Search

An emerging field of research is starting to examine the association of infectious pathogens with type 2 diabetes mellitus (T2DM). An understudied parasite of interest is Toxoplasma gondii. Globally, very few studies have been conducted to investigate this association. Additionally, very little data exists on the prevalence of T. gondii in the general Australian population. Our group sought to determine the prevalence, association, and risk factors between T. gondii infection and T2DM from a representative Australian human population. Through a cross-sectional, age- and gender-matched case-control study, 150 subjects with T2DM together with 150 control subjects from the Busselton Health Study cohort were investigated. Sera samples were tested for the presence of anti-T. gondii IgG and IgM antibodies using enzyme-linked immunosorbent assays. Survey-derived data were also analyzed to evaluate associated risk factors. The IgG seroprevalence was found to be 62% and 66% for the T2DM and control groups, respectively (OR:0.84; p=0.471). IgM antibodies were detected in 5% of the T2DM patients and in 10% of the controls (OR=0.51; p=0.135). There were no significant differences between male and female IgG seroprevalence rates for both groups (OR:0.88, 0.80; p=0.723). The IgG seropositivity rate increased significantly in T2DM patients aged 45-84 years in comparison to those aged 18-44 years (p<0.05), but this was not observed in the control subjects. No risk factors were associated with T. gondii seropositivity in both groups. The first Australian study of its kind found T. gondii infection in Western Australia to be highly prevalent. The results also showed that there is no serological evidence of an association between T. gondii infection and T2DM in the studied subjects. Australian health authorities should focus on raising awareness of toxoplasma infection and target T. gondii transmission control. Further studies are needed to clarify the role of T. gondii in T2DM.

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

Cardiovascular disease is a common complex trait that calls for next-generation biomarkers for precision diagnostics and therapeutics. The most common type of post-translational protein modificatio...

Aberrant immunoglobulin G (IgG) N-glycosylation offers new prospects to detect changes in cell metabolism and by extension, for biomarker discovery in type 2 diabetes mellitus (T2DM). However, past studies did not analyze the individual IgG subclasses in relation to T2DM pathophysiology. We report here original findings through a comparison of the IgG subclass-specific fragment crystallizable (Fc) glycan biosignatures in 115 T2DM patients with 122 healthy controls within the Uyghur population in China. IgG Fc glycosylation profiles were analyzed using nano- liquid chromatography–mass spectrometry to exclude changes attributed to fragment antigen binding N- glycosylation. After correction for clinical covariates, 27 directly measured and 4 derived glycan traits of the IgG subclass-specific N- glycopeptides were significantly associated with T2DM. Furthermore, we observed in T2DM a decrease in bisecting N-acetylglucosamine of IgG2 and agalactosylation of IgG4, and an increase in sialylation of IgG4 and digalactosylation of IgG2. Classification model based on IgG subclass- specific N-glycan traits was able to distinguish patients with T2DM from controls with an area under the receiver operating characteristic curve of 0.927 (95% confidence interval 0.894–0.960, p < 0.001). In conclusion, a robust association between the IgG subclass-specific Fc N-glycomes and T2DM was observed in the Uyghur population sample in China, suggesting a potential for the IgG Fc glycosylation as a biomarker candidate for type 2 diabetes. The integration of glycomics with other system science biomarkers might offer further hope for innovation in diagnosis and treatment of T2DM in the future. Finally, it is noteworthy that “Population Glycomics” is an emerging approach to biomarker discovery for common complex diseases.

Type 2 diabetes mellitus (T2DM) is a common complex trait arising from interactions among multiple environmental, genomic, and postgenomic factors. We report here the first attempt to investigate the association between immunoglobulin G (IgG) N-glycan patterns, T2DM, and their clinical risk factors in an Australian population. N-glycosylation of proteins is one of the most frequently observed co- and post-translational modifications, reflecting, importantly, the real-time status of the interplay between the genomic and postgenomic factors. In a community-based case-control study, 849 participants (217 cases and 632 controls) were recruited from an urban community in Busselton, Western Australia. We applied the ultraperformance liquid chromatography method to analyze the composition of IgG N-glycans. We then conducted Spearman's correlation analyses to explore the association between glycan biomarker candidates and clinical risk factors. We performed area under the curve (AUC) analysis of the receiver operating characteristic curves by fivefold cross-validation for clinical risk factors, IgG glycans, and their combination. Two directly measured and four derived glycan peaks were significantly associated with T2DM, after correction for extensive clinical confounders and false discovery rate, thus suggesting that IgG N-glycan traits are highly correlated with T2DM clinical risk factors. Moreover, adding the IgG glycan profiles to fasting blood glucose in the logistic regression model increased the AUC from 0.799 to 0.859. The AUC for IgG glycans alone was 0.623 with a 95% confidence interval 0.580-0.666. In addition, our study provided new evidence of diversity in T2DM complex trait by IgG N-glycan stratification. Six IgG glycan traits were firmly associated with T2DM, which reflects an increased proinflammatory and biological aging status. In summary, our study reports novel associations between the IgG N-glycome and T2DM in an Australian population and the putative role of proinflammatory mechanisms. Furthermore, IgG N-glycomic alterations offer future prospects as inflammatory biomarker candidates for T2DM diagnosis, and monitoring of T2DM progression to cardiovascular disease or renal failure.

The increasing prevalence of hyperuricemia has been recognized as an emerging public health concern in both developed and developing countries. Hyperuricemia is a metabolic condition characterized by an elevated serum uric acid, and associated with renal damage, diabetes, autoimmune disorders, and cardiovascular diseases. Although human genetic variation has been recognized as a factor, posttranslational cellular processes and glycan biomarkers have not been studied extensively for susceptibility to hyperuricemia. We evaluated whether immunoglobulin (Ig)G N-glycans play a role in hyperuricemia in the general population. This cross-sectional study enrolled 635 participants (208 men and 427 women), ages ≥18 years, from a community-based population in Beijing, China. The IgG N-glycan composition of serum was analyzed by an ultraperformance liquid chromatography method. The prevalence of hyperuricemia observed in this sample was 5.98% (14.9% in men and 1.6% in women). Serum uric acid level was positively correlated with glycan peaks (GP)1, GP2, GP4, GP6, GP10, and GP11, whereas it was negatively correlated with GP12, GP13, GP14, GP15, GP18, and GP20. The combination of GP9, GP10, body mass index, and gender distinguished individuals with hyperuricemia from subjects without hyperuricemia, with an area under the curve value of 0.849 (95% confidence interval: 0.784-0.915). These findings collectively suggest a possible link between hyperuricemia and IgG N-glycans, which might be potentially mediated through inflammation-related mechanisms. Additional research on glycan biomarkers in independent and community-based population samples might allow the development of glycan diagnostics for hyperuricemia and gout in the future.

Glycomics is a new subspecialty in omics systems sciences that offers significant promise for next-generation biomarkers on disease susceptibility, drug target discovery, and precision medicine. In...

BACKGROUND AND PURPOSE Elevated C-reactive protein (CRP) is associated with an increased risk of ischaemic stroke (IS). However, the causality of this association is uncertain. The aim is to investigate whether genetically raised plasma CRP concentration levels are associated with IS on the basis of the Mendelian randomization method. METHODS Based on the National Center for Biotechnology Information single nucleotide polymorphism (SNP) database, the Chinese online genetic database as well as previously published studies, four CRP-associated SNP alleles (rs1130864, rs1205, rs876537 and rs3093059) with minor allele frequency ≥0.15 were selected and the concentration levels of CRP were measured in 378 first-ever IS patients and 613 healthy controls. RESULTS Three SNPs were chosen and used as instrumental variables. The adjusted odds ratios (ORs) [95% confidence interval (95% CI)] of IS per addition of the modelled allele were 1.07 (0.79-1.45) for rs876537, 0.99 (0.73-1.35) for rs1205 and 1.08 (0.71-1.65) for rs3093059. The OR (95% CI) of IS for plasma CRP ≥2.0 mg/l was 2.19 (1.06-4.53) compared with

Background The mechanism by which normal body mass index (BMI) with central adiposity (NWCA) increases the risk of the diseases has not been completely elucidated. The inflammatory role of immunoglobulin G (IgG) N-glycosylation in obesity defined by BMI or central adiposity defined by waist-to-hip ratio (WHR) was reported, respectively. We undertook this three-center cross-sectional study to determine the association between the IgG N-glycans and NWCA. Methods The participants were categorized into four different phenotypes: normal BMI with normal WHR (NW), normal BMI with central adiposity (NWCA), obesity with normal WHR (ONCA) and obesity with central adiposity (OCA). The IgG N-glycans were analyzed using ultra-performance liquid chromatography analysis of released glycans, and differences among groups were compared. Results In total, 17 out of 24 initial IgG N-glycans were significantly different among the four groups (NW, ONCA, NWCA and OCA) (P

IntroductionProfiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%–40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk.Methods and analysisThe prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness–implementation hybrid design, taking place in the UK and China. People are eligible if they are 55–75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention.Ethics and disseminationThe PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London—Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People’s Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal.Trial registration numberISRCTN15986016.

Background: The causal association of C-reactive protein (CRP) and fibrinogen on intracerebral hemorrhage (ICH) remains uncertain. We investigated the causal associations of CRP and fibrinogen with ICH using two-sample Mendelian randomization.Method: We used single-nucleotide polymorphisms associated with CRP and fibrinogen as instrumental variables. The summary data on ICH were obtained from the International Stroke Genetics Consortium (1,545 cases and 1,481 controls). Two-sample Mendelian randomization estimates were performed to assess with inverse-variance weighted and sensitive analyses methods including the weighted median, the penalized weighted median, pleiotropy residual sum and outlier (MR-PRESSO) approaches. MR-Egger regression was used to explore the pleiotropy.Results: The MR analyses indicated that genetically predicted CRP concentration was not associated with ICH, with an odds ratio (OR) of 1.263 (95% CI = 0.935–1.704, p = 0.127). Besides, genetically predicted fibrinogen concentration was not associated with an increased risk of ICH, with an OR of 0.879 (95% CI = 0.060–18.281; p = 0.933). No evidence of pleiotropic bias was detected by MR-Egger. The findings were overall robust in sensitivity analyses.Conclusions: Our findings did not support that CRP and fibrinogen are causally associated with the risk of ICH.

Objectives: Hypertension and type 2 diabetes mellitus comorbidity (HDC) is common, which confers a higher risk of cardiovascular disease than the presence of either condition alone. Describing the underlying glycomic changes of immunoglobulin G (IgG) that predispose individuals to HDC may help develop novel protective immune-targeted and anti-inflammatory therapies. Therefore, we investigated glycosylation changes of IgG associated with HDC. Methods: The IgG N-glycan profiles of 883 plasma samples from the three northwestern Chinese Muslim ethnic minorities and the Han Chinese were analyzed by ultra-performance liquid chromatography instrument. Results: We found that 12 and six IgG N-glycan traits showed significant associations with HDC in the Chinese Muslim ethnic minorities and the Han Chinese, respectively, after adjustment for potential confounders and false discovery rate. Adding the IgG N-glycan traits to the baseline models, the area under the receiver operating characteristic curves (AUCs) of the combined models differentiating HDC from hypertension (HTN), type 2 diabetes mellitus (T2DM), and healthy individuals were 0.717, 0.747, and 0.786 in the pooled samples of Chinese Muslim ethnic minorities, and 0.828, 0.689, and 0.901 in the Han Chinese, respectively, showing improved discriminating performance than both the baseline models and the glycan-based models. Conclusion: Altered IgG N-glycan profiles were shown to associate with HDC, suggesting the involvement of inflammatory processes of IgG glycosylation. The alterations of IgG N-glycome, illustrated here for the first time in HDC, demonstrate a biomarker potential, which may shed light on future studies investigating their potential for monitoring or preventing the progression from HTN or T2DM towards HDC.

Prospective studies have shown that abnormally circulating cholesterol is associated with the risk of dementia. However, whether the association is causal or not remains unclear. We attempt to infer the causal association in a MR meta-analysis by using ApoE gene polymorphisms as instrument variables. Studies with dementia risk (27 studies) or circulating lipid levels (7 studies) were included, with totally 3136 dementia patients and 3103 healthy controls. The analyses showed that carriers of ε2 allele significantly were of decreased risk of AD (OR = 0.70; 95% CI: 0.58–0.84; P P P P P P P P

Background Many contradictory conclusions pertaining to the telomere length in peripheral leukocyte chromosomes as a potential biomarker for ischemic stroke (IS) risk have been reported by the various observational studies in previous years. This study aims to investigate whether the leukocyte telomere length is associated with an increased IS risk or not, based on the Mendelian randomization (MR) approach. Methods Based on the NHGRI-EBI GWAS Catalog database, the Chinese online genetic database as well as the previous published studies, twelve single nucleotide polymorphisms (SNPs) with minor allele frequency ≥ 0.05 were selected and the leukocyte telomere length was measured in 431 first-ever IS patients and 304 healthy controls (quantitative polymerase chain reaction). To explore linear and non-linear effect of telomere length on the IS risk, we preformed the linear MR analysis (the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method), and the non-linear MR analysis (semiparametric method with three tests for non-linearity, including the quadratic test, Cochran’s Q test, and the fractional polynomial test). Results Two verified SNPs (rs11125529 and rs412658) were chosen as instrumental variables. In linear MR analysis, the adjusted odds ratios and 95% confidence intervals of IS for genetically predicted telomere lengths, based on the two SNPs, were 1.312 (0.979 to 1.759), 1.326 (0.932 to 1.888) and 1.226 (0.844 to 1.781) for the inverse-variance weighted method, the maximum likelihood method, and the mode-based estimation method, respectively. Three tests for nonlinearity failed to reject the null exactly, indicating that the relationship between telomere length and IS risk is unlikely to be non-linear. Conclusion This MR study based on individual data does not provide strong evidence for a positive linear or non-linear effect of telomere length on the IS risk.

BACKGROUND: Suboptimal health status (SHS) is a subclinical stage of chronic diseases, and the identification of SHS provides an opportunity for the predictive, preventive, and personalized medicine (PPPM) of chronic diseases. Previous studies have reported the associations between metabolic signatures and early signs of chronic diseases. METHODS: This study aimed to detect the metabolic biomarkers for the identification of SHS in a case-control study. SHS questionnaire-25 (SHSQ-25) was used in a population-based health survey to measure the SHS levels of participants. The liquid chromatography-mass spectrometry-based untargeted metabolomics analysis was conducted on plasma samples collected from 50 SHS participants and 50 age- and sex-matched healthy controls. RESULTS: After adjusting for the confounders, 24 significantly differential metabolites, such as sphingomyelin, sphingosine, sphinganine, progesterone, pregnanolone, and bilirubin, were identified as the candidate biomarkers for SHS. Pathway analysis revealed that sphingolipid metabolism, taurine metabolism, and steroid hormone biosynthesis are the disturbed metabolic pathways related to SHS. A combination of four metabolic biomarkers (sphingosine, pregnanolone, taurolithocholate sulfate, cervonyl carnitine) can distinguish SHS individuals from the controls with a sensitivity of 94.0%, a specificity of 90.0%, and an area under the receiver operating characteristic curve of 0.977. CONCLUSION: Plasma metabolites are valuable biomarkers for SHS identification, and meanwhile, SHSQ-25 can be used as an alternative health screening tool in the population-based health survey. SHS-related metabolic disturbances could be detected at the early onset of SHS, and SHS-related metabolites could create a window opportunity for PPPM of chronic diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13167-020-00200-7) contains supplementary material, which is available to authorized users.

Background Alternative N-glycosylation has significant structural and functional consequences on immunoglobulin G (IgG) and can affect immune responses, acting as a switch between pro- and anti-inflammatory IgG functionality. Studies have demonstrated that IgG N-glycosylation is associated with ageing, body mass index, type 2 diabetes and hypertension. Methods Herein, we have demonstrated patterns of IgG glycosylation that are associated with blood lipids in a cross-sectional study including 598 Han Chinese aged 20–68 years. The IgG glycome composition was analysed by ultra-performance liquid chromatography. Results Blood lipids were positively correlated with glycan peak GP6, whereas they were negatively correlated with GP18 (P

Male infertility is an important global health burden that can benefit from novel biomarkers and diagnostics innovation. Aberrant methylation of the imprinted genes H19 and SNRPN (small nuclear ribonucleoprotein polypeptide N) in sperm DNA has been implicated in abnormal sperm parameters and male infertility. However, whether certain methylation patterns of one or multiple CpG sites within an imprinted gene are pathological for multiple sperm defects remains poorly understood. To examine the diagnostic potential of certain methylation patterns of CpG sites for multiphenotype defects in human sperm, the sperm DNA methylation patterns of individual CpG sites within imprinting control regions (ICRs) of imprinted genes H19 and SNRPN were measured by bisulfite pyrosequencing in a Han Chinese population sample: 39 oligoasthenozoospermia (OA) patients, 36 asthenoteratozoospermia (AT) patients, and 50 normozoospermia (N) controls. A partial least squares discriminant analysis model was built with the CpG sites as independent variables. Among the 16 CpG sites screened, the methylation patterns of eight CpG sites within H19-ICR (CpG sites 1, 6-9, 12 and 15-16), and eight CpG sites within SNRPN-ICR (CpG sites 2, 5-6, 8-10, 13, and 16) correctly classified 74.4% and 72.0% of the samples in terms of male fertile status, respectively. Furthermore, by combination of these 16 selected CpG sites within ICRs of H19 and SNRPN, 88.0% of the samples could be successfully classified. Our study demonstrates that methylation profiles of CpG sites within ICRs of imprinted genes H19 and SNRPN may potentially serve as epigenomic biomarkers for assessment of infertility in men with multiple sperm defects. Further studies in independent population samples are called for diagnostic significance of methylation patterns of CpG sites within imprinted genes.

Background Glycosylation significantly affects protein structure and function and thus participates in multiple physiologic and pathologic processes. Studies demonstrated that immunoglobulin G (IgG) N-glycosylation associates with the risk factors of ischemic stroke (IS), such as aging, obesity, dyslipidemia, type 2 diabetes, and hypertension. Methods The study aimed to investigate the association between IgG N-glycosylation and IS in a Chinese population. IgG glycome composition in patients with IS (n = 78) and cerebral arterial stenosis (CAS) (n = 75) and controls (n = 77) were analyzed by ultra-performance liquid chromatography. Results Eleven initial glycans and 10 derived glycans in IgG glycome representing galactosylation, sialylation, and bisecting GlcNAc significantly differed between IS patients and CAS and healthy controls after controlling for gender, age, obesity, diabetes, hypertension, and dyslipidemia. Logistic regression models incorporating IgG glycan traits were able to distinguish IS from CAS (area under receiver–operator characteristic curves (AUC), 0.802; 95% confidence interval (CI), 0.732–0.872) and controls (AUC, 0.740; 95% CI, 0.661–0.819). The canonical correlation analysis indicated that initial N-glycan structures are significantly correlated with inflammation markers (r = 0.566, p

Suboptimal health status (SHS) is a physical state between health and illness, and previous studies suggested that SHS is associated with majority components of cardiovascular health metrics defined by American Heart Association (AHA). We investigated the association between SHS and cardiovascular health metrics in a cross-sectional analysis of China suboptimal health cohort study (COACS) consisting of 4313 participants (60.30% women) aged from 18 to 65 years old. The respective prevalence of SHS is 7.10%, 9.18%, 10.04% and 10.62% in the first, second, third and fourth quartiles of ideal cardiovascular health (CVH) metrics (P for trend = 0.012). Participants in the largest quartile of ideal CVH metrics show a lower likelihood of having optimal SHS score compared to those in the smallest quartile (odds ratio (OR), 0.43; 95% confidence interval (CI), 0.32–0.59), after adjusting for age, gender, marital status, alcohol consumption, income level and education. Four metrics (smoking, physical inactivity, poor dietary intake and ideal control of blood pressure are significantly correlated with the risk of SHS. The present study suggests that ideal CVH metrics are associated with a lower prevalence of SHS, and the combined evaluation of SHS and CVH metrics allows the risk classification of cardiovascular disease, and thus consequently contributes to the prevention of cardiovascular diseases.

Colon cancer patients have major unmet needs in terms of robust diagnostics and molecular biomarkers for personalized therapeutics. We have previously reported that human CAP10-like protein 46 kDa (hCLP46) is overexpressed in human acute myelogenous leukemia, T acute lymphoblastic leukemia, and leukemia cell lines. We extend this line of biomarker and diagnostic discovery research by investigating hCLP46 expression in colorectal cancer (CRC) tissues and examine the possibility of hCLP46 as a candidate biomarker for diagnosis and prognosis of CRC. Using a tissue microarray analysis approach, we found that hCLP46 is (1) overexpressed in 90 CRC tissues compared with 90 matched noncancerous tissues and (2) positively correlated with higher tumor-node-metastasis (TNM) stage, lymph node metastasis, and shorter survival time. Moreover, in vitro experiments demonstrated that downregulation of hCLP46 in CRC cells results in proliferation arrest and adhesion enhancement, while apoptosis is unchanged. Further transcriptome profile analysis corroborated that the adhesion pathway is related to hCLP46 downregulation. This report for the first time, to the best of our knowledge, demonstrates that hCLP46 promotes tumor malignancy in CRC cells. We suggest that hCLP46 is warranted for further research as a candidate biomarker for clinical phenotypes related to colon cancer.

Despite decades of investment in biomarker research, we still do not have robust and field-tested biomarkers for many chronic diseases so as to anticipate clinical outcomes and thus move toward personalized medicine. Biomarker innovations have tended to focus on genomics, but next-generation biomarkers from the nascent field of glycomics now offer fresh vistas for innovation in chronic disease biomarkers and systems diagnostics. Glycosylation, regarded as a complex enzymatic process where sugars (glycans) bind to proteins and lipids, affects many human biological functions, including cell signaling, adhesion, and motility. Notably, and contrary to proteins, glycan biosynthesis does not require a template; rather its final structure is catalyzed by a repertoire of enzymes that attach or detach monosaccharides in the glycosylation pathway, making glycomics research more challenging than proteomics or genomics. Yet, given glycans' biological significance, alterations in their processing may be detrimental to human health and also offer insights for preventive medicine and wellness interventions. Therefore, studying glycans' structure and understanding their function and molecular interactions in the emerging field of glycomics are key to unraveling the pathogenesis of various common chronic diseases. This review summarizes the major concepts in glycomics, including glycan release methods, techniques for large-scale glycan analysis, and glycoinformatic tools for data handling and storage. In all, this analysis on glycomics offers strategies to build a robust postgenomic innovation roadmap for glycan-driven biomarkers as the field is anticipated to mature further and gain greater prominence in the near future.

Immunoglobulin G (IgG) is the most abundant serum antibody and is a key determinant of the humoral immune response. Its structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. IgG N-glycome patterns change with the age of individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is affected by a combination of genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of whole IgG, analysed in 5 different populations totalling 10,482 IgG glycomes, and of IgG’s fragment crystallisable region (Fc), analysed in 2,530 samples from 27 populations sampled across the world. We observed that country of residence associates with many N-glycan features and is a strong predictor of monogalactosylation variability. IgG galactosylation also strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators. We found that subjects from developing countries had low IgG galactosylation levels, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to country-specific environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.

Male infertility is a complicated disease with causes generally split into 2 broad categories: genetic factors and environmental factors. The present study was designed to investigate the association between the methylation patterns of HI9 and SNRPN imprinting control region (ICR) and male infertility and to assess the gene-environment interactions between environmental factors and methylation patterns. A total of 205 DNA samples from 48 oligozoospermia (OZ), 52 asthenozoospermia (AZ), 55 teratozoospermia (TZ) patients, and 50 normozoospermia (NZ) men were analyzed. The mean methylation level of H/9-ICR in OZ (80.40% ± 12.74%) and AZ patients (81.17% ± 13.18%) was significantly lower than methylation in men with NZ (88.51 % ± 10.54%, P

Malaysia is on its way to achieving developed nation status in the next 4 years. Currently, Malaysia is on track for three Millennium Development Goals (MDG1, MDG4, and MDG7). The maternal mortality rate, infant mortality rate, and mortality rate of children younger than 5 years improved from 25.6% (2012) to 6.6% (2013), and 7.7% (2012) per 100,000 live births, respectively whereas immunization coverage for infants increased to an average of 90%. As of 2013 the ratio of physicians to patients improved to 1:633 while the ratio of health facilities to the population was 1:10,272. The current government administration has proposed a reform in the form of the 10th Malaysian Plan coining the term “One Care for One Malaysia” as the newly improved and reorganized health care plan, where efficiency, effectiveness, and equity are the main focus. This review illustrates Malaysia’s transition from pre-independence to the current state, and its health and socioeconomic achievement as a country. It aims to contribute knowledge through identifying the plans and reforms by the Malaysian government while highlighting the challenges faced as a nation.

Genome-wide association studies have successfully identified over 70 loci associated with the risk of type 2 diabetes mellitus (T2DM) in multiple populations of European ancestry. However, the risk attributable to an individual variant is modest and does not yet provide convincing evidence for clinical utility. Association between these established genetic variants and T2DM in general populations is hitherto understudied in the isolated populations, such as the Uyghurs, resident in Hetian, far southern Xinjiang Uyghur Autonomous Region, China. In this case-control study, we genotyped 13 single-nucleotide polymorphisms (SNPs) at 10 genes associated with diabetes in 130 cases with T2DM and 135 healthy controls of Uyghur, a Chinese minority ethnic group. Three of the 13 SNPs demonstrated significant association with T2DM in the Uyghur population. There were significant differences between the T2DM patients and controls in the risk allele distributions of rs3792267 (CAPN10) (P = 0.002), rs1501299 (APM1) (P = 0.017), and rs3760776 (FUT6) (P = 0.031). Allelic carriers of rs3792267-A, rs1501299-T, and rs3760776-T had a 2.24-fold [OR (95% CI): 1.35-3.71], 0.59-fold [OR (95% CI): 0.39-0.91], 0.57-fold [OR (95% CI): 0.34-0.95] increased risk for T2DM respectively. We further confirmed that the cumulative risk allelic scores calculated from the 13 susceptibility loci for T2DM differed significantly between the T2DM patients and controls (P = 0.001), and the effect of obesity/overweight on T2DM was only observed in the subjects with a combined risk allelic score under a value of 17. This study observed that the SNPs rs3792267 in CAPN10, rs1501299 in APM1, and rs3760776 in FUT6 might serve as potential susceptible biomarkers for T2DM in Uyghurs. The cumulative risk allelic scores of multiple loci with modest individual effects are also significant risk factors in Uyghurs for T2DM, particularly among non-obese individuals. This is the first investigation having observed/found genetic variations on genetic loci functionally linked with glycosylation associated with the risk of T2DM in a Uyghur population.

Why Not Use the Immunoglobulin G N-Glycans as Predictor Variables in Disease Biomarker-Phenotype Association Studies? A Multivariate Analysis. A letter to the Editor.

Background Increased body fat may be associated with an increased risk of developing an underlying pro-inflammatory state, thus leading to greater risk of developing certain chronic conditions. Immunoglobulin G has the ability to exert both anti- and pro-inflammatory effects, and the N-glycosylation of the fragment crystallisable portion is involved in mediating this process. Body mass index, a rudimentary yet gold standard indication for body fat, has been shown to be associated with agalactosylated immunoglobulin G N-glycans. Aim We aimed to determine the association between increased body fat and the immunoglobulin G glycosylation features, comparing body mass index to other measures of body fat distribution. Methods We investigated a sample of 637 community-based 45–69 year olds, with mixed phenotypes, residing in Busselton, Western Australia. Body mass index and the waist-to-hip and waist-to-height ratios were calculated using anthropometry, while dual-energy x-ray absorptiometry was performed to gain an accurate measure of total and area specific body fat. Serum immunoglobulin GN-glycans were analysed by ultra-performance liquid chromatography. Results Twenty-two N-glycan peaks were found to be associated with at least one of the fat measures. While the previous association of body mass index to agalactosylated immunoglobulin G was replicated, measures of central adiposity explained the most variation in the immunoglobulin G glycome. Conclusion Central adiposity is associated with an increased pro-inflammatory fraction of immunoglobulin G, suggesting that the android/gynoid ratio or waist-to-height ratio instead be considered when controlling for adiposity in immunoglobulin G glycome biomarker studies.

BACKGROUND: The prevalence of diabetes, constituted chiefly by type 2 diabetes mellitus (T2DM), is a global public health threat. Suboptimal health status (SHS), a physical state between health and disease, might contribute to the progression or development of T2DM. METHODS: We conducted a prospective cohort study, based on the China Suboptimal Health Cohort Study (COACS), to understand the impact of SHS on the progress of T2DM. We examined associations between SHS and T2DM outcomes using multivariable logistic regression models and constructed predictive models for T2DM onset based on SHS. RESULTS: A total of 61 participants developed T2DM after an average of 3.1 years of follow-up. Participants with higher SHS scores had more T2DM outcomes (p = 0.036). Moreover, compared with the lowest quartile of SHS scores, participants with fourth, third, and second quartile SHS scores were found to be associated with a 1.7-fold, 1.6-fold, and 1.5-fold risk of developing T2DM, respectively. The predictive model constructed with SHS had higher discriminatory power (AUC = 0.848) than the model without SHS (AUC = 0.795). CONCLUSIONS: The present study suggests that a higher SHS score is associated with a higher incidence of T2DM. SHS is a new independent risk factor for T2DM and has the capability to act as a predictive tool for T2DM onset. The evaluation of SHS combined with the analysis of modifiable risk factors for SHS allows the risk stratification of T2DM, which may consequently contribute to the prevention of T2DM development. These findings might require further validation in a longer-term follow-up study. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13167-019-0159-9) contains supplementary material, which is available to authorized users.

Hypertension results from the interaction of genetic and acquired factors. IgG occurs in the form of different subclasses, of which the effector functions show significant variation. The detailed differences between the glycosylation profiles of the individual IgG subclasses may be lost in a profiling method for total IgG N-glycosylation. In this study, subclass-specific IgG Fc glycosylation profile was investigated in the four northwestern Chinese minority populations, namely, Uygur (UIG), Kazak (KZK), Kirgiz (KGZ), and Tajik (TJK), composed of 274 hypertensive patients and 356 healthy controls. The results showed that ten directly measured IgG N-glycan traits (i.e., IgG1G0F, IgG2G0F, IgG2G1FN, IgG2G1FS, IgG2G2S, IgG4G0F, IgG4G1FS, IgG4G1S, IgG4G2FS, and IgG4G2N) representing galactosylation and sialylation are significantly associated with hypertension, with IgG4 consistently showing weaker associations of its sialylation, across the four ethnic groups. We observed a modest improvement on the AUC of ROC curve when the IgG Fc N-glycan traits are added into the glycan-based model (difference between AUCs, 0.044, 95% CI: 0.016–0.072, P = 0.002). The AUC of the diagnostic model indicated that the subclass-specific IgG Fc N-glycan profiles provide more information reinforcing current models utilizing age, gender, BMI, and ethnicity, and demonstrate the potential of subclass-specific IgG Fc N-glycosylation profiles to serve as a biomarker for hypertension. Further research is however required to determine the additive value of subclass-specific IgG Fc N-glycosylation on top of biomarkers, which are currently used.

Suboptimal health status (SHS) has been linked to cardiovascular risk factors, psychosocial stress, and unhealthy lifestyle. These factors also contribute to the shortening of telomere length (TL). A case-control study was conducted to examine the association between subjective health measures of SHS from the behavior perspective and also objective measures of TL at molecular level. SHS (cases = 294) was matched by age, sex, and body mass index with ideal health (controls = 294) using a propensity score matching method. Suboptimal health status questionnaire-25 (SHSQ-25) was used in the community-based health survey. A quantitative polymerase chain reaction was used to measure relative telomere length (RTL). Shorter RTL was found among the SHS group compared to the ideal health group (p 0.05). SHS was almost four times likely to be in the first quartile (odds ratio [OR] = 3.81; 95% confidence interval [CI] 2.21-6.56), almost thrice in second quartile (OR = 2.84; 95% CI 1.65-4.90), and almost twice likely to be in the third quartile (OR = 1.71; 95% CI 1.00-2.94) compared to the fourth quartile (the longest) of RTL after adjusting for socioeconomic, dietary intake, anthropometric, blood pressure, and biochemistry variables (p 0.05). Notably, SHS score was negatively correlated with RTL (r = -0.218, p 0.05). Our study confirms an association between SHS and short RTL. Combination of subjective (SHS) and objective (RTL) measures is a novel tool for health aging investigation. Therefore, SHSQ-25 could be used as a screening tool for measuring biological aging in low-income countries at community level where the expensive technique for RTL measurement is not applicable.

Background: Epidemiological studies observing inconsistent associations of telomere length (TL) with ischemic stroke (IS) are susceptible to bias according to reverse causation and residual confounding. We aimed to assess the causal association between TL, IS, and the subtypes of IS, including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES) by performing a series of two-sample Mendelian randomization (MR) approaches. Methods: Seven single nucleotide polymorphisms (SNPs) were involved as candidate instrumental variables (IVs), summarized from a genome-wide meta-analysis including 37,684 participants of European descent. We analyzed the largest ever genome-wide association studies of stroke in Europe from the MEGASTROKE collaboration with 40,585 stroke cases and 406,111 controls. The weighted median (WM), the penalized weighted median (PWM), the inverse variance weighted (IVW), the penalized inverse variance weighted (PIVW), the robust inverse variance weighted (RIVW), and the Mendelian randomization-Egger (MR-Egger) methods were conducted for the MR analysis to estimate a causal effect and detect the directional pleiotropy. Results: No significant association between genetically determined TL with overall IS, LAS, or CES were found (all p &gt, 0.05). SVS was associated with TL by the RIVW method (odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.54&ndash, 0.97, p = 0.028), after excluding rs9420907, rs10936599, and rs2736100. Conclusions: By a series of causal inference approaches using SNPs as IVs, no strong evidence to support the causal effect of shorter TL on IS and its subtypes were found.

Background: More than 60 genetic susceptibility loci associated with type 2 diabetes mellitus (T2DM) have been established in populations of Asian and European ancestry. Given ethnic differences and environmental factors, validation of the effects of genetic risk variants with reported associations identified by Genome-Wide Association Studies (GWASs) is essential. The study aims at evaluating the associations of T2DM with 29 single nucleotide polymorphisms (SNPs) from 19 candidate genes derived from GWASs in a northern Han Chinese population. Method: In this case-control study, 461 T2DM-diagnosed patients and 434 controls were recruited at the Jidong oil field hospital (Hebei, China) from January 2009 to October 2013. A cumulative genetic risk score (cGRS) was calculated by summation of the number of risk alleles, and a weight GRS (wGRS) was calculated as the sum of risk alleles at each locus multiplied by their effect sizes for T2DM, using the independent variants selected. Result: The allelic frequency of the “A” allele at rs17106184 (Fas-associated factor 1, FAF1) was significantly higher in the T2DM patients than that of the healthy controls (11.7% vs. 6.4%, p < 0.001). Individuals in the highestquartile of wGRS had an over three-fold increased risk for developing T2DM compared with those in the lowest quartile (odds ratio = 3.06, 95% CI = 1.92–4.88, p < 0.001) adjusted for age, sex, BMI, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP) and diastolic blood pressure (DBP). The results were similar when analyzed with the cGRS. Conclusions: We confirmed the association between rs17106184 (FAF1) and T2DM in a northern Han Chinese population. The GRS calculated based on T2DM susceptibility variants may be a useful tool for predicting the T2DM susceptibility.

Rheumatoid arthritis (RA), a systemic, chronic, and progressive inflammatory autoimmune disease, affects up to 1.0% of the world population doubling mortality rate of patients and is a major global health burden. Worrisomely, we lack robust diagnostics of RA and its remission status. Research with the next-generation biomarker technology platforms such as glycomics offers new promises in this context. We report here a clinical case-control study comprising 128 patients suffering from chronic RA (80.22% in remission, 19.78% active clinically) and 195 gender- and age-matched controls, with a view to the putative glycan biomarkers of RA as well as its activity or remission status in Han Chinese RA patients. Hydrophilic interaction liquid chromatography-ultra-performance liquid chromatography (HILIC-UPLC) was used for the analysis of IgG glycans. The regression model identified the glycans that predict RA status, while a receiver operating characteristic (ROC) curve analysis validated the sensitivity and prediction power. Among the total 24 glycan peaks (GP1-GP24), ROC analysis showed only GP1 prediction to be highly sensitive with an area under the curve (AUC) = 0.881. Even though GP21 and GP22 could predict active status among the RA cases (p 0.05), they had lower sensitivity of prediction with an AUC = 0.658. Taken together, these observations suggest that GP1 might have potential as a putative biomarker for RA in the Han Chinese population, while the change in IgG glycosylation shows association with the RA active and remission states. To the best of our knowledge, this is the first glycomics study with respect to disease activity and remission states in RA.

Background Suboptimal health status (SHS) is a physical state between health and disease, characterized by the perception of health complaints, general weakness, chronic fatigue and low energy levels. SHS is proposed by the ancient concept of traditional Chinese medicine (TCM) from the perspective of preservative, predictive and personalized (precision) medicine. We previously created the suboptimal health status questionnaire 25 (SHSQ-25), a novel instrument to measure SHS, validated in various populations. SHSQ-25 thus affords a window of opportunity for early detection and intervention, contributing to the reduction of chronic disease burdens. Methods/design To investigate the causative effect of SHS in non-communicable chronic diseases (NCD), we initiated the China suboptimal health cohort study (COACS), a longitudinal study starting from 2013. Phase I of the study involved a cross-sectional survey aimed at identifying the risk/protective factors associated with SHS; and Phase II: a longitudinal yearly follow-up study investigating how SHS contributes to the incidence and pattern of NCD. Results (1) Cross-sectional survey: in total, 4313 participants (53.8 % women) aged from 18 to 65 years were included in the cohort. The prevalence of SHS was 9.0 % using SHS score of 35 as threshold. Women showed a significantly higher prevalence of SHS (10.6 % in the female vs. 7.2 % in the male, P

Background Type 2 diabetes mellitus (T2DM) is a complex, pandemic disease contributing towards the global burden of health issues. To date, there are no simple clinical tests for the early detection of T2DM. Method To identify potential peptide biomarkers for such applications, 406 sera of T2DM patients (n = 206) and healthy controls (n = 200) were analyzed using MALDI-TOF MS with a cross-sectional case-control design. Result Six peptides (peaks m/z 1452.9, 1692.8, 1946.0, 2115.1, 2211.0 and 4053.6) were identified as candidate biomarkers for T2DM. A diagnostic model constructed with the 6 peptides was able to discriminate T2DM patients from healthy controls, with an accuracy of 82.20%, sensitivity of 82.50%, and specificity of 77.80% in the validation set. Peptide peaks m/z 1452.9 and 1692.8 were identified as fragments of the complement C3f, while peptide peaks m/z 1946.0, 2115.0, and 2211.0 were identified as the fragments of kininogen 1 isoform 1 precursor. Conclusion This study reinforces proteomic analyses as a potential technique for defining significant clinical peptide biomarkers, providing a simple and convenient diagnostic model for T2DM in clinical examination. This article is protected by copyright. All rights reserved

More than half of all known proteins, and almost all membrane and extra-cellular proteins have oligosaccharide structures or glycans attached to them. Defects in glycosylation pathways are directly involved in at least 30 severe human diseases.A multiple center cross-sectional study (China, Croatia, and Scotland) was carried out to investigate the possible association between hypertension and IgG glycosylation. A hydrophilic interaction chromatography of fluorescently labeled glycans was used to analyze N-glycans attached to IgG in plasma samples from a total of 4757 individuals of Chinese Han, Croatian, and Scottish ethnicity.Five glycans (IgG with digalactosylated glycans) significantly differed in participants with prehypertension or hypertension compared to those with normal blood pressure, while additional 17 glycan traits were only significantly differed in participants with hypertension compared to those of normal blood pressure. These glycans were also significant correlated with systolic blood pressure (SBP) or diastolic blood pressure (DBP).The present study demonstrated for the 1st time an association between hypertension and IgG glycome composition. These findings suggest that the individual variation in N-glycosylation of IgG contributes to pathogenesis of hypertension, presumably via its effect on pro- and/or anti-inflammatory pathways.

Background: DNA methylation in sputum has been an attractive candidate biomarker for the non-invasive screening and detection of lung cancer. Materials and Methods: Databases including PubMed, Ovid, Cochrane library, Web of Science databases, Chinese Biological Medicine (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang, Vip Databases and Google Scholar were searched to collect the diagnostic trials on aberrant DNA methylation in the screening and detection of lung cancer published until 1 December 2016. Indirect comparison meta-analysis was used to evaluate the diagnostic value of the included candidate genes. Results: The systematic literature search yielded a total of 33 studies including a total of 4801 subjects (2238 patients with lung cancer and 2563 controls) and covering 32 genes. We identified that methylated genes in sputum samples for the early screening and auxiliary detection of lung cancer yielded an overall sensitivity of 0.46 (0.41–0.50) and specificity of 0.83 (0.80–0.86). Combined indirect comparisons identified the superior gene of SOX17 (sensitivity: 0.84, specificity: 0.88), CDO1 (sensitivity: 0.78, specificity: 0.67), ZFP42 (sensitivity: 0.87, specificity: 0.63) and TAC1 (sensitivity: 0.86, specificity: 0.75). Conclusions: The present meta-analysis demonstrates that methylated SOX17, CDO1, ZFP42, TAC1, FAM19A4, FHIT, MGMT, p16, and RASSF1A are potential superior biomarkers for the screening and auxiliary detection of lung cancer.

Supplemental Digital Content is available in the text, As an important post-translation modifying process, glycosylation significantly affects the structure and function of immunoglobulin G (IgG) molecules and is essential in many steps of the inflammatory cascade. Studies have demonstrated the potential of using glycosylation features of IgG as a component of predictive biomarkers for chronological age in several European populations, whereas no study has been reported in Chinese. Herein, we report various patterns of changes in IgG glycosylation associated with age by analyzing IgG glycosylation in 701 community-based Han Chinese (244 males, 457 females; 23–68 years old). Eleven IgG glycans, including FA2B, A2G1, FA2[6]G1, FA2[3]G1, FA2[6]BG1, FA2[3]BG1, A2G2, A2BG2, FA2G2, FA2G2S1, and FA2G2S2, change considerably with age and specific combinations of these glycan features can explain 23.3% to 45.4% of the variance in chronological age in this population. This indicates that these combinations of glycan features provide more predictive information than other single markers of biological age such as telomere length. In addition, the clinical traits such as fasting plasma glucose and aspartate aminotransferase associated with biological age are strongly correlated with the combined glycan features. We conclude that IgG glycosylation appears to correlate with both chronological and biological ages, and thus its possible role in the aging process merits further study.

Background: Genome-wide association studies (GWAS) found that IGF2BP2 rs4402960 and rs1470579 polymorphisms were associated with type 2 diabetes mellitus (T2DM) risk. Many studies have replicated this association, but yielded inconsistent results. Materials and Methods: A case-control study consisting of 461 T2DM patients and 434 health controls was conducted to detect the genetic susceptibility of IGF2BP2 in a northern Han Chinese population. A meta-analysis was to evaluate the association more precisely in Asians. Results: In the case-control study, the carriers of TT genotype at rs4402960 had a higher T2DM risk than the G carriers (TG + GG) (adjusted odd ratio (AOR) = 1.962, 95% confidence interval (95% CI) = 1.065–3.612, p = 0.031]; CC carriers at rs1470579 were more susceptible to T2DM than A carriers (CA + AA) (AOR = 2.014, 95% CI = 1.114–3.642, p = 0.021). The meta-analysis containing 36 studies demonstrated that the two polymorphisms were associated with T2DM under the allele comparison, genetic models of dominant and recessive in Asians (p < 0.05). The rs4402960 polymorphisms were significantly associated with the T2DM risk after stratification by diagnostic criterion, size of sample and average age and BMI of cases, while there’re no consistent results for rs1470579. Conclusions: Our data suggests that IGF2BP2 polymorphisms are associated with T2DM in Asian populations.

Schizophrenia has increasingly been considered a neurodevelopmental disorder, and the advancement of neuroimaging techniques and associated computational methods has enabled quantitative re-examination of this important theory on the pathogenesis of the disease. Inspired by previous findings from neonatal brains, we proposed that an increase in diffusion magnetic resonance imaging (dMRI) mean diffusivity (MD) should be observed in the cerebral cortex of schizophrenia patients compared with healthy controls, corresponding to lower tissue complexity and potentially a failure to reach cortical maturation. We tested this hypothesis using dMRI data from a Chinese Han population comprising patients from four different hospital sites. Utilizing data-driven methods based on the state-of-the-art tensor-based registration algorithm, significantly increased MD measurements were consistently observed in the cortex of schizophrenia patients across all four sites, despite differences in psychopathology, exposure to antipsychotic medication and scanners used for image acquisition. Specifically, we found increased MD in the limbic system of the schizophrenic brain, mainly involving the bilateral insular and prefrontal cortices. In light of the existing literature, we speculate that this may represent a neuroanatomical signature of the disorder, reflecting microstructural deficits due to developmental abnormalities. Our findings not only provide strong support to the abnormal neurodevelopment theory of schizophrenia, but also highlight an important neuroimaging endophenotype for monitoring the developmental trajectory of high-risk subjects of the disease, thereby facilitating early detection and prevention.