlight exposure and brain structural markers, with the direction changing around 2 h of sunlight exposure. This study demonstrates that prolonged exposure to natural sunlight is associated with brain structural markers change.

The Association between Dietary Protein Intake and Sources and the Rate of Longitudinal Changes in Brain Structure.

Few studies have examined dietary protein intake and sources, in combination with longitudinal changes in brain structure markers. Our study aimed to examine the association between dietary protein intake and different sources of dietary protein, with the longitudinal rate of change in brain structural markers. A total of 2723 and 2679 participants from the UK Biobank were separately included in the analysis. The relative and absolute amounts of dietary protein intake were calculated using a 24 h dietary recall questionnaire. The longitudinal change rates of brain structural biomarkers were computed using two waves of brain imaging data. The average interval between the assessments was three years. We utilized multiple linear regression to examine the association between dietary protein and different sources and the longitudinal changes in brain structural biomarkers. Restrictive cubic splines were used to explore nonlinear relationships, and stratified and sensitivity analyses were conducted. Increasing the proportion of animal protein in dietary protein intake was associated with a slower reduction in the total hippocampus volume (THV, ß: 0.02524, p < 0.05), left hippocampus volume (LHV, ß: 0.02435, p < 0.01) and right hippocampus volume (RHV, ß: 0.02544, p < 0.05). A higher intake of animal protein relative to plant protein was linked to a lower atrophy rate in the THV (ß: 0.01249, p < 0.05) and LHV (ß: 0.01173, p < 0.05) and RHV (ß: 0.01193, p < 0.05). Individuals with a higher intake of seafood exhibited a higher longitudinal rate of change in the HV compared to those that did not consume seafood (THV, ß: 0.004514; p < 0.05; RHV, ß: 0.005527, p < 0.05). In the subgroup and sensitivity analyses, there were no significant alterations. A moderate increase in an individual's intake and the proportion of animal protein in their diet, especially from seafood, is associated with a lower atrophy rate in the hippocampus volume.

Epigenome-wide association study identifies DNA methylation loci associated with handgrip strength in Chinese monozygotic twins.

Background: The decline in muscle strength and function with aging is well recognized, but remains poorly characterized at the molecular level. Here, we report the epigenetic relationship between genome-wide DNA methylation and handgrip strength (HGS) among Chinese monozygotic (MZ) twins. Methods: DNA methylation (DNAm) profiling was conducted in whole blood samples through Reduced Representation Bisulfite Sequencing method. Generalized estimating equation was applied to regress the DNAm of each CpG with HGS. The Genomic Regions Enrichment of Annotations Tool was used to perform enrichment analysis. Differentially methylated regions (DMRs) were detected using comb-p. Causal inference was performed using Inference about Causation through Examination of Familial Confounding method. Finally, we validated candidate CpGs in community residents. Results: We identified 25 CpGs reaching genome-wide significance level. These CpGs located in 9 genes, especially FBLN1, RXRA, and ABHD14B. Many enriched terms highlighted calcium channels, neuromuscular junctions, and skeletal muscle organ development. We identified 21 DMRs of HGS, with several DMRs within FBLN1, SLC30A8, CST3, and SOCS3. Causal inference indicated that the DNAm of 16 top CpGs within FBLN1, RXRA, ABHD14B, MFSD6, and TYW1B might influence HGS, while HGS influenced DNAm at two CpGs within FBLN1 and RXRA. In validation analysis, methylation levels of six CpGs mapped to FLBN1 and one CpG mapped to ABHD14B were negatively associated with HGS weakness in community population. Conclusion: Our study identified multiple DNAm variants potentially related to HGS, especially CpGs within FBLN1 and ABHD14B. These findings provide new clues to the epigenetic modification underlying muscle strength decline.

Mediation role of DNA methylation in association between handgrip strength and cognitive function in monozygotic twins.

Handgrip strength is a crucial indicator to monitor the change of cognitive function over time, but its mechanism still needs to be further explored. We sampled 59 monozygotic twin pairs to explore the potential mediating effect of DNA methylation (DNAm) on the association between handgrip strength and cognitive function. The initial step was the implementation of an epigenome-wide association analysis (EWAS) in the study participants, with the aim of identifying DNAm variations that are associated with handgrip strength. Following that, we conducted an assessment of the mediated effect of DNAm by the use of mediation analysis. In order to do an ontology enrichment study for CpGs, the GREAT program was used. There was a significant positive association between handgrip strength and cognitive function (ß = 0.194, P < 0.001). The association between handgrip strength and DNAm of 124 CpGs was found to be statistically significant at a significance level of P < 1 × 10-4. Fifteen differentially methylated regions (DMRs) related to handgrip strength were found in genes such as SNTG2, KLB, CDH11, and PANX2. Of the 124 CpGs, 4 within KRBA1, and TRAK1 mediated the association between handgrip strength and cognitive function: each 1 kg increase in handgrip strength was associated with a potential decrease of 0.050 points in cognitive function scores, mediated by modifications in DNAm. The parallel mediating effect of these 4 CpGs was -0.081. The presence of DNAm variation associated with handgrip strength may play a mediated role in the association between handgrip strength and cognitive function.

Identification of Key Genes and Imbalanced SNAREs Assembly in the Comorbidity of Polycystic Ovary Syndrome and Depression.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have increased odds of concurrent depression, indicating that the relationship between PCOS and depression is more likely to be comorbid. However, the underlying mechanism remains unclear. Here, we aimed to use bioinformatic analysis to screen for the genetic elements shared between PCOS and depression. METHODS: Differentially expressed genes (DEGs) were screened out through GEO2R using the PCOS and depression datasets in NCBI. Protein-protein interaction (PPI) network analysis and enrichment analysis were performed to identify the potential hub genes. After verification using other PCOS and depression datasets, the associations between key gene polymorphism and comorbidity were further studied using data from the UK biobank (UKB) database. RESULTS: In this study, three key genes, namely, SNAP23, VTI1A, and PRKAR1A, and their related SNARE interactions in the vesicular transport pathway were identified in the comorbidity of PCOS and depression. The rs112568544 at SNAP23, rs11077579 and rs4458066 at PRKAR1A, and rs10885349 at VTI1A might be the genetic basis of this comorbidity. CONCLUSIONS: Our study suggests that the SNAP23, PRKAR1A, and VTI1A genes can directly or indirectly participate in the imbalanced assembly of SNAREs in the pathogenesis of the comorbidity of PCOS and depression. These findings may provide new strategies in diagnosis and therapy for this comorbidity.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Association between famine exposure during infancy and childhood and the risk of chronic kidney disease in adulthood.

BACKGROUND: Famine exposure in childhood is proven to be associated with multiple chornic disease in adult but has not been studied with chronic kidney disease (CKD). AIMS: This study was conducted to identify the relationship between famine exposure during infancy and childhood - specifically, the Chinese famine of 1959-1961 - and the risk of adult-onset chronic kidney disease (CKD) among Chinese individuals. METHODS: This study included 2937 individuals from the Qingdao Diabetes Prevention Program. They were stratified by birth year into infancy-exposed (1956-1958), childhood-exposed (1950-1955) and unexposed (1963-1971) groups. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. CKD was defined as an eGFR of <90 mL/min/1.73 m2 . RESULTS: The mean eGFR values for the infancy-exposed and childhood-exposed groups were 107.23 ± 12.53 and 103.23 ± 12.44 mL/min/1.73 m2 , respectively, both of which were lower than that of the unexposed group (114.82 ± 13.39 mL/min/1.73 m2 ; P < 0.05). In the crude model, the odds ratio (OR) for CKD was 2.00 (95% confidence interval (CI): 1.39-2.88) in the infancy-exposed group and 2.92 (95% CI: 2.17-3.93) in the childhood-exposed group. Further adjustments for urban/rural residence, body mass index, age, current smoking, type 2 diabetes, systolic blood pressure, diastolic blood pressure and total cholesterol did not significantly alter the association between famine exposure and CKD. The corresponding ORs were 1.71 (95% CI: 1.17-2.50) and 2.48 (95% CI: 1.81-3.40) for the infancy-exposed and childhood-exposed groups respectively. CONCLUSIONS: Famine exposure during infancy and childhood is associated with a long-term decline in eGFR and an increased adult-onset CKD risk. Early intervention for high-risk individuals may mitigate the risk of adult-onset CKD.

A meta-analysis comparing the diagnostic performance of computed tomography-derived fractional flow reserve and coronary computed tomography angiography at different levels of coronary artery calcium score.

OBJECTIVES: The impact of coronary calcification on the diagnostic accuracy of computed tomography-derived fractional flow reserve (CT-FFR) and coronary computed tomography angiography (CCTA) remains a crucial consideration. This meta-analysis aims to compare the diagnostic performance of CT-FFR and CCTA at different levels of coronary artery calcium score (CACS). METHODS AND RESULTS: We searched PubMed, Embase, and the Cochrane Library for relevant articles on CCTA, CT-FFR, and invasive fractional flow reserve (FFR). Ten studies were included to evaluate the diagnostic performance of CT-FFR and CCTA at the per-patient and per-vessel levels in four CACS groups. Invasive FFR was used as the reference standard. Except for the CACS ≥ 400 group, the AUC of CT-FFR was higher than those of CCTA in other subgroups of CACS (in CACS < 100 (per-patient, 0.9 (95% CI 0.87-0.92) vs. 0.32 (95% CI 0.28-0.36); per-vessel, 0.92 (95% CI 0.89-0.94) vs. 0.66 (95% CI 0.62-0.7); both p < 0.001), CACS ≥ 100 (per-patient, 0.86 (95% CI 0.82-0.88) vs. 0.44 (95% CI 0.4-0.48); per-vessel, 0.88 (95% CI 0.85-0.9) vs. 0.51 (95% CI 0.46-0.55); both p < 0.001), and CACS < 400 (per-patient, 0.9 (95% CI 0.87-0.93) vs. 0.74 (95% CI 0.7-0.78), p < 0.001; per-vessel, 0.8 (95% CI 0.76-0.83) vs. 0.74 (95% CI 0.7-0.78); p = 0.02)). CONCLUSIONS: CT-FFR demonstrates superior diagnostic performance in low CACS groups (CACS < 400) than CCTA in detecting hemodynamic stenoses in patients with coronary artery disease (CAD). CLINICAL RELEVANCE STATEMENT: Computed tomography-derived fractional flow reserve might be utilized to determine the necessity of invasive coronary angiography in coronary artery disease patients with coronary artery calcium score < 400. KEY POINTS: • There is a lack of meta-analysis comparing the diagnostic performance of computed tomography-derived fractional flow reserve and coronary computed tomography angiography at different levels of calcification. • Computed tomography-derived fractional flow reserve only has a better diagnostic performance than coronary computed tomography angiography with low amounts of coronary calcium. • For the low coronary artery calcium score group, computed tomography-derived fractional flow reserve might be a good non-invasive method to detect hemodynamic stenoses in coronary artery disease patients.

Identification of Piperazinyl-Difluoro-indene Derivatives Containing Pyridyl Groups as Potent FGFR Inhibitors against FGFR Mutant Tumor: Design, Synthesis, and Biological Evaluation.

The fibroblast growth factor receptor (FGFR) signaling pathway plays important roles in cellular processes such as proliferation, differentiation, and migration. In this study, we highlighted the potential of FGFR inhibitors bearing the (S)-3,3-difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene scaffold containing a crucial 3-pyridyl group for the treatment of FGFR mutant cancers. The representative compound (S)-23, which was identified through comprehensive evaluation, exhibited potent antiproliferative activity with GI50 in the range of 6.4-10.4 nM against FGFR1 fusion protein-carrying, FGFR2-amplified, and FGFR2 mutant cancer cell lines and good antiproliferative activity against FGFR3 translocation and mutant FGFR4 cancer cell lines, as well as potency assessment against FGFR1-4 kinases. Moreover, compound (S)-23 exhibited favorable pharmacokinetic properties, low potential for drug-drug interactions, and very potent antitumor activity in MFE-296 xenograft mouse models with a TGI of 99.1% at the dose of 10 mg/kg. These findings demonstrate that compound (S)-23 is a potential therapeutic agent for FGFR mutant tumors.

DNA Methylation Mediated the Association of Body Mass Index With Blood Pressure in Chinese Monozygotic Twins.

Obesity is an established risk factor for hypertension, but the mechanisms are only partially understood. We examined whether body mass index (BMI)-related DNA methylation (DNAm) variation would mediate the association of BMI with blood pressure (BP). We first conducted a genomewide DNA methylation analysis in monozygotic twin pairs to detect BMI-related DNAm variation and then evaluated the mediating effect of DNAm on the relationship between BMI and BP levels using the causal inference test (CIT) method and mediation analysis. Ontology enrichment analysis was performed for CpGs using the GREAT tool. A total of 60 twin pairs for BMI and systolic blood pressure (SBP) and 58 twin pairs for BMI and diastolic blood pressure (DBP) were included. BMI was positively associated with SBP (ß = 1.86, p = .0004). The association between BMI and DNAm of 85 CpGs reached p < 1×10-4 level. Eleven BMI-related differentially methylated regions (DMRs) within LNCPRESS1, OGDHL, RNU1-44P, NPHS1, ECEL1P2, LLGL2, RNY4P15, MOGAT3, PHACTR3, and BAI2 were found. Of the 85 CpGs, 9 mapped to C10orf71-AS1, NDUFB5P1, KRT80, BAI2, ABCA2, PEX11G and FGF4 were significantly associated with SBP levels. Of the 9 CpGs, 2 within ABCA2 negatively mediated the association between BMI and SBP, with a mediating effect of -0.24 (95% CI [-0.65, -0.01]). BMI was also positively associated with DBP (ß = 0.60, p = .0495). The association between BMI and DNAm of 193 CpGs reached p < 1×10-4 level. Twenty-five BMI-related DMRs within OGDHL, POU4F2, ECEL1P2, TTC6, SMPD4, EP400, TUBA1C and AGAP2 were found. Of the 193 CpGs, 33 mapped to ABCA2, ADORA2B, CTNNBIP1, KDM4B, NAA60, RSPH6A, SLC25A19 and STIL were significantly associated with DBP levels. Of the 33 CpGs, 12 within ABCA2, SLC25A19, KDM4B, PTPRN2, DNASE1, TFCP2L1, LMNB2 and C10orf71-AS1 negatively mediated the association between BMI and DBP, with a total mediation effect of -0.66 (95% CI [-1.07, -0.30]). Interestingly, BMI might also negatively mediate the association between the DNAm of most CpG mediators mentioned above and BP. The mediating effect of DNAm was also found when stratified by sex. In conclusion, DNAm variation may partially negatively mediate the association of BMI with BP. Our findings may provide new clues to further elucidate the pathogenesis of obesity to hypertension and identify new diagnostic biomarkers and therapeutic targets for hypertension.

Exploring the cross-cancer effect of circulating proteins and discovering potential intervention targets for 13 site-specific cancers.

BACKGROUND: The proteome is an important reservoir of potential therapeutic targets for cancer. This study aimed to examine the causal associations between plasma proteins and cancer risk and to identify proteins with cross-cancer effects. METHODS: Genetic instruments for 3991 plasma proteins were extracted from a large-scale proteomic study. Summary-level data of 13 site-specific cancers were derived from publicly available datasets. Proteome-wide Mendelian randomization and colocalization analyses were used to investigate the causal effect of circulating proteins on cancers. Protein-protein interactions and druggability assessment were conducted to prioritize potential therapeutic targets. Finally, systematical Mendelian randomization analysis between healthy lifestyle factors and cancer-related proteins was conducted to identify which proteins could act as interventional targets by lifestyle changes. RESULTS: Genetically determined circulating levels of 58 proteins were statistically significantly associated with 7 site-specific cancers. A total of 39 proteins were prioritized by colocalization, of them, 11 proteins (ADPGK, CD86, CLSTN3, CSF2RA, CXCL10, GZMM, IL6R, NCR3, SIGLEC5, SIGLEC14, and TAPBP) were observed to have cross-cancer effects. Notably, 5 of these identified proteins (CD86, CSF2RA, CXCL10, IL6R, and TAPBP) have been targeted for drug development in cancer therapy; 8 proteins (ADPGK, CD86, CXCL10, GZMM, IL6R, SIGLEC5, SIGLEC14, TAPBP) could be modulated by healthy lifestyles. CONCLUSION: Our study identified 39 circulating protein biomarkers with convincing causal evidence for 7 site-specific cancers, with 11 proteins demonstrating cross-cancer effects, and prioritized the proteins as potential intervention targets by either drugs or lifestyle changes, which provided new insights into the etiology, prevention, and treatment of cancers.

Co-methylation analyses identify CpGs associated with lipid traits in Chinese discordant monozygotic twins.

To control genetic background and early life milieu in genome-wide DNA methylation analysis for blood lipids, we recruited Chinese discordant monozygotic twins to explore the relationships between DNA methylations and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). 132 monozygotic (MZ) twins were included with discordant lipid levels and completed data. A linear mixed model was conducted in Epigenome-wide association study (EWAS). Generalized estimating equation model was for gene expression analysis. We conducted Weighted correlation network analysis (WGCNA) to build co-methylated interconnected network. Additional Qingdao citizens were recruited for validation. Inference about Causation through Examination of Familial Confounding (ICE FALCON) was used to infer the possible direction of these relationships. A total of 476 top CpGs reached suggestively significant level (P < 10-4), of which, 192 CpGs were significantly associated with TG (FDR < 0.05). They were used to build interconnected network and highlight crucial genes from WGCNA. Finally, four CpGs in GATA4 were validated as risk factors for TC; six CpGs at ITFG2-AS1 were negatively associated with TG; two CpGs in PLXND1 played protective roles in HDL-C. ICE FALCON indicated abnormal TC was regarded as the consequence of DNA methylation in CpGs at GATA4, rather than vice versa. Four CpGs in ITFG2-AS1 were both causes and consequences of modified TG levels. Our results indicated that DNA methylation levels of 12 CpGs in GATA4, ITFG2-AS1, and PLXND1 were relevant to TC, TG, and HDL-C, respectively, which might provide new epigenetic insights into potential clinical treatment of dyslipidemia.

Association of seafood consumption with cardiovascular disease among adults in Qingdao, China.

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

Association between all aspects of dietary diversity and risk of depressive symptoms in US adults.

The impact of dietary diversity on depressive symptoms remains one-sided. We aim to explore the associations between all aspects of dietary diversity and the risk of depressive symptoms in US adults and their dose-response relationships. We selected 16 820 adults from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2018. Depressive symptoms were assessed using patient health questionnaire-9 (PHQ-9). Dietary diversity contains four indexes: count (dietary diversity score, DDS), evenness (Healthy Food Diversity Index, HFDI), dissimilarity (Jaccard distance, JD), and quality (Healthy Eating Index, HEI). Binary logistic regression was conducted to assess relationships between the four aspects of dietary diversity and depressive symptoms in whole and subgrouped populations. A restricted cubic spline was performed to explore the dose-response relationships. We revealed that DDS [0.20 (0.05, 0.73)], HFDI [0.51 (0.28, 0.94)], and HEI [0.46 (0.26, 0.80)] were inversely associated with the risk of depressive symptoms for the highest VS lowest quintile, especially in females and elders. Analysis of dose-response relationships determined linear relationships of DDS, HEI and depressive symptoms, while an "L" shaped relationship of HFDI and depressive symptoms. Adequate dietary diversity showed a significant effect on decreasing the risk of depressive symptoms at a score of 4 in DDS, 0.3 in HFDI, and a score of 51 in HEI. In conclusion, this study found that higher levels of dietary diversity, including count, evenness, and quality, might be protective factors against depressive symptoms, especially in females and elders. The DDS, HFDI, and HEI scores are recommended as 4, 0.3, and 51, respectively. Further investigation is needed to validate our results.

Long-term Impact of Prenatal Famine on Differential DNA Methylation of Genes in the Serotonin Receptor Signalling Pathway in Adults.

The correlation of early life adversity with adulthood psychopathology has already been revealed by epidemiological studies. To find the biological mechanisms underlying the cross-talk between prenatal adversity and mental health, molecular genetic studies have been performed using animal models of prenatal undernutrition and stress, reporting altered expression of serotonin receptors which modulate the release of many neurotransmitters that regulate a broad range of physiological functions including psychopathology. Unfortunately, no such study has been possible on humans due to ethical reasons. Using the Chinese Famine of 1959-1961 as a natural experiment, we investigated DNA methylation patterns in genes of the serotonin receptor signaling pathway in the whole blood of adults born during the famine. A significant pattern of reduced DNA methylation was observed in sex combined samples (p value, 0.022). In a sex-stratified analysis, the pattern was only significant in females (p-value, 0.019) but not in males. We further tested the DNA methylation patterns specifically in HTR1A, HTR2A and the X-linked HTR2C and found reduced DNA methylation in females for HTR2A (p-value 0.033) and HTR2C (p-value 0.014) but not in males. Overall, this study reveals altered epigenetic regulation of the serotonin receptor signaling pathway in association with prenatal adversity in humans providing novel epigenetic evidence in support of neurodevelopmental origin of psychiatric disorders.

Famine exposure in early life and type 2 diabetes in adulthood: findings from prospective studies in China.

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

Association of dietary mineral mixture with depressive symptoms: A combination of Bayesian approaches.

The relationships between mixtures of multiple minerals and depression have not been explored. Therefore, we analyzed the relationship between the mixture of nine dietary minerals [calcium (Ca), phosphorus, magnesium (Mg), iron (Fe), zinc, copper (Cu), sodium, potassium (K), and selenium (Se)] and depressive symptoms in the general population. We screened 20,342 participants from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. We fitted the general linear regression, Bayesian kernel machine regression (BKMR), and Bayesian semiparametric regression models to explore associations and interactions. We obtained the relative importance of dietary minerals by calculating posterior inclusion probabilities (PIPs). The dietary intakes of minerals were obtained using the 24-h dietary recall interview, and depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). The linear analysis showed that nine minerals were negatively associated with PHQ-9 scores. The BKMR analysis showed a negative association between the dietary mineral mixture and PHQ-9 scores, with Se having the largest PIP at 1.0000, followed by K (0.7784). We also observed potential interactions between Ca and Fe, Se and Fe, and K and Mg. Among them, the interaction of Ca and Fe had the largest PIP of 0.986. In addition, the overall effect was more pronounced in females than males, and Cu's PIP (0.8376) was higher in females. Two sensitivity analyses showed that our results were robust. Our study provides a basis for formulating nutritional intervention programs for depression in the future.

Weight change across adulthood in relation to the risk of depression.

Background: Studies examining weight change patterns and depression are scarce and report inconsistent findings. This study-aimed to elucidate the association between weight change patterns and the risk of depression in a large, representative sample of US adults. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 was analyzed. Five weight change groups were categorized: stable normal, weight loss, weight gain, maximum overweight, and stable obesity. Depression was ascertained using the validated Patient Health Questionnaire (PHQ-9) and depression was defined as PHQ score ≥ 10. Results: A total of 17,556 participants were included. Compared with participants who maintained normal weight, stable obesity participants had increased risks of depression across adulthood from age 25 years to 10 years before the survey (OR = 1.61, 95% CI =1.23 to 2.11), in the 10 years period before the survey (OR = 2.15, 95% CI =1.71 to 2.70), and from age 25 years to survey (OR = 1.88, 95% CI =1.44 to 2.44). Weight gain was associated with an increased risk of depression from age 25 years to 10 years before the survey (OR = 1.71, 95% CI = 1.41 to 2.04), in the 10 years period before the survey (OR = 1.73, 95% CI = 1.35 to 2.21), and for the period from age 25 years to survey (OR = 1.83, 95% CI = 1.49 to 2.24). In the stratified analyses, we found statistically significant interactions with sex. Conclusion: Our study suggested that stable obesity and weight gain across adulthood were associated with increased risks of depression.

Genome-wide DNA methylation analysis of body composition in Chinese monozygotic twins.

BACKGROUND: Little is currently known about epigenetic alterations associated with body composition in obesity. Thus, we aimed to explore epigenetic relationships between genome-wide DNA methylation levels and three common traits of body composition as measured by body fat percentage (BF%), fat mass (FM) and lean body mass (LBM) among Chinese monozygotic twins. METHODS: Generalized estimated equation model was used to regress the methylation level of CpG sites on body composition. Inference about Causation Through Examination Of Familial Confounding was used to explore the evidence of a causal relationship. Gene expression analysis was further performed to validate the results of differentially methylated genes. RESULTS: We identified 32, 22 and 28 differentially methylated CpG sites (p < 10-5 ) as well as 20, 17 and eight differentially methylated regions (slk-corrected p < 0.05) significantly associated with BF%, FM and LBM which were annotated to 65 genes, showing partially overlapping. Causal inference demonstrated bidirectional causality between DNA methylation and body composition (p < 0.05). Gene expression analysis revealed significant correlations between expression levels of five differentially methylated genes and body composition (p < 0.05). CONCLUSIONS: These DNA methylation signatures will contribute to increased knowledge about the epigenetic basis of body composition and provide new strategies for early prevention and treatment of obesity and its related diseases.