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BackgroundIn observational studies, Alzheimer’s disease (AD) has been associated with an increased risk of Coronavirus disease 2019 (COVID-19), and the prognosis of COVID-19 can affect nervous systems. However, the causality between these conditions remains to be determined.MethodsThis study sought to investigate the bidirectional causal relations of AD with COVID-19 using two-sample Mendelian randomization (MR) analysis.ResultsWe found that genetically predicted AD was significantly associated with higher risk of severe COVID-19 (odds ratio [OR], 3.329; 95% confidence interval [CI], 1.139-9.725; P=0.028). It’s interesting that genetically predicted severe COVID-19 was also significantly associated with higher risk of AD (OR, 1.004; 95% CI, 1.001-1.007; P=0.018). In addition, the two strong genetic variants associated with severe COVID-19 was associated with higher AD risk (OR, 1.018; 95% CI, 1.003-1.034; P=0.018). There is no evidence to support that genetically predicted AD was significantly associated with COVID-19 susceptibility, and vice versa. No obvious pleiotropy bias and heterogeneity were observed.ConclusionOverall, AD may causally affect severe COVID-19, and vice versa, performing bidirectional regulation through independent biological pathways.

Background: The relationship between IgG N-glycosylation, type 2 diabetes (T2D) and hypertension is not well understood.Methods: A genome-wide association study (GWAS) of IgG N-glycosylation traits from 536 individuals was performed and 1203 IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) variants targeting 24 IgG N-glycosylation were mapped traits after multi-testing correction. Network with bidirectional mendelian randomization (MR) analysis was performed to examine the causal association between IgG N-glycosylation, T2D and hypertension.Results: By linking IgG N-glycan-QTL variants with GWAS results for T2D and hypertension, 19 putatively causal IgG N-glycans for T2D and 21 putatively causal IgG N-glycans for hypertension were identified. IgG N-glycan-QTL determined IgG N-glycosylation to higher T2D was associated with higher hypertension risk (β [95% CI] =1.234 [0.939-1.529], P

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.

Additional file 1: Table S1. Association between SNP genotypes and telomere length under co-dominant and additive model.

Additional file 1: Table S2. Association between SNP genotypes and telomere length under dominant, recessive and over-dominant model.

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 this context, alternative immunoglobulin G (IgG)

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 modification involves glycosylation. Glycans participate in key intercellular and intracellular functions, such as protein quality control, cell adhesion, cell-cell recognition, signal transduction, cell proliferation, and cell differentiation. In this context, immunoglobulin G (IgG)

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.

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

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

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.

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.

Objective: To evaluate factors associated with myopic shift among primary school children. Methods: In a one-year prospective school-based study, 5052 children from ten schools were enrolled using a multi-stage random cluster approach. The baseline examination included non-cycloplegic auto-refractometry and questionnaire interview. Measurements were repeated at the follow-up. Results: Among 5052 students at baseline investigated, 4292 students (85.0%) returned for the follow-up examination. The mean refractive error (-1.13±1.57 diopters) had changed -0.52±0.73 diopters from the baseline to the follow-up examination. 2170 (51.0%) had a rate of significant myopic shift (significant myopic shift is defined as the change of spherical equivalent of the refraction ≤ -0.50D between the follow-up and baseline measures). We confirmed that common associated factors (older age, parental myopia, lower refractive status at baseline, shorter reading distance and lower frequency of outdoor activities during class recesses) were associated with greater shift towards myopia. After controlling for age, sex, region of habitation, parental myopia and refractive status at baseline, greater shift towards myopia was independently associated with distance from near-work (OR=1.48 , 95% CI=1.26-1.74, P

Figure S1. The correlation coefficients in independent variables. Statistically significant associations between two variables are shown, pâ

Suboptimal health status (SHS) has become a new public health challenge in China. This study investigated whether high SHS is associated with psychosocial stress, changes in cortisol level and/or glucocorticoid receptor (GR) isoform expression. Three-hundred eighty-six workers employed in three companies in Beijing were recruited. The SHS score was derived from data collection in the SHS questionnaire (SHSQ-25). The short standard version of the Copenhagen Psychosocial Questionnaire (COPSOQ) was used to assess job-related psychosocial stress. The mean value of the five scales of COPSOQ and distribution of plasma cortisol and mRNA expression of GRα/GRβ between the high level of SHS group and the low level of SHS group were compared using a general linear model procedure. Multiple linear regression analysis was used to analyze the effect of psychosocial stress on SHS. We identified three factors that were predictive of SHS, including "demands at work", "interpersonal relations and leadership" and "insecurity at work". Significantly higher levels of plasma cortisol and GRβ/GRα mRNA ratio were observed among the high SHS group. High level of SHS is associated with decreased mRNA expression of GRα. This study confirmed the association between chronic psychosocial stress and SHS, indicating that improving the psychosocial work environment may reduce SHS and then prevent chronic diseases effectively.

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.

To investigate the association of tag-SNPs and haplotype structures of the CIDEA gene with obesity in a Han Chinese population. Five single nucleotide polymorphisms (SNPs) (rs1154588/V115F, rs4796955/SNP1, rs8092502/SNP2, rs12962340/SNP3 and rs7230480/SNP4) in the CIDEA gene were genotyped in a case–control study. Genotyping was performed using the sequenom matrix-assisted laser desorption/ionization time-of-flight mass spectrometry iPLEX platform. There were significant differences between the obese and control groups in genotype distributions of V115F (P

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

The outcome of human immunodeficiency virus (HIV)-1 infection and course to AIDS are variable among individuals. Both chemokine receptor 5 (CCR5) and CCR2 gene polymorphisms play essential roles in the susceptibility of HIV-1 infection. To investigate the main and epistatic effects of the CCR5 promoter and CCR2-V64I polymorphisms on HIV-1 infection in the Northern Han Chinese, subjects of 91 HIV-1-infected patients and 91 health controls were recruited. Single-nucleotide polymorphisms (SNPs) in the CCR5 promoter region and CCR2-V64I variants were genotyped. In the single-locus analysis, CCR5 58755-G and CCR5 59653-T alleles were significantly associated with HIV-1 infection (odds ratio [OR]=0.529, 95% confidence interval [CI]: 0.295-0.948; OR=1.710, 95% CI: 1.039-2.814). After adjustment with age and gender, subjects with the CCR5 59653-CT genotype showed the increased risk of HIV-1 infection compared with those with the wild-type CC genotype (adjusted OR=2.502; 95% CI: 1.332-4.698). No positive association was observed in other SNPs. Haplotype-based association analysis revealed that the haplotype TATGC was associated with the susceptibility to HIV-1 infection (p=0.003). Besides, we found the significant epistatic effects between the CCR5 58755-A/G and CCR5 59029-A/G polymorphisms associated with the lower risk of HIV-1 infection. In addition, we also identified the best three-factor interaction model, including the CCR5 58755-A/G, 59029-A/G, and CCR2-V64I polymorphisms, indicating that there were also strong gene-gene interactions between the CCR5 promoter and CCR2 polymorphisms on the susceptibility of HIV-1 infection. These findings contribute to understanding the genetic mechanism for the susceptibility of HIV-1 infection in Northern Han Chinese.

The study aims at evaluating the association between brain-derived neurotrophic factor (BDNF) gene polymorphisms and heroin-dependent patients in the Chinese population. Three polymorphisms of the BDNF-gene (rs10835210, rs16917234, and rs6265) in 486 heroin-dependent patients and in 226 healthy controls were genotyped for analyzing the association of these polymorphisms with age of onset of heroin dependence. We defined the healthy cases as "unknown phenotype" and used the endophenotype (behavior traits) to stratify the heroin dependents group on the basis of self-reporting traits for examining the association between BDNF polymorphisms (rs10835210, rs16917234, and rs6265) and heroin dependence.Allelic distributions of BDNF gene polymorphisms did not differ significantly between heroin-dependent patients and controls. However, we found that the AA carriers of BDNF rs6265 had an earlier onset of heroin dependence and a clearer tendency of family history of heroin-dependent than GG carriers after controlling behavior characteristics across rs6265 genotypes.Our findings suggested that the BDNF genetic polymorphism (rs6265) may have effects on the age of onset of heroin dependence among the Chinese population. The BDNF gene could contribute to vulnerabilities to heroin dependence.

Objective: To describe the technical performance of nested PCR for identifying hepatitis B viral (HBV) DNA. Methods: Hepatitis B viral DNA was extracted from a dried bloodstain on filter paper by a Chelex-100 method. Then the DNA fragment was amplified by nested polymerase chain reaction (PCR). The sensitivity and specificity of this method were also analyzed. The positive rate of the nested PCR-based method was compared with that of the enzyme-linked immunosorbent assays (ELISA) method. Results: The lowest detection limit of the test was 5 copies of HBV DNA per μL by this method. McNemar’s test showed that the difference between the positive rates of these 2 methods was not statistically significant (P =0.289, P >0.05). Hepatitis B viral test results showed a good concordance between these 2 methods (kappa=0.727). Conclusion: A very small amount of the dried blood sample is required for the detection, which could overcome the shortage of the normal ELISA method that requires a relatively large amount of fresh blood samples.

Mannose-binding lectin (MBL) is a key molecule of the innate immune system and a competent to bind carbohydrates of a variety of microorganisms, resulting in complement activation and opsonophagocytosis against various pathogens. However, there is no systemic investigation on the MBL's role in innate immune responses against HIV-1 infection among northern Han Chinese. This study investigated the association between MBL and HIV-1 infection susceptibility among northern Han Chinese. A total of 91 HIV-1 infected patients and 91 HIV-1 seronegative healthy individuals were recruited. Six polymorphisms of MBL2 gene were genotyped by pyrosequencing. The quantitative measurement of serum MBL concentration and MBL complex activity were performed by ELISA. The CD4+ T-cell counts were determined by flow cytometry. The plasma viral loads of 91 HIV-1 infected patients were determined by bDNA method. The results show that there is an association between MBL and HIV-1 infection susceptibility among northern Han Chinese. The individuals with B variant, low serum MBL concentration and low MBL complex activity are more susceptible to HIV-1 infection.

Normal function of the dopaminergic system is necessary for speech fluency. There was evidence that the activities of dopamine transporter (DAT) and dopamine D2 receptor (DRD2) could be altered in people with speech disfluency. This study aims to ascertain the possible correlation between two dopaminergic genes (SLC6A3 and DRD2) and disorder of speech fluency, and to determine the allelic frequencies of the five single-nucleotide polymorphisms (SNPs) (rs2617604, rs28364997, rs28364998 in SLC6A3 and rs6275, rs6277 in DRD2) among Han Chinese patients with this disorder. A sample of 112 patients with speech disfluency and 112 gender-matched controls were included in this case–control study. The results show that the presence of C allele at rs6277 in DRD2 gene is associated with increased susceptibility to the disorder, whereas T allele is protective. Haplotype 939T/957T is also a protective factor.

Severe acute respiratory syndrome (SARS), caused by infection with a novel coronavirus (SARS-CoV), was the first major novel infectious disease at the beginning of the 21st century, with China especially affected. SARS was characterized by high infectivity, morbidity and mortality, and the confined pattern of the disease spreading among the countries of South-East and East Asia suggested the existence of susceptible factor(s) in these populations. Studies in the populations of Hong Kong and Taiwan showed an association of human leucocyte antigen (HLA) polymorphisms with the development and/or severity of SARS, respectively. The aim of the present study was to define the genotypic patterns of HLA-A, -B and -DRB1 loci in SARS patients and a co-resident population of Guangdong province, southern China, where the first SARS case was reported. The samples comprised 95 cases of recovered SARS patients and 403 unrelated healthy controls. HLA -A, -B and -DRB1 alleles were genotyped using polymerase chain reaction with sequence-specific primers. The severity of the disease was assessed according to the history of lung infiltration, usage of assisted ventilation and occurrence of lymphocytopenia. Although the allelic frequencies of A23, A34, B60, DRB1*12 in the SARS group were slightly higher, and A33, -B58 and -B61 were lower than in the controls, no statistical significance was found when the Pc value was considered. Similarly, no association of HLA alleles with the severity of the disease was detected. Thus, variations in the major histocompatibility complex are unlikely to have contributed significantly to either the susceptibility or the severity of SARS in the population of Guangdong.

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.

Substantial evidence suggests that type 2 diabetes mellitus (T2DM) is a multi-factorial disease with a strong genetic component. A list of genetic susceptibility loci in populations of European and Asian ancestry has been established in the literature. Little is known on the inter-ethnic contribution of such established functional polymorphic variants. We performed a case-control study to explore the genetic susceptibility of 16 selected T2DM-related SNPs in a cohort of 102 Uyghur objects (51 cases and 51 controls). Three of the 16 SNPs showed significant association with T2DM in the Uyghur population. There were significant differences between the T2DM and control groups in frequencies of the risk allelic distributions of rs7754840 (CDKAL1) (p=0.014), rs864745 (JAZF1) (p=0.032), and rs35767 (IGF1) (p=0.044). Carriers of rs7754840-C, rs35767-A, and rs864745-C risk alleles had a 2.32-fold [OR (95% CI): 1.19-4.54], 2.06-fold [OR (95% CI): 1.02-4.17], 0.48-fold [OR (95% CI): 0.24-0.94] increased risk for T2DM, respectively. The cumulative risk allelic scores of these 16 SNPs differed significantly between the T2DM patients and the controls [17.1±8.1 vs. 15.4±7.3; OR (95%CI): 1.27(1.07-1.50), p=0.007]. This is the first study to evaluate genomic variation at 16 SNPs in respective T2DM candidate genes for the Uyghur population compared with other ethnic groups. The SNP rs7754840 in CDKAL1, rs864745 in JAZF1, and rs35767 in IGF1 might serve as potential susceptibility loci for T2DM in Uyghurs. We suggest a broader capture and study of the world populations, including who that are hitherto understudied, are essential for a comprehensive understanding of the genetic/genomic basis of T2DM.

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.