Proteomic insights into the associations between obesity, lifestyle factors, and coronary artery disease.

BACKGROUND: We aimed to investigate the protein pathways linking obesity and lifestyle factors to coronary artery disease (CAD). METHODS: Summary-level genome-wide association statistics of CAD were obtained from the CARDIoGRAMplusC4D consortium (60,801 cases and 123,504 controls) and the FinnGen study (R8, 39,036 cases and 303,463 controls). Proteome-wide Mendelian randomization (MR) analysis was conducted to identify CAD-associated blood proteins, supplemented by colocalization analysis to minimize potential bias caused by linkage disequilibrium. Two-sample MR analyses were performed to assess the associations of genetically predicted four obesity measures and 13 lifestyle factors with CAD risk and CAD-associated proteins' levels. A two-step network MR analysis was conducted to explore the mediating effects of proteins in the associations between these modifiable factors and CAD. RESULTS: Genetically predicted levels of 41 circulating proteins were associated with CAD, and 17 of them were supported by medium to high colocalization evidence. PTK7 (protein tyrosine kinase-7), RGMB (repulsive guidance molecule BMP co-receptor B), TAGLN2 (transgelin-2), TIMP3 (tissue inhibitor of metalloproteinases 3), and VIM (vimentin) were identified as promising therapeutic targets. Several proteins were found to mediate the associations between some modifiable factors and CAD, with PCSK9, C1S, AGER (advanced glycosylation end product-specific receptor), and MST1 (mammalian Ste20-like kinase 1) exhibiting highest frequency among the mediating networks. CONCLUSIONS: This study suggests pathways explaining the associations of obesity and lifestyle factors with CAD from alterations in blood protein levels. These insights may be used to prioritize therapeutic intervention for further study.

Health effects of milk consumption: phenome-wide Mendelian randomization study.

BACKGROUND: We performed phenome-wide Mendelian randomization analysis (MR-PheWAS), two-sample MR analysis, and systemic review to comprehensively explore the health effects of milk consumption in the European population. METHODS: Rs4988235 located upstream of the LCT gene was used as the instrumental variable for milk consumption. MR-PheWAS analysis was conducted to map the association of genetically predicted milk consumption with 1081 phenotypes in the UK Biobank study (n=339,197). The associations identified in MR-PheWAS were examined by two-sample MR analysis using data from the FinnGen study (n=260,405) and international consortia. A systematic review of MR studies on milk consumption was further performed. RESULTS: PheWAS and two-sample MR analyses found robust evidence in support of inverse associations of genetically predicted milk consumption with risk of cataract (odds ratio (OR) per 50 g/day increase in milk consumption, 0.89, 95% confidence interval (CI), 0.84-0.94; p=3.81×10-5), hypercholesterolemia (OR, 0.91, 95% CI 0.86-0.96; p=2.97×10-4), and anal and rectal polyps (OR, 0.85, 95% CI, 0.77-0.94; p=0.001). An inverse association for type 2 diabetes risk (OR, 0.92, 95% CI, 0.86-0.97; p=0.003) was observed in MR analysis based on genetic data with body mass index adjustment but not in the corresponding data without body mass index adjustment. The systematic review additionally found evidence that genetically predicted milk consumption was inversely associated with asthma, hay fever, multiple sclerosis, colorectal cancer, and Alzheimer's disease, and positively associated with Parkinson's disease, renal cell carcinoma, metabolic syndrome, overweight, and obesity. CONCLUSIONS: This study suggests several health effects of milk consumption in the European population.

Circulating vitamin C concentration and risk of cancers: a Mendelian randomization study.

BACKGROUND: Circulating vitamin C concentrations have been associated with several cancers in observational studies, but little is known about the causal direction of the associations. This study aims to explore the potential causal relationship between circulating vitamin C and risk of five most common cancers in Europe. METHODS: We used summary-level data for genetic variants associated with plasma vitamin C in a large vitamin C genome-wide association study (GWAS) meta-analysis on 52,018 Europeans, and the corresponding associations with lung, breast, prostate, colon, and rectal cancer from GWAS consortia including up to 870,984 participants of European ancestry. We performed two-sample, bi-directional Mendelian randomization (MR) analyses using inverse-variance-weighted method as the primary approach, while using 6 additional methods (e.g., MR-Egger, weighted median-based, and mode-based methods) as sensitivity analysis to detect and adjust for pleiotropy. We also conducted a meta-analysis of prospective cohort studies and randomized controlled trials to examine the association of vitamin C intakes with cancer outcomes. RESULTS: The MR analysis showed no evidence of a causal association of circulating vitamin C concentration with any examined cancer. Although the odds ratio (OR) per one standard deviation increase in genetically predicted circulating vitamin C concentration was 1.34 (95% confidence interval 1.14 to 1.57) for breast cancer in the UK Biobank, this association could not be replicated in the Breast Cancer Association Consortium with an OR of 1.05 (0.94 to 1.17). Smoking initiation, as a positive control for our reverse MR analysis, showed a negative association with circulating vitamin C concentration. However, there was no strong evidence of a causal association of any examined cancer with circulating vitamin C. Sensitivity analysis using 6 different analytical approaches yielded similar results. Moreover, our MR results were consistent with the null findings from the meta-analysis exploring prospective associations of dietary or supplemental vitamin C intakes with cancer risk, except that higher dietary vitamin C intake, but not vitamin C supplement, was associated with a lower risk of lung cancer (risk ratio: 0.84, 95% confidence interval 0.71 to 0.99). CONCLUSIONS: These findings provide no evidence to support that physiological-level circulating vitamin C has a large effect on risk of the five most common cancers in European populations, but we cannot rule out very small effect sizes.

Dietary fruit and vegetable intake, gut microbiota, and type 2 diabetes: results from two large human cohort studies.

BACKGROUND: Little is known about the inter-relationship among fruit and vegetable intake, gut microbiota and metabolites, and type 2 diabetes (T2D) in human prospective cohort study. The aim of the present study was to investigate the prospective association of fruit and vegetable intake with human gut microbiota and to examine the relationship between fruit and vegetable-related gut microbiota and their related metabolites with type 2 diabetes (T2D) risk. METHODS: This study included 1879 middle-age elderly Chinese adults from Guangzhou Nutrition and Health Study (GNHS). Baseline dietary information was collected using a validated food frequency questionnaire (2008-2013). Fecal samples were collected at follow-up (2015-2019) and analyzed for 16S rRNA sequencing and targeted fecal metabolomics. Blood samples were collected and analyzed for glucose, insulin, and glycated hemoglobin. We used multivariable linear regression and logistic regression models to investigate the prospective associations of fruit and vegetable intake with gut microbiota and the association of the identified gut microbiota (fruit/vegetable-microbiota index) and their related fecal metabolites with T2D risk, respectively. Replications were performed in an independent cohort involving 6626 participants. RESULTS: In the GNHS, dietary fruit intake, but not vegetable, was prospectively associated with gut microbiota diversity and composition. The fruit-microbiota index (FMI, created from 31 identified microbial features) was positively associated with fruit intake (p < 0.001) and inversely associated with T2D risk (odds ratio (OR) 0.83, 95%CI 0.71-0.97). The FMI-fruit association (p = 0.003) and the FMI-T2D association (OR 0.90, 95%CI 0.84-0.97) were both successfully replicated in the independent cohort. The FMI-positive associated metabolite sebacic acid was inversely associated with T2D risk (OR 0.67, 95%CI 0.51-0.86). The FMI-negative associated metabolites cholic acid (OR 1.35, 95%CI 1.13-1.62), 3-dehydrocholic acid (OR 1.30, 95%CI 1.09-1.54), oleylcarnitine (OR 1.77, 95%CI 1.45-2.20), linoleylcarnitine (OR 1.66, 95%CI 1.37-2.05), palmitoylcarnitine (OR 1.62, 95%CI 1.33-2.02), and 2-hydroglutaric acid (OR 1.47, 95%CI 1.25-1.72) were positively associated with T2D risk. CONCLUSIONS: Higher fruit intake-associated gut microbiota and metabolic alteration were associated with a lower risk of T2D, supporting the public dietary recommendation of adopting high fruit intake for the T2D prevention.

Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities.

BACKGROUND: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. OBJECTIVES: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities. METHODS: A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy. RESULTS: The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Low-density lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%-49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. Five proteins (interleukin-6 receptor subunit alpha, LRP12, prothrombin, angiopoietin-1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities. CONCLUSION: This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.

Plasma proteins and onset of type 2 diabetes and diabetic complications: Proteome-wide Mendelian randomization and colocalization analyses.

We conduct proteome-wide Mendelian randomization and colocalization analyses to decipher the associations of blood proteins with the risk of type 2 diabetes and diabetic complications. Genetic data on plasma proteome are obtained from 54,306 UK Biobank participants and 35,559 Icelanders. Summary-level data on type 2 diabetes are obtained from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis consortium) consortium (74,124 cases) and FinnGen study (33,043 cases). Data on 10 diabetic complications are obtained from FinnGen and corresponding studies. Among 1,886 proteins, genetically predicted levels of 47 plasma proteins are associated with type 2 diabetes. Eleven of these proteins have strong support of colocalization. Seventeen proteins are associated with at least one diabetic complication, although a few have colocalization support. HLA-DRA, AGER, HSPA1A, and HSPA1B are associated with most microvascular complications. This study reveals causal proteins for the onset of type 2 diabetes and diabetic complications, which enhances the understanding of molecular etiology and development of therapeutics.

Air Kerma Calculation in Diagnostic Medical Imaging Devices Using Group Method of Data Handling Network.

The air kerma, which is the amount of energy given off by a radioactive substance, is essential for medical specialists who use radiation to diagnose cancer problems. The amount of energy that a photon has when it hits something can be described as the air kerma (the amount of energy that was deposited in the air when the photon passed through it). Radiation beam intensity is represented by this value. Hospital X-ray equipment has to account for the heel effect, which means that the borders of the picture obtain a lesser radiation dosage than the center, and that air kerma is not symmetrical. The voltage of the X-ray machine can also affect the uniformity of the radiation. This work presents a model-based approach to predict air kerma at various locations inside the radiation field of medical imaging instruments, making use of just a small number of measurements. Group Method of Data Handling (GMDH) neural networks are suggested for this purpose. Firstly, a medical X-ray tube was modeled using Monte Carlo N Particle (MCNP) code simulation algorithm. X-ray tubes and detectors make up medical X-ray CT imaging systems. An X-ray tube's electron filament, thin wire, and metal target produce a picture of the electrons' target. A small rectangular electron source modeled electron filaments. An electron source target was a thin, 19,290 kg/m3 tungsten cube in a tubular hoover chamber. The electron source-object axis of the simulation object is 20° from the vertical. For most medical X-ray imaging applications, the kerma of the air was calculated at a variety of discrete locations within the conical X-ray beam, providing an accurate data set for network training. Various locations were taken into account in the aforementioned voltages inside the radiation field as the input of the GMDH network. For diagnostic radiology applications, the trained GMDH model could determine the air kerma at any location in the X-ray field of view and for a wide range of X-ray tube voltages with a Mean Relative Error (MRE) of less than 0.25%. This study yielded the following results: (1) The heel effect is included when calculating air kerma. (2) Computing the air kerma using an artificial neural network trained with minimal data. (3) An artificial neural network quickly and reliably calculated air kerma. (4) Figuring out the air kerma for the operating voltage of medical tubes. The high accuracy of the trained neural network in determining air kerma guarantees the usability of the presented method in operational conditions.

Comparison of fecal and blood metabolome reveals inconsistent associations of the gut microbiota with cardiometabolic diseases.

Blood metabolome is commonly used in human studies to explore the associations of gut microbiota-derived metabolites with cardiometabolic diseases. Here, in a cohort of 1007 middle-aged and elderly adults with matched fecal metagenomic (149 species and 214 pathways) and paired fecal and blood targeted metabolomics data (132 metabolites), we find disparate associations with taxonomic composition and microbial pathways when using fecal or blood metabolites. For example, we observe that fecal, but not blood butyric acid significantly associates with both gut microbiota and prevalent type 2 diabetes. These findings are replicated in an independent validation cohort involving 103 adults. Our results suggest that caution should be taken when inferring microbiome-cardiometabolic disease associations from either blood or fecal metabolome data.

The Association between Circulating 25-Hydroxyvitamin D and Carotid Intima-Media Thickness Is Mediated by Gut Microbiota and Fecal and Serum Metabolites in Adults.

SCOPE: Vitamin D is vital to cardiovascular health. This study examines the association between plasma 25-hydroxyvitamin D (25[OH]D) and the progression of carotid intima-media thickness (cIMT) and identifies the potential mediating biomarkers of gut microbiota and metabolites in adults. METHODS AND RESULTS: This 9-year prospective study includes 2975 subjects with plasma 25(OH)D at baseline and determined cIMT every 3 years. Higher circulating 25(OH)D is associated with decreased odds of higher (≥median) 9-year cIMT changes at the common carotid artery (hΔCCA-cIMT) (p-trend < 0.001). Multivariable-adjusted OR (95%CI) of hΔCCA-cIMT for tertiles 2 and 3 (vs. 1) of 25(OH)D is 0.87 (0.73-1.04) and 0.68 (0.57-0.82). Gut microbiome and metabolome analysis identify 18 biomarkers significantly associated with both 25(OH)D and hΔCCA-cIMT, including three microbial genera, seven fecal metabolites, eight serum metabolites, and pathway of synthesis and degradation of ketone bodies. Mediation/path analyses show the scores generated from the overlapped differential gut microbiota, fecal and serum metabolites, and serum acetoacetic acid alone could mediate the beneficial association between 25(OH)D and hΔCCA-cIMT by 10.8%, 23.1%, 59.2%, and 62.0% (all p < 0.05), respectively. CONCLUSIONS: These findings show a beneficial association between plasma 25(OH)D and the CCA-cIMT progression. The identified multi-omics biomarkers provide novel mechanistic insights for the epidemiological association.

Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases.

BACKGROUND: To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy. METHODS: The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue-specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence. FINDINGS: PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects. INTERPRETATION: This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoimmune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects. FUNDING: None.

The gut microbiota-bile acid axis mediates the beneficial associations between plasma vitamin D and metabolic syndrome in Chinese adults: A prospective study.

BACKGROUND & AIMS: Previous studies have suggested that circulating 25-hydroxyvitamin D (25 [OH]D, VD) and the gut microbiota-bile acid axis play crucial roles in metabolic health. Exploring the mediating role of the gut microbiota-bile acid axis would improve our understanding of the mechanisms underlying the effects of VD on human metabolic health. This study examined the association between plasma 25(OH)D and the prevalence/incidence of metabolic syndrome (MetS) and the mediating role of the gut microbiota-bile acid axis. METHODS: This prospective study included 3180 participants with plasma 25(OH)D data at baseline and 2966 participants with a 9-year follow-up. MetS was determined every three years. The gut microbiota was analyzed by 16S rRNA sequencing in 1752 participants, and targeted bile acid metabolites in feces were further determined in 974 participants using UPLC‒MS/MS at the middle of the study. Mediating roles of microbiota and bile acids in the VD-MetS associations were analyzed using mediation/path analyses adjusted for potential confounders. RESULTS: Among the 2966 participants who were followed-up, 1520, 193, 647, and 606 were MetS-free (normal), recovered, had incident MetS, and had persistent MetS, respectively. The multivariable-adjusted ORs (95% CIs) of MetS prevalence were 0.65 (0.50, 0.84) for baseline MetS and 0.46 (0.33, 0.65) for 9-year persistent MetS in quartile 4 (compared to quartile 1) of plasma 25(OH)D (median: 37.7 vs. 19.6, ng/ml). The corresponding HR (95% CI) of 9-year MetS incidence was 0.71 (0.56, 0.90) (all P-trend < 0.05). Higher VD concentrations were associated with greater α-diversity of the gut microbiota, which was inversely correlated with MetS risk. The groups classified by VD and MetS status had significantly different ß-diversity. Ruminiclostridium-6 and Christensenellaceae R-7 group were enriched in the high-VD group and were inversely associated with MetS. However, opposite associations were observed for Lachnoclostridium and Acidaminococcus. The overlapping differential microbial score (ODMS) developed from the four differential genera explained 12.2% of the VD-MetS associations (Pmediation = 0.015). Furthermore, the fecal bile acid score created from 11 differential bile acids related to ODMS and MetS mediated 34.2% of the association between ODMS and MetS (Pmediation = 0.029). Path analyses showed that the inverse association between plasma 25(OH)D and MetS could be mediated by the gut microbiota-bile acid axis. CONCLUSIONS: The findings suggest that the gut microbiota-bile acid axis partially mediates the beneficial association between plasma 25(OH)D and the risk of persistent MetS and incident MetS in the Chinese population.

Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses.

BACKGROUND: Identifying new drug targets for inflammatory bowel disease (IBD) is urgently needed. The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) and colocalization analyses to identify possible targets for IBD. METHODS: Summary-level data of 4907 circulating protein levels were extracted from a large-scale protein quantitative trait loci study including 35,559 individuals. Genetic associations with IBD and its subtypes were obtained from the Inflammatory Bowel Disease Genetics Consortium (25,024 cases and 34,915 controls), the FinnGen study (7206 cases and 253,199 controls), and the UK Biobank study (7045 cases and 449,282 controls). MR analysis was conducted to estimate the associations between protein and IBD risk. The colocalization analysis was used to examine whether the identified proteins and IBD shared casual variants. FINDINGS: Genetically predicted levels of 3, and 5 circulating proteins were associated with IBD and ulcerative colitis (UC), respectively. With high supporting evidence of colocalization, genetically predicted MST1 (macrophage stimulating 1) and HGFAC (hepatocyte growth factor activator) levels were inversely associated with IBD risks. The associations of STAT3 (signal transducer and activator of transcription 3), MST1, CXCL5 (C-X-C motif chemokine ligand 5), and ITPKA (inositol-trisphosphate 3-kinase A) with the risk of UC were supported by colocalization analysis. INTERPRETATION: The proteome-wide MR investigation identified many proteins associated with the risk of IBD. MST1, HGFAC, STAT3, ITPKA, and CXCL5 deserve further investigation as potential therapeutic targets for IBD. FUNDING: SCL is supported by research grants from the Swedish Research Council for Health, Working Life and Welfare (Forte; grant no. 2018-00123) and the Swedish Research Council (Vetenskapsrådet; grant no. 2019-00977). XYW is supported by research grants from the National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province (2019SK2041). XL is supported by research grants from the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001).

Deciphering the genetic architecture of atrial fibrillation offers insights into disease prediction, pathophysiology and downstream sequelae.

Aims: The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathogenesis using Mendelian randomization analysis. Methods and results: We conducted a genome-wide association study meta-analysis including 109,787 AF cases and 1,165,920 controls of European ancestry and identified 215 loci, among which 91 were novel. We performed Genomic Structural Equation Modeling analysis between AF and four cardiovascular comorbidities (coronary artery disease, ischemic stroke, heart failure, and vneous thromboembolism) and found 189 loci shared across these diseases as well as a universal genetic locus shared by atherosclerotic outcomes (i.e., rs1537373 near CDKN2B). Three genetic loci (rs10740129 near JMJD1C, rs2370982 near NRXN3, and rs9931494 near FTO) were associated with AF and cardiometabolic traits. A polygenic risk score derived from this genome-wide meta-analysis was associated with AF risk (odds ratio 2.36, 95% confidence interval 2.31-2.41 per standard deviation increase) in the UK biobank. This score, combined with age, sex, and basic clinical features, predicted AF risk (AUC 0.784, 95% CI 0.781-0.787) in Europeans. Phenome-wide association analysis of the polygenic risk score identified many AF-related comorbidities of the circulatory, endocrine, and respiratory systems. Phenome-wide and multi-omic Mendelian randomization analyses identified associations of blood lipids and pressure, diabetes, insomnia, obesity, short sleep, and smoking, 27 blood proteins, one gut microbe (genus.Catenibacterium), and 11 blood metabolites with risk to AF. Conclusions: This genome-wide association study and trans-omic Mendelian randomization analysis provides insights into disease risk prediction, pathophysiology and downstream sequelae.

Continuous glucose monitoring-derived glycemic metrics and adverse pregnancy outcomes among women with gestational diabetes: a prospective cohort study.

Background: Continuous glucose monitoring (CGM) has shown potential in improving maternal and neonatal outcomes in individuals with type 1/2 diabetes, but data in gestational diabetes mellitus (GDM) is limited. We aimed to explore the relationship between CGM-derived metrics during pregnancy and pregnancy outcomes among women with GDM. Methods: We recruited 1302 pregnant women with GDM at a mean gestational age of 26.0 weeks and followed them until delivery. Participants underwent a 14-day CGM measurement upon recruitment. The primary outcome was any adverse pregnancy outcome, defined as having at least one of the outcomes: preterm birth, large-for-gestational-age (LGA) birth, fetal distress, premature rupture of membranes, and neonatal intensive care unit (NICU) admission. The individual outcomes included in the primary outcome were considered as secondary outcomes. We conducted multivariable logistic regression to evaluate the association of CGM-derived metrics with these outcomes. Findings: Per 1-SD difference in time above range (TAR), glucose area under the curve (AUC), nighttime mean blood glucose (MBG), daytime MBG, and daily MBG was associated with higher risk of any adverse pregnancy outcome, with odds ratio: 1.22 (95% CI 1.08-1.36), 1.22 (95% CI 1.09-1.37), 1.18 (95% CI 1.05-1.32), 1.21 (95% CI 1.07-1.35), and 1.22 (95% CI 1.09-1.37), respectively. Time in range, TAR, AUC, nighttime MBG, daytime MBG, daily MBG, and mean amplitude of glucose excursions were positively associated, while time blow range was inversely associated with the risk of LGA. Additionally, higher value for TAR was associated with higher risk of NICU admission. We further summarized the potential thresholds of TAR (2.5%) and daily MBG (4.8 mmol/L) to distinguish individuals with and without any adverse pregnancy outcome. Interpretation: The CGM-derived metrics may help identify individuals at higher risk of adverse pregnancy outcomes. These CGM biomarkers could serve as potential new intervention targets to maintain a healthy pregnancy status among women with GDM. Funding: National Key R&D Program of China, National Natural Science Foundation of China, and Westlake Laboratory of Life Sciences and Biomedicine.

Genome-wide genotype-serum proteome mapping provides insights into the cross-ancestry differences in cardiometabolic disease susceptibility.

Identification of protein quantitative trait loci (pQTL) helps understand the underlying mechanisms of diseases and discover promising targets for pharmacological intervention. For most important class of drug targets, genetic evidence needs to be generalizable to diverse populations. Given that the majority of the previous studies were conducted in European ancestry populations, little is known about the protein-associated genetic variants in East Asians. Based on data-independent acquisition mass spectrometry technique, we conduct genome-wide association analyses for 304 unique proteins in 2,958 Han Chinese participants. We identify 195 genetic variant-protein associations. Colocalization and Mendelian randomization analyses highlight 60 gene-protein-phenotype associations, 45 of which (75%) have not been prioritized in Europeans previously. Further cross-ancestry analyses uncover key proteins that contributed to the differences in the obesity-induced diabetes and coronary artery disease susceptibility. These findings provide novel druggable proteins as well as a unique resource for the trans-ancestry evaluation of protein-targeted drug discovery.

Population serum proteomics uncovers a prognostic protein classifier for metabolic syndrome.

Metabolic syndrome (MetS) is a complex metabolic disorder with a global prevalence of 20%-25%. Early identification and intervention would help minimize the global burden on healthcare systems. Here, we measured over 400 proteins from ∼20,000 proteomes using data-independent acquisition mass spectrometry for 7,890 serum samples from a longitudinal cohort of 3,840 participants with two follow-up time points over 10 years. We then built a machine-learning model for predicting the risk of developing MetS within 10 years. Our model, composed of 11 proteins and the age of the individuals, achieved an area under the curve of 0.774 in the validation cohort (n = 242). Using linear mixed models, we found that apolipoproteins, immune-related proteins, and coagulation-related proteins best correlated with MetS development. This population-scale proteomics study broadens our understanding of MetS and may guide the development of prevention and targeted therapies for MetS.

Human Gut Antibiotic Resistome and Progression of Diabetes.

The antibiotic resistance crisis underlies globally increasing failures in treating deadly bacterial infections, largely due to the selection of antibiotic resistance genes (ARG) collection, known as the resistome, in human gut microbiota. So far, little is known about the relationship between gut antibiotic resistome and host metabolic disorders such as type 2 diabetes (T2D). Here, metagenomic landscape of gut antibiotic resistome is profiled in a large multiomics human cohort (n = 1210). There is a significant overall shift in gut antibiotic resistome structure among healthy, prediabetes, and T2D groups. It is found that larger ARG diversity is associated with a higher risk of T2D. The novel diabetes ARG score is positively associated with glycemic traits. Longitudinal validation analysis confirms that the ARG score is associated with T2D progression, characterized by the change of insulin resistance. Collectively, the data describe the profiles of gut antibiotic resistome and support its close relationship with T2D progression.

The gut microbiota-bile acid axis links the positive association between chronic insomnia and cardiometabolic diseases.

Evidence from human cohorts indicates that chronic insomnia is associated with higher risk of cardiometabolic diseases (CMD), yet whether gut microbiota plays a role is unclear. Here, in a longitudinal cohort (n = 1809), we find that the gut microbiota-bile acid axis may link the positive association between chronic insomnia and CMD. Ruminococcaceae UCG-002 and Ruminococcaceae UCG-003 are the main genera mediating the positive association between chronic insomnia and CMD. These results are also observed in an independent cross-sectional cohort (n = 6122). The inverse associations between those gut microbial biomarkers and CMD are mediated by certain bile acids (isolithocholic acid, muro cholic acid and nor cholic acid). Habitual tea consumption is prospectively associated with the identified gut microbiota and bile acids in an opposite direction compared with chronic insomnia. Our work suggests that microbiota-bile acid axis may be a potential intervention target for reducing the impact of chronic insomnia on cardiometabolic health.

Interaction of n-3 polyunsaturated fatty acids with host CD36 genetic variant for gut microbiome and blood lipids in human cohorts.

BACKGROUND & AIMS: Previous studies suggest an interaction of CD36 genetic variant rs1527483 with n-3 polyunsaturated fatty acids (PUFAs) to modulate blood lipids. However, successful replication is lacking and the role of gut microbiome remains unclear. Here, we aimed to replicate these gene-diet interactions on blood lipids and investigate their possible associations with gut microbiome. METHODS: We evaluated the n-3 PUFA-rs1527483 interaction on blood lipids in two population-based cohorts (n = 4,786). We profiled fecal microbiome and short-chain fatty acids among 1,368 participants. The associations between n-3 PUFAs and bacterial alpha-diversity, taxonomies and short-chain fatty acids by rs1527483 genotypes were analyzed using regression models. RESULTS: CD36 rs1527483-GG carriers responded better to high n-3 PUFA exposure; higher blood HDL-C (beta (95% CI): 0.05 (0.01, 0.08) mmol/L) and lower TG (log-transformed, beta (95% CI): -0.08 (-0.14, -0.02)) were observed among participants whose n-3 PUFA exposure ranked in the top quartile comparing with those in the bottom quartile. We identified docosahexaenoic acid (DHA) as the driven individual n-3 PUFA biomarker, which showed interaction with rs1527483. Among the rs1527483-GG carriers, but not other genotype groups, DHA exposure was positively associated with bacterial Faith's phylogenetic diversity, Observed OTUs, Shannon's diversity index, Dorea, Coriobacteriales Incertae Sedis spp, and fecal propionic acid levels. Another independent longitudinal cohort validated the DHA-rs1527483 interaction on gut microbiome. The identified microbial features were correlated with blood lipids, and the host biosynthesis and metabolism pathways of bile acids and aromatic amino acids. CONCLUSIONS: The present study found that higher n-3 PUFAs were associated with improved blood lipids and gut microbial features only among rs1527483-GG carriers. These findings highlight a potential role of gut microbiome to link the CD36 genetic variant, n-3 PUFAs and blood lipids, revealing a new research direction to interpret the gene-diet interaction for cardiometabolic health.

Associations of dietary diversity with the gut microbiome, fecal metabolites, and host metabolism: results from 2 prospective Chinese cohorts.

BACKGROUND: Dietary diversity is essential for human health. The gut ecosystem provides a potential link between dietary diversity, host metabolism, and health, yet this mechanism is poorly understood. OBJECTIVES: Here, we aimed to investigate the relation between dietary diversity and the gut environment as well as host metabolism from a multiomics perspective. METHODS: Two independent longitudinal Chinese cohorts (a discovery and a validation cohort) were included in the present study. Dietary diversity was evaluated with FFQs. In the discovery cohort (n = 1916), we performed shotgun metagenomic and 16S ribosomal ribonucleic acid (rRNA) sequencing to profile the gut microbiome. We used targeted metabolomics to quantify fecal and serum metabolites. The associations between dietary diversity and the microbial composition were replicated in the validation cohort (n = 1320). RESULTS: Dietary diversity was positively associated with α diversity of the gut microbiota. We identified dietary diversity-related gut environment features, including the microbial structure (ß diversity), 68 microbial genera, 18 microbial species, 8 functional pathways, and 13 fecal metabolites. We further found 332 associations of dietary diversity and related gut environment features with circulating metabolites. Both the dietary diversity and diversity-related features were inversely correlated with 4 circulating secondary bile acids. Moreover, 16 mediation associations were observed among dietary diversity, diversity-related features, and the 4 secondary bile acids. CONCLUSIONS: These results suggest that high dietary diversity is associated with the gut microbial environment. The identified key microbes and metabolites may serve as hypotheses to test for preventing metabolic diseases.