Associations of metabolic changes and polygenic risk scores with cardiovascular outcomes and all-cause mortality across BMI categories: a prospective cohort study.

BACKGROUND: Associations between metabolic status and metabolic changes with the risk of cardiovascular outcomes have been reported. However, the role of genetic susceptibility underlying these associations remains unexplored. We aimed to examine how metabolic status, metabolic transitions, and genetic susceptibility collectively impact cardiovascular outcomes and all-cause mortality across diverse body mass index (BMI) categories. METHODS: In our analysis of the UK Biobank, we included a total of 481,576 participants (mean age: 56.55; male: 45.9%) at baseline. Metabolically healthy (MH) status was defined by the presence of < 3 abnormal components (waist circumstance, blood pressure, blood glucose, triglycerides, and high-density lipoprotein cholesterol). Normal weight, overweight, and obesity were defined as 18.5 ≤ BMI < 25 kg/m2, 25 ≤ BMI < 30 kg/m2, and BMI ≥ 30 kg/m2, respectively. Genetic predisposition was estimated using the polygenic risk score (PRS). Cox regressions were performed to evaluate the associations of metabolic status, metabolic transitions, and PRS with cardiovascular outcomes and all-cause mortality across BMI categories. RESULTS: During a median follow-up of 14.38 years, 31,883 (7.3%) all-cause deaths, 8133 (1.8%) cardiovascular disease (CVD) deaths, and 67,260 (14.8%) CVD cases were documented. Among those with a high PRS, individuals classified as metabolically healthy overweight had the lowest risk of all-cause mortality (hazard ratios [HR] 0.70; 95% confidence interval [CI] 0.65, 0.76) and CVD mortality (HR 0.57; 95% CI 0.50, 0.64) compared to those who were metabolically unhealthy obesity, with the beneficial associations appearing to be greater in the moderate and low PRS groups. Individuals who were metabolically healthy normal weight had the lowest risk of CVD morbidity (HR 0.54; 95% CI 0.51, 0.57). Furthermore, the inverse associations of metabolic status and PRS with cardiovascular outcomes and all-cause mortality across BMI categories were more pronounced among individuals younger than 65 years (Pinteraction < 0.05). Additionally, the combined protective effects of metabolic transitions and PRS on these outcomes among BMI categories were observed. CONCLUSIONS: MH status and a low PRS are associated with a lower risk of adverse cardiovascular outcomes and all-cause mortality across all BMI categories. This protective effect is particularly pronounced in individuals younger than 65 years. Further research is required to confirm these findings in diverse populations and to investigate the underlying mechanisms involved.

Genome-Wide Mapping of Plasma IgG N-Glycan Quantitative Trait Loci Identifies a Potentially Causal Association between IgG N-Glycans and Rheumatoid Arthritis.

Observational studies highlight associations of IgG N-glycosylation with rheumatoid arthritis (RA); however, the causality between these conditions remains to be determined. Standard and multivariable two-sample Mendelian randomization (MR) analyses integrating a summary genome-wide association study for RA and IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) data were performed to explore the potentially causal associations of IgG N-glycosylation with RA. After correcting for multiple testing (p < 2 × 10-3), the standard MR analysis based on the inverse-variance weighted method showed a significant association of genetically instrumented IgG N-glycan (GP4) with RA (odds ratioGP4 = 0.906, 95% confidence interval = 0.857-0.958, p = 5.246 × 10-4). In addition, we identified seven significant associations of genetically instrumented IgG N-glycans with RA by multivariable MR analysis (p < 2 × 10-3). Results were broadly consistent in sensitivity analyses using MR_Lasso, MR_weighted median, MR_Egger regression, and leave-one-out analysis with different instruments (all p values <0.05). There was limited evidence of pleiotropy bias (all p values > 0.05). In conclusion, our MR analysis incorporating genome-wide association studies and IgG N-glycan-QTL data revealed that IgG N-glycans were potentially causally associated with RA. Our findings shed light on the role of IgG N-glycosylation in the development of RA. Future studies are needed to validate our findings and to explore the underlying physiological mechanisms in the etiology of RA.

Bidirectional Two-Sample Mendelian Randomization Study of Immunoglobulin G N-Glycosylation and Senescence-Associated Secretory Phenotype.

Observational studies revealed changes in Immunoglobulin G (IgG) N-glycosylation during the aging process. However, it lacks causal insights and remains unclear in which direction causal relationships exist. The two-sample bidirectional Mendelian randomization (MR) design was adopted to explore causal associations between IgG N-glycans and the senescence-associated secretory phenotype (SASP). Inverse variance weighted (IVW) and Wald ratio methods were used as the main analyses, supplemented by sensitivity analyses. Forward MR analyses revealed causal associations between the glycan peak (GP) and SASP, including GP6 (odds ratio [OR] = 0.428, 95% confidence interval [CI] = 0.189-0.969) and GP17 (OR = 0.709, 95%CI = 0.504-0.995) with growth/differentiation factor 15 (GDF15), GP19 with an advanced glycosylation end-product-specific receptor (RAGE) (OR = 2.142, 95% CI = 1.384-3.316), and GP15 with matrix metalloproteinase 2 (MMP2) (OR = 1.136, 95% CI =1.008-1.282). The reverse MR indicated that genetic liability to RAGE was associated with increased levels of GP17 (OR = 1.125, 95% CI = 1.003-1.261) and GP24 (OR = 1.222, 95% CI = 1.046-1.428), while pulmonary and activation-regulated chemokines (PARC) exhibited causal associations with GP10 (OR = 1.269, 95% CI = 1.048-1.537) and GP15 (OR = 1.297, 95% CI = 1.072-1.570). The findings provided suggested evidence on the bidirectional causality between IgG N-glycans and SASP, which might reveal potential regulatory mechanisms.

The Causality between Human Immunoglobulin G (IgG) N-Glycosylation and Aging: A Mendelian Randomization Study.

BACKGROUND: Immunoglobulin G (IgG) N-glycosylation is considered a potential biomarker for aging and various pathological conditions. However, whether these changes in IgG N-glycosylation are a consequence or a contributor to the aging process remains unclear. This study aims to investigate the causality between IgG N-glycosylation and aging using Mendelian randomization (MR) analysis. METHODS: We utilized genetic variants associated with IgG N-glycosylation traits, the frailty index (FI), and leukocyte telomere length (LTL) from a previous genome-wide association study (GWAS) on individuals of European ancestry. Two-sample and multivariable MR analyses were conducted, employing the inverse-variance weighted (IVW) method. Sensitivity analyses were performed to assess potential confounding factors. RESULTS: Using the IVW method, we found suggestive evidence of a causal association between GP14 and FI (ß 0.026, 95% CI 0.003 to 0.050, p = 0.027) and LTL (ß -0.020, 95% CI -0.037 to -0.002, p = 0.029) in the two-sample MR analysis. In the multivariable MR analysis, suggestive evidence was found for GP23 and FI (ß -0.119, 95% CI -0.219 to -0.019, p = 0.019) and GP2 and LTL (ß 0.140, 95% CI 0.020 to 0.260, p = 0.023). CONCLUSIONS: In conclusion, our results supported a potentially causal effect of lower GP23 levels on an advanced aging state. Additional verification is required to further substantiate the causal relationship between glycosylation and aging.

Time spent in a better cardiovascular health and risk of cardiovascular diseases and mortality: a prospective cohort study.

BACKGROUND: The protective effect of a higher ideal cardiovascular health (CVH) score on cardiovascular diseases (CVDs) and mortality is well recognized. However, little is known regarding the length of favorable CVH status associated with CVDs and mortality. This study aimed to examined whether the duration of better (ideal or intermediate) CVH is associated with risk of developing CVDs and mortality. METHODS: This prospective cohort study used data from 83,536 individuals from 2006 to 2020 who were enrolled in the Kailuan Study. The CVH scores of individuals were assessed at visits 1, 2, 3, and 4, respectively. The years spent in better CVH were estimated for each individual as the number of examination cycles (0-4) in which the participant was in that CVH score ≥ 8 multiplied by 2 (the mean year interval of each visit). The primary outcomes are CVD events and all-cause mortality. RESULTS: After a median follow-up period of 7.48 years, 5486 (7.07%) cases of incident CVD events and 7669 (9.18%) deaths occurred. Compared with participants in " ≤ 4 years" group, those who maintained for > 4 years had less likely to develop adverse outcomes (CVD events: hazard ratio (HR): 0.60, 95% confidence interval (CI 0.56-0.63; all-cause mortality: HR: 0.77, 95% CI 0.74-0.81). The number of years spent in better CVH was nonlinearly correlated with CVD events or mortality (all Ps for nonlinear < 0.05). The results indicated that maintaining more than 6 years in a better CVH status was associated with a decreased risk of CVD events or mortality. CONCLUSION: Our study indicates that individuals maintaining more than 6 years in better CVH could increase cardiometabolic benefits and a lower risk of all-cause mortality.

Unravelling the genetic causality of immunoglobulin G N-glycans in ischemic stroke.

BACKGROUND: Evidence suggests that immunoglobulin G (IgG) N-glycosylation is associated with ischemic stroke (IS). However, the causality of IgG N-glycosylation for IS remains unknown. METHODS: Two-sample Mendelian randomization (MR) analyses were performed to investigate the potential causal effects of genetically determined IgG N-glycans on IS using publicly available summarized genetic data from East Asian and European populations. Genetic instruments were used as proxies for IgG N-glycan traits. IgG N-glycans were analysed using ultra-performance liquid chromatography. Four complementary MR methods were performed, including the inverse variance weighted method (IVW), MR‒Egger, weighted median and penalized weighted median. Furthermore, to further test the robustness of the results, MR based on Bayesian model averaging (MR-BMA) was then applied to select and prioritize IgG N-glycan traits as risk factors for IS. RESULTS: After correcting for multiple testing, in two-sample MR analyses, genetically predicted IgG N-glycans were unrelated to IS in both East Asian and European populations, and the results remained consistent and robust in the sensitivity analysis. Moreover, MR-BMA also showed consistent results in both East Asian and European populations. CONCLUSIONS: Contrary to observational studies, the study did not provide enough genetic evidence to support the causal associations of genetically predicted IgG N-glycan traits and IS, suggesting that N-glycosylation of IgG might not directly involve in the pathogenesis of IS.

Vascular endothelial growth factor and the risk of venous thromboembolism: a genetic correlation and two-sample Mendelian randomization study.

BACKGROUND: The relationship between vascular endothelial growth factor (VEGF) and the risk of venous thromboembolism (VTE) has always been one of the concerns in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders or reverse causality. We performed a two-sample bidirectional Mendelian randomization (MR) to infer the associations between VEGF and VTE. METHODS: Summary statistics from genome-wide association studies (GWAS) for VEGF and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly associated with exposure were selected as instrumental variables. Linkage disequilibrium score regression (LDSC) and five robust MR analytical approaches were conducted to estimate the genetic correlations and causal inference. The MR-Egger intercept, Cochran's Q, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on outcomes. Notably, replication analyses were performed using different subgroups of VTE. RESULTS: LDSC failed to identify genetic correlations between VEGF and VTE. Based on 9 SNPs, the circulating VEGF level was positively related to the risk of VTE using inverse variance weighting (IVW) method (odds ratio (OR) = 1.064, 95% confidence interval (CI), 1.009-1.122). Reverse MR analyses showed that genetic liability for VTE was not associated with increased VEGF level (ß = -0.021, 95% CI, -0.087-0.045). Pleiotropy-robust methods indicated no bias in any estimates. CONCLUSIONS: Our findings failed to detect coheritability between VEGF and VTE. The suggestive positive effect of the higher VEGF level on the VTE risk may have clinical implications, suggesting that VEGF as a possible predictor and therapeutic target for VTE prevention need to be further warranted.

Causal associations between COVID-19 and atrial fibrillation: A bidirectional Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies showed that coronavirus disease (2019) (COVID-19) attacks universally and its most menacing progression uniquely endangers the elderly with cardiovascular disease (CVD). The causal association between COVID-19 infection or its severity and susceptibility of atrial fibrillation (AF) remains unknown. METHODS AND RESULTS: The bidirectional causal relationship between COVID-19 (including COVID-19, hospitalized COVID-19 compared with not hospitalized COVID-19, hospitalized COVID-19 compared with the general population, and severe COVID-19) and AF are determined by using two-sample Mendelian randomization (MR) analysis. Genetically predicted severe COVID-19 was not significantly associated with the risk of AF [odds ratio (OR), 1.037; 95% confidence interval (CI), 1.005-1.071; P = 0.023, q = 0.115]. In addition, genetically predicted AF was also not causally associated with severe COVID-19 (OR, 0.993; 95% CI, 0.888-1.111; P = 0.905, q = 0.905). There was no evidence to support the association between genetically determined COVID-19 and the risk of AF (OR, 1.111; 95% CI, 0.971-1.272; P = 0.127, q = 0.318), and vice versa (OR, 1.016; 95% CI, 0.976-1.058; P = 0.430, q = 0.851). Besides, no significant association was observed for hospitalized COVID-19 with AF. MR-Egger analysis indicated no evidence of directional pleiotropy. CONCLUSION: Overall, this MR study provides no clear evidence that COVID-19 is causally associated with the risk of AF.

Association of suboptimal health status with intestinal microbiota in Chinese youths.

Suboptimal health status (SHS), a physical state between health and disease, is a subclinical and reversible stage of chronic disease. Previous studies have shown alterations in the intestinal microbiota in patients with some chronic diseases. This study aimed to investigate the association between SHS and intestinal microbiota in a case-control study with 50 SHS individuals and 50 matched healthy controls. Intestinal microbiota was analysed by MiSeq 250PE. Alpha diversity of intestinal microbiota in SHS individuals was higher compared with that of healthy controls (Simpson index, W = 2238, P = .048). Beta diversity was different between SHS and healthy controls (P = .018). At the phylum level, the relative abundance of Verrucomicrobia was higher in the SHS group than that in the controls (W = 2201, P = .049). Compared with that of the control group, nine genera were significantly higher and five genera were lower in abundance in the SHS group (all P < .05). The intestinal microbiota, analysed by a random forest model, was able to distinguish individuals with SHS from the controls, with an area under the curve of 0.79 (95% confidence interval: 0.77-0.81). We demonstrated that the alteration of intestinal microbiota occurs with SHS, an early stage of disease, which might shed light on the importance of intestinal microbiota in the primary prevention of noncommunicable chronic diseases.

Metabolic Traits and Risk of Ischemic Stroke in Japanese and European Populations: A Two-Sample Mendelian Randomization Study.

The role of metabolic traits in ischemic stroke (IS) has been explored through observational studies and a few Mendelian randomization (MR) studies employing limited methods in European populations. This study aimed to investigate the causal effects of metabolic traits on IS in both East Asian and European populations utilizing multiple MR methods based on genetic insights. Two-sample and multivariable MR were performed, and MR estimates were calculated as inverse-variance weighted (IVW), weighted median, and penalized weighted median. Pleiotropy was assessed by MR-Egger and Mendelian randomization pleiotropy residual sum and outlier tests. Systolic blood pressure (SBP) was associated with an increased risk of IS by IVW in both European (ORIVW: 1.032, 95% CI: 1.026-1.038, p < 0.001) and Japanese populations (ORIVW: 1.870, 95% CI: 1.122-3.116, p = 0.016), which was further confirmed by other methods. Unlike the European population, the evidence for the association of diastolic blood pressure (DBP) with IS in the Japanese population was not stable. No evidence supported an association between the other traits and IS (all Ps > 0.05) in both races. A positive association was found between SBP and IS in two races, while the results of DBP were only robust in Europeans.

Frailty mediating the causality between leucocyte telomere length and mortality: a cohort study of 440,551 UK Biobank participants.

Introduction: Previous studies reported leucocyte telomere length (LTL) and frailty were associated with mortality, but it remains unclear whether frailty serves as a mediator in the relationship between leucocyte telomere length and mortality risk. This study aimed to evaluate how measuring LTL and frailty can support early monitoring and prevention of risk of mortality from the prospective of predictive, preventive, and personalized medicine (PPPM/3PM). Methods: We included 440,551 participants from the UK Biobank between the baseline visit (2006-2010) and November 30, 2022. The time-dependent Cox proportional hazards model was conducted to assess the association between LTL and frailty index with the risk of mortality. Furthermore, we conducted causal mediation analyses to examine the extent to which frailty mediated the association between LTL and mortality. Results: During a median follow-up of 13.74 years, each SD increase in LTL significantly decreased the risk of all-cause [hazard ratio (HR): 0.94, 95% confidence interval (CI): 0.93-0.95] and CVD-specific mortality (HR: 0.92, 95% CI: 0.90-0.95). The SD increase in FI elevated the risk of all-cause (HR: 1.35, 95% CI: 1.34-1.36), CVD-specific (HR: 1.47, 95% CI: 1.44-1.50), and cancer-specific mortality (HR: 1.22, 95% CI: 1.20-1.24). Frailty mediated approximately 10% of the association between LTL and all-cause and CVD-specific mortality. Conclusions: Our results indicate that frailty mediates the effect of LTL on all-cause and CVD-specific mortality. There findings might be valuable to predict, prevent, and reduce mortality through primary prevention and healthcare in context of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00355-7.

Association of IgG N-glycomics with prevalent and incident type 2 diabetes mellitus from the paradigm of predictive, preventive, and personalized medicine standpoint.

Objectives: Type 2 diabetes mellitus (T2DM), a major metabolic disorder, is expanding at a rapidly rising worldwide prevalence and has emerged as one of the most common chronic diseases. Suboptimal health status (SHS) is considered a reversible intermediate state between health and diagnosable disease. We hypothesized that the time frame between the onset of SHS and the clinical manifestation of T2DM is the operational area for the application of reliable risk assessment tools, such as immunoglobulin G (IgG) N-glycans. From the viewpoint of predictive, preventive, and personalized medicine (PPPM/3PM), the early detection of SHS and dynamic monitoring by glycan biomarkers could provide a window of opportunity for targeted prevention and personalized treatment of T2DM. Methods: Case-control and nested case-control studies were performed and consisted of 138 and 308 participants, respectively. The IgG N-glycan profiles of all plasma samples were detected by an ultra-performance liquid chromatography instrument. Results: After adjustment for confounders, 22, five, and three IgG N-glycan traits were significantly associated with T2DM in the case-control setting, baseline SHS, and baseline optimal health participants from the nested case-control setting, respectively. Adding the IgG N-glycans to the clinical trait models, the average area under the receiver operating characteristic curves (AUCs) of the combined models based on repeated 400 times fivefold cross-validation differentiating T2DM from healthy individuals were 0.807 in the case-control setting and 0.563, 0.645, and 0.604 in the pooled samples, baseline SHS, and baseline optimal health samples of nested case-control setting, respectively, which presented moderate discriminative ability and were generally better than models with either glycans or clinical features alone. Conclusions: This study comprehensively illustrated that the observed altered IgG N-glycosylation, i.e., decreased galactosylation and fucosylation/sialylation without bisecting GlcNAc, as well as increased galactosylation and fucosylation/sialylation with bisecting GlcNAc, reflects a pro-inflammatory state of T2DM. SHS is an important window period of early intervention for individuals at risk for T2DM; glycomic biosignatures as dynamic biomarkers have the ability to identify populations at risk for T2DM early, and the combination of evidence could provide suggestive ideas and valuable insight for the PPPM of T2DM. Supplementary information: The online version contains supplementary material available at 10.1007/s13167-022-00311-3.

Leveraging IgG N-glycosylation to infer the causality between T2D and hypertension.

BACKGROUND: Observational studies demonstrated a bidirectional association between type 2 diabetes (T2D) and hypertension, whereas Mendelian randomization (MR) analyses supported the causality from T2D to hypertension but not causal from hypertension to T2D. We previously found that IgG N-glycosylation is associated with both T2D and hypertension, and thus IgG N-glycosylation might link the causality between them. METHODS: We carried out a genome-wide association study (GWAS) to identify IgG N-glycosylation-quantitative-trait loci (QTLs) integrating GWAS for T2D and hypertension and then performed bidirectional univariable and multivariable MR analyses to infer the causal association among them. The inverse-variance-weighted (IVW) analysis was performed as the primary analysis, followed by some sensitivity analyses to explore the stability of the results. RESULTS: Six putatively causal IgG N-glycans for T2D and four for hypertension were identified in the IVW method. Genetically predicted T2D increased the risk of hypertension (odds ratio [OR] = 1.177, 95% confidence interval (95% CI) = 1.037-1.338, P = 0.012) and vice versa (OR = 1.391, 95% CI = 1.081-1.790, P = 0.010). Multivariable MR showed that T2D remained at risk effect with hypertension ([OR] = 1.229, 95% CI = 1.140-1.325, P = 7.817 × 10-8) after conditioning on T2D-related IgG-glycans. Conversely, hypertension was associated with higher T2D risk (OR = 1.287, 95% CI = 1.107-1.497, P = 0.001) after adjusting for related IgG-glycans. No evidence of horizontal pleiotropy was observed, as MR‒Egger regression provided P values for intercept > 0.05. CONCLUSION: Our study validated the mutual causality between T2D and hypertension from the perspective of IgG N-glycosylation, further validating the "common soil" hypothesis underlying the pathogenesis of T2D and hypertension.

Externalizing traits: Shared causalities for COVID-19 and Alzheimer's dementia using Mendelian randomization analysis.

Externalizing traits have been related with the outcomes of coronavirus disease 2019 (COVID-19) and Alzheimer's dementia (AD); however, whether these associations are causal remains unknown. We used the two-sample Mendelian randomization (MR) approach with more than 200 single-nucleotide polymorphisms (SNPs) for externalizing traits to explore the causal associations of externalizing traits with the risk of COVID-19 (infected COVID-19, hospitalized COVID-19, and severe COVID-19) or AD based on the summary data. The inverse variance-weighted method (IVW) was used to estimate the main effect, followed by several sensitivity analyses. IVW analysis showed significant associations of externalizing traits with COVID-19 infection (odds ratio [OR] = 1.456, 95% confidence interval [95% CI] = 1.224-1.731), hospitalized COVID-19 (OR = 1.970, 95% CI = 1.374-2.826), and AD (OR = 1.077, 95% CI = 1.037-1.119). The results were consistent using weighted median (WM), penalized weighted median (PWM), MR-robust adjusted profile score (MR-RAPS), and leave-one-out sensitivity analyses. Our findings assist in exploring the causal effect of externalizing traits on the pathophysiology of infection and severe infection of COVID-19 and AD. Furthermore, our study provides evidence that shared externalizing traits underpin the two diseases.

Glycomic biomarkers are instrumental for suboptimal health status management in the context of predictive, preventive, and personalized medicine.

Objectives: Suboptimal health status (SHS), a reversible borderline condition between optimal health status and disease, has been recognized as a main risk factor for non-communicable diseases (NCDs). From the standpoint of predictive, preventive, and personalized medicine (PPPM/3PM), the early detection of SHS provides a window of opportunity for targeted prevention and personalized treatment of NCDs. Considering that immunoglobulin G (IgG) N-glycosylation levels are associated with NCDs, it can be speculated that IgG N-glycomic alteration might occur at the SHS stage. Methods: A case-control study was performed and it consisted of 124 SHS individuals and 124 age-, gender-, and body mass index-matched healthy controls. The IgG N-glycan profiles of 248 plasma samples were analyzed by ultra-performance liquid chromatography instrument. Results: After adjustment for potential confounders (i.e., age, levels of education, physical activity, family income, depression score, fasting plasma glucose, and low-density lipoprotein cholesterol), SHS was significantly associated with 16 IgG N-glycan traits at 5% false discovery rate, reflecting decreased galactosylation and fucosylation with bisecting GlcNAc, as well as increased agalactosylation and fucosylation without bisecting GlcNAc. Canonical correlation analysis showed that glycan peak (GP) 20, GP9, and GP12 tended to be significantly associated with the 5 domains (fatigue, the cardiovascular system, the digestive system, the immune system, and mental status) of SHS. The logistic regression model including IgG N-glycans was of moderate performance in tenfold cross-validation, achieving an average area under the receiver operating characteristic curves of 0.703 (95% confidence interval: 0.637-0.768). Conclusions: The present findings indicated that SHS-related alteration of IgG N-glycans could be identified at the early onset of SHS, suggesting that IgG N-glycan profiles might be potential biomarker of SHS. The altered SHS-related IgG N-glycans are instrumental for SHS management, which could provide a window opportunity for PPPM in advanced treatment of NCDs and shed light on future studies investigating the pathogenesis of progression from SHS to NCDs. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00278-1.

Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies.

Observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have yielded inconsistent results on the associations of vitamin D concentrations with multiple health outcomes. In the present umbrella review we aimed to evaluate the effects of low vitamin D concentrations and vitamin D supplementation on multiple health outcomes. We summarized current evidence obtained from meta-analyses of observational studies that examined associations between vitamin D concentrations and multiple health outcomes, meta-analyses of RCTs that investigated the effect of vitamin D supplementation on multiple health outcomes, and MR studies that explored the causal associations of vitamin D concentrations with various diseases (international prospective register of systematic reviews PROSPERO registration number CRD42018091434). A total of 296 meta-analyses of observational studies comprising 111 unique outcomes, 139 meta-analyses of RCTs comprising 46 unique outcomes, and 73 MR studies comprising 43 unique outcomes were included in the present umbrella review. Twenty-eight disease outcomes were identified by both meta-analyses of observational studies and MR studies. Seventeen of these reported disease outcomes had consistent results, demonstrating that lower concentrations of vitamin D were associated with a higher risk for all-cause mortality, Alzheimer's disease, hypertension, schizophrenia, and type 2 diabetes. The combinations of consistent evidence obtained by meta-analyses of observational studies and MR studies together with meta-analyses of RCTs showed that vitamin D supplementation was associated with a decreased risk for all-cause mortality but not associated with the risk for Alzheimer's disease, hypertension, schizophrenia, or type 2 diabetes. The results indicated that vitamin D supplementation is a promising strategy with long-term preventive effects on multiple chronic diseases and thus has the potential to decrease all-cause mortality. However, the current vitamin D supplementation strategy might not be an efficient intervention approach for these diseases, suggesting that new strategies are highly needed to improve the intervention outcomes.

Assessment of the Causal Effect of IgG N-Glycosylation Level on Risk of Dementia: A 2-Sample Mendelian Randomization Study.

BACKGROUND: Previous prospective studies highlighted aberrant immunoglobulin G (IgG) N-glycosylation as a risk factor for dementia [such as Alzheimer's disease (AD) and vascular dementia (VaD)]. It is unclear whether this association is causal or explained by confounding or reverse causation. OBJECTIVE: The aim is to examine the association of genetically predicted IgG N-glycosylation with dementia using 2-sample Mendelian randomization (MR). METHODS: Independent genetic variants for IgG N-glycosylation traits were selected as instrument variables from published genome-wide association studies (GWAS) among individuals of European ancestry. We extracted their corresponding summary statistics from large-scale clinically diagnosed AD GWAS dataset and FinnGen biobank VaD GWAS dataset. The inverse variance weighted (IVW) was performed to calculate the effect estimates. Meanwhile, multiple sensitivity analyses were used to assess horizontal pleiotropy and outliers. RESULTS: There were no associations of genetically predicted IgG N-glycosylation traits with the risk of AD and VaD using the IVW method (all Bonferroni corrected p > 0.0013). These estimates of four additional sensitivity analyses methods were consistent with the IVW estimates in terms of direction and magnitude. Additionally, the MR-PRESSO global test and the intercept of MR-Egger regression indicated no evidence of horizontal pleiotropy. Meanwhile, the heterogeneity test showed no significant heterogeneity using the Cochran Q statistic. The leave-one-out sensitivity analyses also did not detect any significant change. CONCLUSION: Our MR study did not support evidence for the hypothesis that IgG N-glycosylation level may be causally associated with the risk of dementia.

Choroidal and Retinal Thickness and Axial Eye Elongation in Chinese Junior Students.

Purpose: To explore the associations between macular choroidal and retinal thickness and axial elongation in non-myopic and myopic junior students. Methods: In this school-based longitudinal observational study, axial length was measured by optical low-coherence reflectometry, and choroidal thickness and retinal thickness were measured by spectral-domain optical coherence tomography. Myopia was defined as non-cycloplegic objective spherical equivalent refraction ≤ -0.50 diopters. Structural equation modeling and multiple linear regression models were used to analyze the associations between baseline choroidal and retinal thickness with axial elongation. Results: Out of 1307 students examined at baseline in 2017, 1197 (91.58%) returned for follow-up examination in 2018, with a median age of 12.00 years (interquartile range [IQR], 1.00) and included 667 boys (55.72%). Within a 1-year period, the median axial elongation of right eyes was 230 µm (IQR, 180) in boys and 200 µm (IQR, 160) in girls (P = 0.032). The thinner temporal choroidal thickness was associated with greater 1-year axial elongation only in myopic students (ß, -0.20; 95% confidence interval [CI], -0.37, -0.03), the thinner temporal retinal thickness was associated with greater 1-year axial elongation in both non-myopic (ß, -2.67; 95% CI, -4.52, -0.82) and myopic (ß, -0.99; 95% CI, -1.68, -0.30) students, after adjustment for sex, age, and height. Subfoveal and nasal choroidal and retinal thickness were not significantly associated with axial elongation in either non-myopic or myopic students. Conclusions: A thinner temporal choroid at age 12 years may predict greater 1-year axial elongation in myopic students, and a thinner temporal retina may predict greater 1-year axial elongation in both non-myopic and myopic students. This finding may help to identify children at risk and control axial elongation with potential preventive strategies.

Causal Relationship Between Lung Function and Atrial Fibrillation: A Two Sample Univariable and Multivariable, Bidirectional Mendelian Randomization Study.

Background: Observational studies have identified impaired lung function accessed by forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or the ratio of FEV1 over FVC (FEV1/FVC) as an independent risk factor for atrial fibrillation (AF). However, the result may be affected by confounders or reverse causality. Methods: We performed univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR to jointly estimate the causality of lung function with AF. Apart from the inverse variance weighted (IVW) approach as the main MR analysis, three complementary sensitive analyses approaches including MR-Egger regression, weighted median (WM) MR and Pleiotropy Residual Sum and Outlier (MR-PRESSO) in uvMR as well as mvMR-Egger and mvMR-PRESSO in mvMR were applied to control for pleiotropy. Linkage disequilibrium score (LDSC) regression was applied to estimate genetic correlation between lung function and AF. Results: All forward and reverse uvMR analyses consistently suggested absent causal relations between lung function and AF risk [forward IVW: odds ratio (OR)FEV1 = 1.031, 95% CI = 0.909-1.169, P = 0.630; ORFVC = 1.002, 95% CI = 0.834-1.204, P = 0.982; ORFEV1/FVC = 1.076, 95% CI = 0.966-1.199, P = 0.182; reverse IVW: ORFEV1 = 0.986, 95% CI = 0.966-1.007, P = 0.187; ORFVC = 0.985, 95% CI = 0.965-1.006, P = 0.158; ORFEV1/FVC = 0.994, 95% CI = 0.973-1.015, P = 0.545]. The forward MR-Egger showed that each standard deviation (SD) increase in FEV1/FVC was related to a higher AF risk (OR = 1.502, 95% CI = 1.178-1.915, P = 0.006) without heterogeneity (Q_pval = 0.064), but pleiotropy effect exist (intercept = -0.017, P = 0.012). However, this significant effect disappeared after adjustment of FEV1 and FVC (OR = 1.523, 95% CI = 0.445-5.217, P = 0.503) in mvMR. No evidence was found for independent causal effects of FEV1 and FVC on AF in mvMR analysis by using mvIVW method (ORFEV1 = 0.501, 95% CI = 0.056-4.457, P = 0.496; ORFVC = 1.969, 95% CI = 0.288-13.474, P = 0.490). Notably, the association between lung function and AF were replicated using the FinnGen cohort data. Conclusions: Our findings reported no coheritability between lung function and AF, and failed to find substantial causal relation between decreased lung function and risk of AF. However, lung function and AF were both associated with inflammation, which may be potential pathway, warranting further study.

Association of dementia with immunoglobulin G N-glycans in a Chinese Han Population.

Immunoglobulin G (IgG) functionality can drastically change from anti- to proinflammatory by alterations in the IgG N-glycan patterns. Our previous studies have demonstrated that IgG N-glycans associated with the risk factors of dementia, such as aging, dyslipidemia, type 2 diabetes mellitus, hypertension, and ischemic stroke. Therefore, the aim is to investigate whether the effects of IgG N-glycan profiles on dementia exists in a Chinese Han population. A case-control study, including 81 patients with dementia, 81 age- and gender-matched controls with normal cognitive functioning (NC) and 108 non-matched controls with mild cognitive impairment (MCI) was performed. Plasma IgG N-glycans were separated by ultra-performance liquid chromatography. Fourteen glycan peaks reflecting decreased of sialylation and core fucosylation, and increased bisecting N-acetylglucosamine (GlcNAc) N-glycan structures were of statistically significant differences between dementia and NC groups after controlling for confounders (p < 0.05; q < 0.05). Similarly, the differences for these 14 initial glycans were statistically significant between AD and NC groups after adjusting for the effects of confounders (p < 0.05; q < 0.05). The area under the receiver operating curve (AUC) value of the model consisting of GP8, GP9, and GP14 was determined to distinguish dementia from NC group as 0.876 [95% confidence interval (CI): 0.815-0.923] and distinguish AD from NC group as 0.887 (95% CI: 0.819-0.936). Patients with dementia were of an elevated proinflammatory activity via the significant changes of IgG glycome. Therefore, IgG N-glycans might contribute to be potential novel biomarkers for the neurodegenerative process risk assessment of dementia.