A panel of differentially methylated regions enable prognosis prediction for colorectal cancer.

We aim to identify a panel of differentially methylated regions (DMRs) for predicting survival outcomes for patients with CRC from the TCGA (n = 393). Four DMRs (MUC12, TBX20, CHN2, and B3GNT7) were selected as candidate prognostic markers for CRC. The prediction potential of selected DMRs was validated by the targeted bisulfite sequencing method in an independent cohort with 251 Chinese CRC patients. DMR methylation scores (DMSs) were constructed to evaluate the prognosis of CRC. Results of the validation cohort confirmed that higher DMSs were associated with poor overall survival (OS) of CRC, with hazard ratio (HR) value ranged from 1.445 to 2.698 in multivariable Cox models. Patients in the high prognostic index (high-PI) group showed a markedly unfavorable prognosis compared to the low-PI group in both TCGA discovery cohort (HR = 3.508, 95%CI: 2.196-5.604, P < 0.001) and independent validation cohort (HR = 1.912, 95%CI: 1.258-2.907, P = 0.002).

Inhibitory immune checkpoints PDCD-1 and LAG-3 hypermethylation may reduce the risk of colorectal cancer.

BACKGROUND: Changes in DNA methylation of immunosuppressive checkpoints may impact express and consequently affect antigen processing and presentation by tumor cells and facilitates evasion of immunosurveillance and lead to colorectal cancer (CRC). This study is to investigate the effect of PDCD-1, LAG-3 methylation statuses in peripheral blood leukocytes on CRC risk. METHODS: GSE51032 dataset from Gene Expression Omnibus comprised of 166 CRC patients and 424 normal samples was used to identify significantly differentially methylated CpG sites of the two genes. A case-control study with 390 CRC patients and 397 cancer-free controls was carried out to validate the relationship between the methylation levels of the two genes and CRC susceptibility and then estimated their interactions with environmental factors on CRC risk. RESULTS: In the GSE51032 dataset, cg06291111 (PDCD-1) and cg10191002 (LAG-3) were screened as the candidate CpG sites for the following study. There were significant associations between hypermethylation of PDCD-1 and LAG-3 and lower risk of CRC (ORadj = 0.322, 95% CI 0.197-0.528; ORadj = 0.666, 95% CI 0.446-0.5996, respectively). Moreover, the results in case-control study showed similar trend, that hypermethylation of PDCD-1 and LAG-3 were associated with lower CRC risk (ORadj = 0.448, 95% CI 0.322-0.622; ORadj = 0.417, 95% CI 0.301-0.578, respectively). A synergistic interaction between LAG-3 hypermethylation and intake of eggs on CRC risk was observed. There were combination effects between hypermethylation of PDCD-1 and LAG-3 and environmental factors on CRC risk. CONCLUSIONS: PDCD-1 and LAG-3 may potentially serve as blood-based predictive biomarkers for CRC risk.

Development and validation of 3-CpG methylation prognostic signature based on different survival indicators for colorectal cancer.

Abnormal DNA methylation is considered a vital hallmark to regulate gene expression and influence the development and progression of colorectal cancer (CRC). Although CRC-related methylation prognostic models have been developed, their clinical application is limited due to the lack of external validation and extension to other survival evaluation indicators. Therefore, this study aimed to develop and validate novel methylation prognostic models correlated with different survival indicators for individualized prognosis prediction for CRC patients. The prognostic-related CpG sites of methylation-driven genes screened by the MethylMix algorithm were identified and validated in The Cancer Genome Atlas (TCGA) CRC methylation data and our methylation data. The prognostic models correlated with different survival evaluation indicators (overall survival [OS] and disease-free survival [DFS]) were developed and validated in the TCGA CRC dataset (N = 376) and our independent CRC dataset (N = 227). We utilized the combination of selected 3-CpG methylation sites in three genes (DAPP1, FAM3D, and PIGR) to construct a prognostic risk-score model. In the training dataset, Kaplan-Meier survival analysis demonstrated that high-risk patients had significantly poorer survival than low-risk patients (pOS = .0014; pDFS < .001). Then, the 3-CpG methylation signature was successfully validated as an independent predictor in the testing data set (pOS = .016; pDFS = .016). A prognostic nomogram was constructed and validated. Additionally, mediation analysis revealed the direct effect of the methylation signature on CRC prognosis (pOS = 9.149e-06; pDFS = .001). In summary, our study revealed that the 3-CpG methylation signature might be a potential prognostic indicator to facilitate individualized survival prediction for CRC patients.

Growth variations of Dahurian larch plantations across northeast China: Understanding the effects of temperature and precipitation.

Climate change is affecting the growth and distribution of trees in the Chinese boreal forest. Such changes in China, the southern terminus of the extensive Eurasian boreal forests, reflect on the changes that could occur further north under a warming climate. Most studies have found that tree growth increases with increasing temperature and precipitation in boreal forests, but there is little observational evidence of the climate thresholds that might slow these growth rates at the more extreme temperatures which are predicted to occur under future global warming. Here, we examine growth responses of this dominant boreal tree species (Larix gmelinii) to climate based on the data from plantation sample plots across a broad region (40° 51'-52° 58'N, 118° 12'E-133° 42'E) in northeast China. From statistically significant fits to quadratic equations, temperature and precipitation are the important climatic factors determining tree growth in L. gmelinii plantations at two age classes (<10 year and 10-30 year-old stands). The maximum rates of tree height and diameter at breast height (DBH) were about 0.53 m/year and 0.46 cm/year at <10 year stands, and about 0.63 m/year and 0.60 cm/year at 10-30 year stands, respectively. For stands with the highest values of mean annual increment (MAI), the corresponding optimal mean annual temperature (MATopt) focused between 0.66 °C and 1.57 °C. The optimal mean annual precipitation (MAPopt) between 663 mm and 708 mm produced the maximal growth increments. With mean annual temperature of -2.4 °C and precipitation of 470 mm averaged over 1954-2005 in Chinese boreal forest region as baseline, we conservatively estimated that trees in Chinese boreal forest appear to have higher growth potentials with the maximum temperature increase of 3.6 °C and precipitation increase of 40%.

DNA methylation of SFRP1, SFRP2, and WIF1 and prognosis of postoperative colorectal cancer patients.

BACKGROUND: As biomarkers, DNA methylation is used to detect colorectal cancer (CRC) and make assessment of CRC prognosis. The published findings showed the association between the methylation of SFRP1, SFRP2, and WIF1, located in the Wnt signaling pathway, and the prognosis of CRC were not consistent. Our study aimed to explore the potential possibility of SFRP1, SFRP2, and WIF1 concomitant promoter methylation as prognostic biomarkers of postoperative CRC patients. METHODS: As a total of 307 sporadic postoperative CRC patients were followed up, we detected SFRP1, SFRP2, and WIF1 methylation obtained from tumor tissues and adjacent non-tumor tissues respectively on the basis of methylation-sensitive high resolution melting analysis. Univariate and multivariate Cox regressions were carried out so as to assess the potential possibility of SFRP1, SFRP2, and WIF1 promoter methylation as predictors of prognosis. Confounders in our study were controlled by Propensity Score (PS) analysis. RESULTS: The SFRP1, SFRP2, and WIF1 methylation levels in tumor tissues were significantly higher than that in adjacent non-tumor tissues (P < 0.001). SFRP2 hypermethylation was significantly associated with a favorable clinical outcome at the hazard ratio (HR) of 0.343 [95% confidence intervals (CI): 0.164-0.718, P = 0.005] and 0.410 (95% CI: 0.200-0.842, P = 0.015) in multivariate Cox regression and PS analysis, respectively. Co-hypermethylation of SFRP1 and SFRP2 was significantly associated with a favorable clinical outcome at the HR of 0.333 (95% CI: 0.159-0.694, P = 0.003) and 0.398 (95% CI: 0.192-0.821, P = 0.013) in multivariate Cox regression and PS analysis, respectively. Co-hypermethylation of SFRP1, SFRP2 and WIF1 was significantly associated with a favorable clinical outcome at the HR of 0.326 (95% CI: 0.117-0.908, P = 0.032) and 0.401 (95% CI: 0.146-1.106, P = 0.077) in multivariate Cox regression and PS analysis, respectively. CONCLUSIONS: SFRP1, SFRP2, and WIF1 were frequently hypermethylated in CRC tumor tissues. It was apparent that the promoter hypermethylation of SFRP2 and co-hypermethylation of SFRP1 and SFRP2 might be considered as independent prognostic predictors for survival advantage of postoperative CRC patients.

Combined effect between WT1 methylation and Helicobacter pylori infection, smoking, and alcohol consumption on the risk of gastric cancer.

BACKGROUND: Peripheral blood leukocyte DNA methylation status has been proposed to be a surrogate marker for evaluating susceptibility to gastric cancer (GC). Helicobacter pylori (H pylori) infection, smoking, and alcohol consumption are known to induce gene methylation. A case-control study was performed to investigate the interactions between the methylation of two candidate genes and H pylori infection, smoking, and alcohol consumption in the risk of GC. METHODS: A total of 400 GC cases and 402 controls were included in this study. The methylation status of WT1 and IGF2 was semiquantitatively determined by using methylation-sensitive high-resolution melting assays. H pylori IgG antibodies were detected by ELISA method. RESULTS: Based on the area under the curve (AUC), 0% methylated DNA and 0.5% methylated DNA were used as the cutoff values for WT1 and IGF2, respectively. WT1 methylation was significantly associated with increased GC risk (OR = 1.65, 95% CI = 1.09-2.51, P = .019), especially in males (OR = 1.80, 95% CI: 1.10-2.95, P = .019) and older individuals (≥60 years) (OR = 2.03, 95% CI: 1.15-3.57, P = .014). A significant combination was observed between WT1 methylation and H pylori infection, alcohol consumption, and smoking for the risk of GC (ORc  = 2.28, 95% CI = 1.47-3.55, P = .003, ORc  = 2.19, 95% CI = 1.37-3.51, P = .001, ORc  = 2.21, 95% CI = 1.39-3.51, P = .001, respectively). However, no association between IGF2 methylation and the risk of GC was found in this study. CONCLUSIONS: WT1 methylation may serve as a new potential biomarker for GC susceptibility and can combine with H pylori infection, smoking, and alcohol consumption to influence GC risk.

CHST7 Gene Methylation and Sex-Specific Effects on Colorectal Cancer Risk.

BACKGROUND: X chromosome aberrations are involved in carcinogenesis and are associated with gender differences in cancer development. Abnormal DNA methylation also contributes to cancer. Carbohydrate Sulfotransferase 7 (CHST7), encoded by the X chromosome, is abnormally expressed during tumor development. However, its impact on colorectal cancer (CRC) and the effect of CHST7 methylation on sex-specific CRC risk remain unclear. AIMS: To investigate the effect of CHST7 methylation in white blood cells on CRC risk and to evaluate its impact on gender-specific differences. METHODS: CHST7 methylation in white blood cells was determined using methylation-sensitive high-resolution melting. A propensity score analysis was performed to control potential confounders. Furthermore, extensive sensitivity analyses were applied to assess the robustness of our findings. In addition, we validated the initial findings with a GEO dataset (GSE51032). RESULTS: CHST7 hypermethylation in white blood cells was associated with an increased CRC risk [odds ratio (OR)adj = 4.447, 95% confidence interval (CI) 2.662-7.430; p < 0.001]. The association was validated with the GEO dataset (ORadj = 2.802, 95% CI 1.235-6.360; p = 0.014). In particular, CHST7 hypermethylation significantly increased the CRC risk in females (ORadj = 7.704, 95% CI 4.222-14.058; p < 0.001) and younger patients (≤ 60 years) (ORadj = 5.755, 95% CI 2.540-13.038; p < 0.001). Subgroup analyses by tumor location and Duke's stage also observed these associations. CONCLUSION: CHST7 methylation in white blood cells is positively associated with CRC risk, especially in females, and may potentially serve as a blood-based predictive biomarker for CRC risk.

Diet quality score and survival rate in patients with colorectal cancer.

BACKGROUND AND OBJECTIVES: Results regarding associations between specific-food and prognosis of colorectal cancer (CRC) are limited and inconsistent, and few studies have examined this issue in Asian population. This study examined the association between diet and prognosis of CRC, and developed a diet quality score for prognosis of CRC. METHODS AND STUDY DESIGN: 352 participants who provided completed dietary information were recruited during 2004 to 2014, and there are 154 death case documented with 10-year follow-up. Cox regression models were used to examine associations between food groups and survival rate, and to develop the diet quality score for prognosis of CRC. RESULTS: Intake of whole grain, fruit and coffee consumption habitus were associated with higher survival rate (HR 0.56 [95% CI 0.35, 0.89] for whole grain; HR 0.62 [95% CI 0.40, 0.97] for fruit; HR 0.46 [95% CI 0.24, 0.87] for coffee), whereas intake of red meat and frequency of grilled food were associated with lower survival rate (HR 1.68 [95% CI 1.08, 2.61] for red meat; HR 1.78 [95% CI 1.05, 3.02] for grilled food). The overall diet quality based on these nutritional factors was negatively associated with survival rate (HR 1.60 [95% CI 1.07, 2.39] with adjustment for age, sex, BMI, smoking, drinking, energy intake, UICC stage, chemotherapy, postoperative adjuvant radiotherapy, tumor size, carcinoembryonic antigen and carbohydrate antigen 19-9 levels. CONCLUSIONS: Whole grain, fruit, red meat, coffee consumption habitus and frequency of grilled food were significantly associated with survival rate in Chinese population. The diet quality score may be useful for Chinese healthcare providers to advise patients on the optimal diet.

The adverse effects of developmental exposure to polystyrene nanoparticles on cognitive function in weaning rats and the protective role of trihydroxy phenolacetone.

Polystyrene nanoplastic(PS-NP) can originate from sources such as plastic waste and industrial wastewater and have been shown to have deleterious effects on abnormal neurobehaviors. However, evidence regarding the health impacts, biological mechanisms, and treatment strategies underlying developmental exposure to low dose PS-NP is still lacking. This study aimed to fill this knowledge gap by administering low doses of PS-NP(50 and 100 µg/L) to weaning rats for 4 consecutive weeks. Behavioral and morphological experiments were performed to evaluate hippocampal damage, and transcriptomics and Assay for Transposase Accessible Chromatin with hight-throughput sequencing(ATAC) analyses were conducted to identify potential key targets. Additionally, Connectivity Map(CMap) database, Limited proteolysis-mass spectrometry(LiP-SMap), and molecular-protein docking were used to examine potential phytochemicals with therapeutic effects on key targets. The results indicated that developmental exposure to PS-NP can induce hippocampal impairment and aberrant neurobehaviors in adulthood. Multi-omics analyses consistently showed that apoptosis-related signaling pathways were sensitive to PS-NP exposure, and mitogen-activated protein kinase 3(Mapk3) was identified as the core gene by the gene network, which was further validated in vitro experiments. The CMap database provided a series of phytochemicals that might regulate Mapk3 expression, and trihydroxy-phenolacetone(THP) was found to have directly binding sites with Mapk3 through LiP-SMap and molecular docking analysis. Furthermore, THP administration could significantly alleviate apoptosis induced by PS-NP exposure in primary hippocampal cells through down-regulation of Mapk3. These findings suggested that developmental exposure to PS-NP has adverse effects on cognitive function and that THP can alleviate these effects by directly binding to Mapk3.

Insulin-like growth factor 2 hypermethylation in peripheral blood leukocytes and colorectal cancer risk and prognosis: a propensity score analysis.

Background: To comprehensively assess and validate the associations between insulin-like growth factor 2 (IGF2) gene methylation in peripheral blood leukocytes (PBLs) and colorectal cancer (CRC) risk and prognosis. Methods: The association between IGF2 methylation in PBLs and CRC risk was initially evaluated in a case-control study and then validated in a nested case-control study and a twins' case-control study, respectively. Meanwhile, an initial CRC patient cohort was used to assess the effect of IGF2 methylation on CRC prognosis and then the finding was validated in the EPIC-Italy CRC cohort and TCGA datasets. A propensity score (PS) analysis was performed to control for confounders, and extensive sensitivity analyses were performed to assess the robustness of our findings. Results: PBL IGF2 hypermethylation was associated with an increased risk of CRC in the initial study (ORPS-adjusted, 2.57, 95% CI: 1.65 to 4.03, P<0.0001), and this association was validated using two independent external datasets (ORPS-adjusted, 2.21, 95% CI: 1.28 to 3.81, P=0.0042 and ORPS-adjusted, 10.65, 95% CI: 1.26 to 89.71, P=0.0295, respectively). CRC patients with IGF2 hypermethylation in PBLs had significantly improved overall survival compared to those patients with IGF2 hypomethylation (HRPS-adjusted, 0.47, 95% CI: 0.29 to 0.76, P=0.0019). The prognostic signature was also observed in the EPIC-Italy CRC cohort, although the HR did not reach statistical significance (HRPS-adjusted, 0.69, 95% CI: 0.37 to 1.27, P=0.2359). Conclusions: IGF2 hypermethylation may serve as a potential blood-based predictive biomarker for the identification of individuals at high risk of developing CRC and for CRC prognosis.

Task Cortical Connectivity Reveals Different Network Reorganizations between Mild Stroke Patients with Cortical and Subcortical Lesions.

Accumulating efforts have been made to investigate cognitive impairment in stroke patients, but little has been focused on mild stroke. Research on the impact of mild stroke and different lesion locations on cognitive impairment is still limited. To investigate the underlying mechanisms of cognitive dysfunction in mild stroke at different lesion locations, electroencephalograms (EEGs) were recorded in three groups (40 patients with cortical stroke (CS), 40 patients with subcortical stroke (SS), and 40 healthy controls (HC)) during a visual oddball task. Power envelope connectivity (PEC) was constructed based on EEG source signals, followed by graph theory analysis to quantitatively assess functional brain network properties. A classification framework was further applied to explore the feasibility of PEC in the identification of mild stroke. The results showed worse behavioral performance in the patient groups, and PECs with significant differences among three groups showed complex distribution patterns in frequency bands and the cortex. In the delta band, the global efficiency was significantly higher in HC than in CS (p = 0.011), while local efficiency was significantly increased in SS than in CS (p = 0.038). In the beta band, the small-worldness was significantly increased in HC compared to CS (p = 0.004). Moreover, the satisfactory classification results (76.25% in HC vs. CS, and 80.00% in HC vs. SS) validate the potential of PECs as a biomarker in the detection of mild stroke. Our findings offer some new quantitative insights into the complex mechanisms of cognitive impairment in mild stroke at different lesion locations, which may facilitate post-stroke cognitive rehabilitation.

Association between the methylation of CpG islands in JAK-STAT pathway-related genes and colorectal cancer.

BACKGROUND: Aberrant promoter methylation of CpG islands plays an important role in carcinogenesis. However, the association between the DNA methylation of JAK-STAT pathway-related genes in peripheral blood leukocytes and colorectal cancer (CRC) susceptibility remains unclear. METHODS: We conducted a case-control study of 403 patients with CRC and 419 cancer free controls, and the DNA methylation levels of JAK2, STAT1, STAT3, and SOCS3 in peripheral blood samples from all subjects were assessed using a methylation-sensitive high-resolution melting (MS-HRM) analysis. RESULTS: Compared with controls, the methylation of the JAK2, STAT1 and SOCS3 genes increased the CRC risk (ORadjusted=1.96, 95% CI, 1.12-3.41, P=0.01; ORadjusted=5.37, 95% CI, 3.74-7.71, P<0.01; ORadjusted=3.30, 95% CI, 1.58-6.87, P<0.01). In the multiple CpG site methylation (MCSM) analysis, a high MCSM value denoted an increased CRC risk (ORadjusted=4.97, 95% CI, 3.34-7.37, P<0.01). CONCLUSION: In peripheral blood, the methylation of JAK2, STAT1, and high levels of MCSM are promising biomarkers for CRC risk.

Primary health care system responses to non-communicable disease prevention and control: a scoping review of national policies in Mainland China since the 2009 health reform.

This study aims to review China's national policies related to non-communicable disease (NCD) prevention and control at the primary health care (PHC) level since China's 2009 health system reform. Policy documents from official websites of China's State Council and 20 affiliated ministries were screened, where 151 out of 1,799 were included. Thematic content analysis was performed, and fourteen 'major policy initiatives' were identified, including the basic health insurance schemes and essential public health services. Several areas showed to have strong policy support, including service delivery, health financing, and leadership/governance. Compared with WHO recommendations, several gaps remain, including lack of emphasis on multi-sectoral collaboration, underuse of non-health-professionals, and lack of quality-oriented PHC services evaluations. Over the past decade, China continues to demonstrate its policy commitment to strengthen the PHC system for NCD prevention and control. We recommend future policies to facilitate multi-sectoral collaboration, enhance community engagement, and improve performance evaluation mechanisms.

Methylation of Immune-Related Genes in Peripheral Blood Leukocytes and Breast Cancer.

Abnormal DNA methylation contributes to breast cancer (BC). Immune-related genes play crucial roles in BC development and progression. This study aims to investigate the effect of methylation of immune-related genes in peripheral blood leukocytes (PBLs) on BC risk. GSE51032 and GSE104942 datasets were used to identify significantly differentially methylated CpG sites (DMCs) of immune-related genes. A case-control study was conducted using MethylTarget sequencing to validate the relationship between the methylation levels of the screened genes and BC risk. We also evaluated the association between methylation haplotypes of screened genes and BC risk. Moreover, we sorted the blood leukocytes into T cells, B cells, and monocytes to detect the difference of DNA methylation in different cell subtypes. A total of five DMCs were screened from GEO datasets, including cg01760846 (PSMC1), cg07141527 (SPPL3), cg15658543 (CARD11), cg21568368 (PSMB8), and cg24045276 (NCF2). In the case-control study, there were significant associations between methylation of the CpG sites in the five genes and BC risk. Methylation haplotype burdens of PSMC1, CARD11, and PSMB8 were associated with reduced BC risk. Moreover, there were heterogeneities in the methylation levels of the genes in different cell subtypes. In conclusion, methylation of PSMC1, SPPL3, CARD11, PSMB8, and NCF2 in PBLs were associated with BC risk. The five-gene methylation could be the potential biomarkers for predicting BC risk.

The Association of Consumption Time for Food With Cardiovascular Disease and All-Cause Mortality Among Diabetic Patients.

AIMS: This study aims to investigate whether food intake time across 3 meals is associated with long-term survival among the people with diabetes. MATERIALS AND METHODS: This study included 4642 diabetic patients participating in the National Health and Nutrition Examination Survey from 2003 to 2014. Food consumed across a day including the forenoon, afternoon, and evening was divided into quantiles based on their distribution. Cox proportional hazards regression models were used to analyze the survival relationship between food intakes time and mortality. RESULTS: In the forenoon, compared to the participants in the lowest quantile of potato and starchy vegetable, participants in the highest quantile had lower mortality risk of cardiovascular disease (CVD) [hazard ratio (HR)potato = 0.46, 95% CI 0.24-0.89; HRstarchy-vegetable = 0.32, 95% CI 0.15-0.72]. In the afternoon, participants who consumed whole grain had lower mortality of CVD (HRwhole grain = 0.67, 95% CI 0.48-0.95). In the evening, the highest quantile of dark vegetable and milk intake is related to lower mortality risk of CVD (HRdark vegetable = 0.55, 95% CI 0.35-0.87; HRmilk = 0.56, 95% CI 0.36-0.88) and all-cause mortality (HRmilk = 0.71, 95% CI 0.54-0.92), whereas participants in the highest quantile of intakes of processed meat are more likely to die due to CVD (HRprocessed-meat = 1.74, 95% CI 1.07-2.82). Isocalorically switching 0.1 serving potato or starchy vegetable consumed in the afternoon or evening to the forenoon, 0.1 serving dark vegetable consumed in the afternoon to the evening, and 0.1 serving whole grain consumed in the forenoon to the afternoon reduced the risk of CVD mortality. CONCLUSIONS: Higher intake of potato or starchy vegetable in forenoon, whole grain in the afternoon, and dark vegetable and milk in the evening and lower intake of processed meat in the evening was associated with better long-term survival in people with diabetes.

Causal Relationships Between Relative Intake from the Macronutrients and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Some observational studies indicated the associations of relative carbohydrate, sugar, fat, and protein intake and Alzheimer's disease (AD). But it remains unclear whether the associations are causal. OBJECTIVE: This study aimed to identify the effects of relative carbohydrate, sugar, fat, and protein intake in the diet on AD. METHODS: A two-sample Mendelian randomization was employed. Finally, 14 independent lead SNPs remained in the Social Science Genetic Association Consortium. These SNPs of relative carbohydrate, sugar, fat, and protein intake at the level of genome-wide significance (p < 5×10-8) were used as instrumental variables. The summary data for AD were acquired from the International Genomics of Alzheimer's Project with a total of 54,162 individuals (17,008 AD patients and 37,154 control participants). RESULTS: This two-sample Mendelian randomization indicated that increased relative protein intake (per 1 standard deviation) causally decreased the AD risk (OR = 0.48, 95% CI: 0.24-0.95, p = 0.036), and increased relative fat intake may decrease the risk of AD (OR = 0.22, 95% CI: 0.06-0.86, p = 0.029). No statistical significance with AD risk was seen for relative carbohydrate or relative sugar intake. CONCLUSION: A higher relative intake of protein can causally reduce the risk of AD in the elderly. Additionally, a higher relative intake of fat may be protective against AD. No evidence showed that AD was associated with relative carbohydrate and sugar intake.

Community prevalence and dyad disease pattern of multimorbidity in China and India: a systematic review.

BACKGROUND: Driven by the increasing life expectancy, China and India, the two most populous countries in the world are experiencing a rising burden of multimorbidity. This study aims to explore community prevalence and dyad patterns of multimorbidity in China and India. METHODS: We conducted a systematic review of five English and Chinese electronic databases. Studies involving adults 18 years or older at a community level, which reported multimorbidity prevalence and/or patterns were included. A modified Newcastle-Ottawa Scale was used for quality assessment. Despite large heterogeneity among reported studies, a systematic synthesis of the results was conducted to report the findings. RESULTS: From 13 996 studies retrieved, 59 studies met the inclusion criteria (46 in China, 9 in India and 4 in both). The median prevalence of multimorbidity was 30.7% (IQR 17.1, 49.4), ranging from 1.5% to 90.5%. There was a large difference in multimorbidity prevalence between China and India, with median prevalence being 36.1% (IQR 19.6, 48.8) and 28.3% (IQR 8.9, 56.8), respectively. Among 27 studies that reported age-specific prevalence, 19 studies found multimorbidity prevalence increased with age, while 8 studies observed a paradoxical reduction in the oldest age group. Of the 34 studies that reported sex-specific prevalence, 86% (n=32) observed a higher prevalence in females. The most common multimorbidity patterns from 14 studies included hypertensive diseases combined with diabetes mellitus, arthropathies, heart diseases and metabolic disorders. All included studies were rated as fair or poor quality. CONCLUSION: Multimorbidity is highly prevalent in China and India with hypertensive diseases and other comorbidities being the most observed patterns. The overall quality of the studies was low and there was a lack of representative samples in most studies. Large epidemiology studies, using a common definition of multimorbidity and national representative samples, with sex disaggregation are needed in both countries. PROSPERO REGISTRATION NUMBER: CRD42020176774.

Association of folate intake with cardiovascular-disease mortality and all-cause mortality among people at high risk of cardiovascular-disease.

BACKGROUND & AIMS: Due to the beneficial effect of folate on cardiovascular disease (CVD), folic acid supplementation is a more common practice among people at high-risk of CVD. However, long-term prospective investigations regarding the association of folate-intake with CVD-mortality and all-cause mortality among this specific population are still lacking. Therefore, this study aims to assess the association of folate-intake with CVD-mortality and all-cause mortality. METHODS: A total of 14,234 participants at high-risk of CVD were enrolled. Total folate equivalent (TFE), dietary folate equivalent (DFE), food folate, folic acid in fortified food, folic acid supplements, serum folate and red blood cell (RBC) folate were measured. The main outcome measures were CVD-mortality and all-cause mortality from baseline until 31 December 2015. RESULTS: During the 98,890 person-year follow-up, 2036 deaths including 682 deaths due to CVD were documented. After multivariate adjustment, a J shaped association was found: modest intake of TFE and DFE was associated with lower risk of CVD-mortality and all-cause mortality, whereas higher intake did not persistently reduce these risks. Compared to the participants without folic acid supplementation matched 28-covariates using propensity score, folic acid supplementation was associated with higher risk of CVD-mortality (HR:1.44, 95%CI:1.06-1.97, P = 0.022) and all-cause mortality (HR:1.28,95%CI:1.09-1.51, P = 0.003). The levels of serum-folate and RBC-folate in participants with folic acid supplementation were significantly greater than participants without folic acid supplementation (41.8 nmol/l vs. 64.2 nmol/l, P < 0.001 for serum-folate; 1201 nmol/l vs. 1608 nmol/l, P < 0.001 for RBC-folate). Compared with the lowest-quintile of serum-folate, the second-quintile was consistently associated with CVD-mortality (HR:0.72, 95%CI:0.53-0.99, P = 0.048) and all-cause mortality (HR:0.78, 95%CI:0.64-0.94, P = 0.013). Compared to the lowest-quintile of RBC-folate, the second-quintile was associated with lower all-cause mortality (HR:0.71,95%CI:0.56-0.90, P = 0.005), whereas the highest-quintile was associated with higher CVD-mortality (HR:1.40,95%CI:1.02-1.93, P = 0.030). The J shaped association of serum-folate and RBC-folate with CVD-mortality and all-cause mortality was also demonstrated, further supporting the results of TFE and propensity score analysis. CONCLUSIONS: This study suggested the beneficial effects of modest folate-intake on the improvement of long-term survival, and emphasized the potentially deleterious effects of excess folic acid supplementation among US adults at high-risk of CVD.

DNA Methylation of Imprinted Genes KCNQ1, KCNQ1OT1, and PHLDA2 in Peripheral Blood Is Associated with the Risk of Breast Cancer.

Methylation alterations of imprinted genes lead to loss of imprinting (LOI). Although studies have explored the mechanism of LOI in breast cancer (BC) development, the association between imprinted gene methylation in peripheral blood and BC risk is largely unknown. We utilized HumanMethylation450 data from TCGA and GEO (n = 1461) to identify the CpG sites of imprinted genes associated with BC risk. Furthermore, we conducted an independent case-control study (n = 1048) to validate DNA methylation of these CpG sites in peripheral blood and BC susceptibility. cg26709929, cg08446215, cg25306939, and cg16057921, which are located at KCNQ1, KCNQ1OT1, and PHLDA2, were discovered to be associated with BC risk. Subsequently, the association between cg26709929, cg26057921, and cg25306939 methylation and BC risk was validated in our inhouse dataset. All 22 CpG sites in the KCNQ1OT1 region were associated with BC risk. Individuals with a hypermethylated KCNQ1OT1 region (>0.474) had a lower BC risk (OR: 0.553, 95% CI: 0.397−0.769). Additionally, the methylation of the KCNQ1OT1 region was not significantly different among B cells, monocytes, and T cells, which was also observed at CpG sites in PHLDA2. In summary, the methylation of KCNQ1, KCNQ1OT1, and PHLDA2 was associated with BC risk, and KCNQ1OT1 methylation could be a potential biomarker for BC risk assessment.

Discovery and validation of tissue-specific DNA methylation as noninvasive diagnostic markers for colorectal cancer.

BACKGROUND: Noninvasive diagnostic markers that are capable of distinguishing patients with colorectal cancer (CRC) from healthy individuals or patients with other cancer types are lacking. We report the discovery and validation of a panel of methylation-based markers that specifically detect CRC. METHODS: This was a large-scale discovery study based on publicly available datasets coupled with a validation study where multiple types of specimens from six cohorts with CRC, other cancer types, and healthy individuals were used to identify and validate the tissue-specific methylation patterns of CRC and assess their diagnostic performance. RESULTS: In the discovery and validation cohort (N = 9307), ten hypermethylated CpG sites located in three genes, C20orf194, LIFR, and ZNF304, were identified as CRC-specific markers. Different analyses have suggested that these CpG sites are CRC-specific hypermethylated and play a role in transcriptional silencing of corresponding genes. A random forest model based on ten markers achieved high accuracy rates between 85.7 and 94.3% and AUCs between 0.941 and 0.970 in predicting CRC in three independent datasets and a low misclassification rate in ten other cancer types. In the in-house validation cohort (N = 354), these markers achieved consistent discriminative capabilities. In the cfDNA pilot cohort (N = 14), hypermethylation of these markers was observed in cfDNA samples from CRC patients. In the cfDNA validation cohort (N = 155), the two-gene panel yielded a sensitivity of 69.5%, specificity of 91.7%, and AUC of 0.806. CONCLUSIONS: Hypermethylation of the ten CpG sites is a CRC-specific alteration in tissue and has the potential use as a noninvasive cfDNA marker to diagnose CRC.