Glucagon-like peptide-1 receptor agonists in neoplastic diseases.

Glucagon-like peptide-1 receptor agonist (GLP-1RA), a novel hypoglycemic agent for the treatment of type 2 diabetes, has well-known effects such as lowering blood sugar, ameliorating inflammation, reducing weight, and lowering blood lipids. It has also been shown that it can influence the proliferation and survival of cells and has a certain effect on the prognosis of some neoplastic diseases. In this study, the potential effects of GLP-1RAs on the occurrence and development of tumors were reviewed to provide new ideas for the prevention and treatment of tumors in patients.

Advancements in Cardiovascular Disease Research Affected by Smoking.

The harmful substances in tobacco are widely recognized to exert a significant detrimental impact on human health, constituting one of the most substantial global public health threats to date. Tobacco usage also ranks among the principal contributors to cardiovascular ailments, with tobacco being attributed to up to 30% of cardiovascular disease-related deaths in various countries. Cardiovascular disease is influenced by many kinds of pathogenic factors, among them, tobacco usage has led to an increased year by year incidence of cardiovascular disease. Exploring the influencing factors of harmful substances in tobacco and achieving early prevention are important means to reduce the incidence of cardiovascular diseases and maintain health. This article provides a comprehensive review of the effects of smoking on health and cardiovascular diseases.

Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

INTRODUCTION: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. OBJECTIVES: To explore the role of Midline-1 (Mid1) in synovial activation. METHODS: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/-Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. RESULTS: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. CONCLUSION: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization.

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

The role of myeloid-derived immunosuppressive cells in cardiovascular disease.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population found in the bone marrow, peripheral blood, and tumor tissue. Their role is mainly to inhibit the monitoring function of innate and adaptive immune cells, which leads to the escape of tumor cells and promotes tumor development and metastasis. Moreover, recent studies have found that MDSCs are therapeutic in several autoimmune disorders due to their strong immunosuppressive ability. Additionally, studies have found that MDSCs have an important role in the formation and progression of other cardiovascular diseases, such as atherosclerosis, acute coronary syndrome, and hypertension. In this review, we will discuss the role of MDSCs in the pathogenesis and treatment of cardiovascular disease.

Association of Lifestyle Factors and Antihypertensive Medication Use With Risk of All-Cause and Cause-Specific Mortality Among Adults With Hypertension in China.

Importance: The joint association of antihypertensive medication use and healthy lifestyle with mortality among individuals with hypertension is unclear. Objective: To examine the association of lifestyle factors combined with antihypertensive medication use, as well as changes in lifestyle, with all-cause and cause-specific mortality among individuals with hypertension. Design, Setting, and Participants: This cohort study used data from the Dongfeng-Tongji cohort, a long-term, prospective cohort including employees at a manufacturer in China, with baseline from 2008 to 2010. Participants with hypertension were followed up for a median (IQR) of 7.3 (5.7-10.3) years, ending in 2018. Data were analyzed from February to April 2021. Exposures: Lifestyle factors, including body mass index, smoking status, diet, physical activity, and sleep duration, were coded on a 3-point scale (range, 0-2, with higher score indicating a healthier lifestyle). Lifestyle was evaluated according to the total score of all 5 factors, and categorized into 3 groups: unfavorable (scores 0-4), intermediate (scores 5-7), and favorable (scores 8-10). Antihypertensive medication use was defined as use within the last 2 weeks. Main Outcomes and Measures: All-cause, cardiovascular, and cancer mortality were identified by linking the cohort database with the health care system through December 31, 2018. Results: A total of 14 392 participants (mean [SD] age, 65.6 [7.4] years; 7277 [50.6%] men and 7115 [49.4%] women) with hypertension were included, and 2015 deaths were documented, including 761 cardiovascular deaths and 525 cancer deaths. Compared with individuals not using antihypertensive medication and with a lifestyle score of 0 to 4, the combination of using antihypertensive medication and having a lifestyle score of 8 to 10 was associated with the lowest risk of all-cause mortality (hazard ratio [HR], 0.32; 95% CI, 0.25-0.42), cardiovascular mortality (HR, 0.33; 95% CI, 0.21-0.53), and cancer mortality (HR, 0.30; 95% CI, 0.19-0.47). In addition, improvement in lifestyle score after hypertension diagnosis was associated with lower risk of all-cause mortality (HR, 0.52; 95% CI, 0.36-0.76) and cardiovascular mortality (HR, 0.53; 95% CI, 0.30-0.94). Conclusions and Relevance: These findings suggest that adherence to healthy lifestyle and antihypertensive medication treatment were associated with lower risk of mortality among adults with hypertension. These findings further support that, in addition to antihypertensive medication use, adopting a healthy lifestyle is associated with benefits in the prevention of premature death among individuals with hypertension.

Effect of GLP-1/GLP-1R on the Polarization of Macrophages in the Occurrence and Development of Atherosclerosis.

AIMS: To investigate the effect of GLP-1/GLP-1R on the polarization of macrophages in the occurrence and development of atherosclerosis. METHODS: Totally, 49 patients with coronary heart disease (CHD) and 52 cases of health control (HC) were recruited, all subjects accept coronary angiography gold standard inspection. One or more major coronary arteries (LM, LAD, LCx, and RCA) stenosis degree in 50% of patients as CHD group; the rest of the stenosis less than 50% or not seen obvious stenosis are assigned to the HC group. Flow cytometry were used to detect the percentage of (CD14+) M macrophages, (CD14+CD80+) M1 macrophages, (CD14+CD206+) M2 macrophages, and their surface GLP-1R expression differences in the two groups, using BD cytokine kit to detect the levels of IL-8, IL-1ß, IL-6, IL-10, TNF, and IL-12p70. RESULTS: GLP-1R expression on the surface of total macrophages and M2 macrophages was different between the CHD group and the HC group (P < 0.05). There was no difference in the percentage of total, M1 or M2 macrophages (P > 0.05). Concentration of IL-8 in the HC group was higher than that in the CHD group (P < 0.05). There is no significant difference in the cytokine IL-1ß, IL-6, IL-10, TNF, and IL-12p70 in the two groups (P > 0.05). After controlling for potential confounders including age, gender, smoking status (S.S.), drinking status (D.S.), HR, SBP, DBP, PP, TC, TG, HDL-C, LDL-C, GHbA1c, M, M1, M2, GLP-1R_M, GLP-1R_M1, GLP-1R_M2, IL-8, IL-1ß, IL-6, IL-10, TNF, and IL-12p70 by multiple linear regression, decreasing Gensini Score was significantly associated with increased percentage of M1 macrophage. CONCLUSION: GLP-1R agonist is independent of the hypoglycemic effect of T2DM and has protective effect on cardiovascular system. GLP-1R may regulate the polarization of macrophages toward M2, thus playing a protective role in the progression of coronary atherosclerosis.

Association of blood lipid profile with incident chronic kidney disease: A Mendelian randomization study.

BACKGROUND AND AIMS: Cohort studies found blood lipid traits were associated with the risk of chronic kidney disease (CKD). We aimed to investigate whether blood lipid traits were causally associated with the risk of CKD in the Chinese. METHODS: 15,244 participants without kidney disease and cancer from the Dongfeng-Tongji cohort were recruited in 2008-2010 in Shiyan City, China. Blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and triglyceride (TG) levels were measured. 5251 participants had genotype data and were included in the Mendelian randomization analysis. Incident CKD was defined as estimated glomerular filtration rate <60 ml/min per 1.73 m2 in 2013. Logistic regression and Mendelian randomization methods were used to estimate the observed and causal associations of blood lipid traits with incident CKD. RESULTS: Various blood lipid traits were associated with CKD risk, and the odds ratios (95% confidence intervals) for incident CKD comparing the extreme quartiles were 1.45 (1.24-1.70) for TG, 1.26 (1.08-1.46) for nonHDL-c, 2.21 (1.91-2.57) for TC:HDL-c ratio, 2.14 (1.83-2.51) for TG:HDL-c ratio, and 0.47 (0.40-0.55) for HDL-c. The Mendelian randomization analysis indicated that 1 mmol/l increase in the genetic predicted blood TG level was associated with a 5% (95% confidence interval, 0-10%) higher risk of CKD. CONCLUSIONS: Although blood levels of HDL-c, TG, nonHDL-c, TC:HDL-c ratio, and TG:HDL-c ratio were observed to be associated with incident CKD, the Mendelian randomization analysis provided genetic evidence to support causal relation for blood TG level only.

PHACTR1 gene polymorphism with the risk of coronary artery disease in Chinese Han population.

BACKGROUND: Coronary artery disease (CAD) is the most frequent multifactorial disease worldwide and is characterised by endothelial injury, lipid deposition and coronary artery calcification. The purpose of this study was to determine the allelic and genotypic frequencies of two loci (rs2026458 and rs9349379) of phosphatase and actin regulator 1 (PHACTR1) to the risk of developing CAD in the Chinese Han population. METHODS: A case-control study was conducted including 332 patients with CAD and 119 controls. Genotype analysis was performed by PCR and Sanger sequencing. Genetic model analysis was performed to evaluate the association between single nucleotide polymorphisms and CAD susceptibility using Pearson's χ2 test and logistic regression analysis. RESULTS: The GG genotype of rs9349379 represented 50% and 29% of patients with CAD and controls, respectively (p<0.001). The CC genotype of rs2026458 was more prevalent in the controls than in patients with CAD compared with TT genotype (OR=0.548, 95% CI 0.351 to 0.856, p=0.008). Logistic regression analyses revealed that PHACTR1 rs9349379 GG genotype was significantly associated with increased risk of CAD in the recessive model (OR=2.359, 95% CI 1.442 to 3.862, p=0.001), even after adjusting for age gender, hypertension, type 2 diabetes, hyperlipidaemia and smoking habit. Heterogeneity test proved that rs9349379's risk effects on CAD were more significant among women. CONCLUSIONS: Our study indicate that the PHACTR1 rs9349379 polymorphism is associated with the increased risk for CAD in the female Chinese Han population.

Direct, indirect and total bilirubin and risk of incident coronary heart disease in the Dongfeng-Tongji cohort.

BACKGROUND: Total bilirubin (TBIL) is known to be inversely associated with coronary heart disease (CHD) risk, however, whether this association is dose-response remains inconsistent and it is unclear which subtype of bilirubin is responsible for the potential protective effect. METHODS: We included 12,097 participants who were free of CHD, stroke, cancer and potential liver, biliary and renal diseases at baseline from September 2008 to June 2010 and were followed-up until October 2013. Cox proportional hazards models were used to assess the hazard ratios (HR) and 95% confidence interval (95% CI) of bilirubin with incident CHD risk. RESULTS: The adjusted HRs for incident CHD increased with increasing direct bilirubin (DBIL) (p for trend = .013). Participants within the highest quintile of DBIL had 30% higher risk of incident CHD compared to those in the lowest quintile (95% CI: 1.07, 1.58). In contrast, compared with subjects in the lowest quintile of TBIL, those in the third quintile had the lowest of 24% risk for CHD incidence (95% CI: 0.63, 0.92), which showed a U-shaped association (p for quadratic trend = .040). CONCLUSIONS: DBIL was associated with a dose-response increased risk for CHD incidence. However, a U-shaped association existed between TBIL, indirect bilirubin and incident CHD risk. Key messages Direct bilirubin is independently associated with incident coronary heart disease (CHD) in a dose-response manner. A similarly consistent U-shaped association was found between total bilirubin, indirect bilirubin and incident CHD. The potential protective effect of total bilirubin within the normal range on incident CHD should be mainly attributed to mild-to moderate elevated levels of indirect bilirubin.

Association of drinking pattern with risk of coronary heart disease incidence in the middle-aged and older Chinese men: Results from the Dongfeng-Tongji cohort.

BACKGROUND: Epidemiologic studies have found that moderate alcohol consumption was associated with a decreased risk of coronary heart disease (CHD) incidence. Nevertheless, whether the drinking pattern is associated with CHD incidence still remains inconclusive. METHODS: We included 8,469 Chinese men aged 45-81 years, who were free of CHD, stroke, or cancer at baseline from Dongfeng-Tongji cohort. A semi-structured questionnaire was used to collect information on alcohol consumption and other covariates. Cox proportional hazard regression model was applied to estimate the multivariable-adjusted hazard rations (HRs) and 95% confidence intervals (95% CIs). RESULTS: During an average of 4.36 years of follow-up, we identified 959 incident CHD events. Compared with non-drinkers, the multivariable-adjusted HR (95% CI) of CHD incidence was 0.84 (0.71-0.98) in current drinkers. With respect to drinking pattern, men who consumed 20.01-40 grams ethanol once a time had a 24% lower risk of incident CHD (HR = 0.76, 95% CI = 0.62, 0.94) compared with non-drinkers. The adjusted HRs (95% CI) of CHD incidence were 0.80 (0.65, 0.99), 1.02 (0.84, 1.22), and 0.75 (0.59-0.96) in subjects who consumed 0.01-10, 10.01-30, and > 30 grams ethanol per day, respectively. Participants who consumed 20.01-40 grams ethanol per time with less than 5 times per week had the lowest risk of CHD incidence (HR = 0.73, 95% CI = 0.52, 0.96). No significant associations were observed between type or frequency of alcohol consumption and CHD incidence. CONCLUSIONS: Drinking was associated with a lower risk of CHD incidence in middle-aged and older Chinese men and moderate quantity of ethanol amounts once a time with lower frequency could been considered as a healthy drinking pattern, which might modify the relationship between alcohol consumption and incident CHD.

Dose-response relationship between serum uric acid levels and risk of incident coronary heart disease in the Dongfeng-Tongji Cohort.

BACKGROUND: In prospective studies, relationship of serum uric acid (SUA) with risk of coronary heart disease (CHD) incidence is inconsistent. We evaluated the association of SUA with incident CHD and the potential modifying effect of major CHD risk factors related to SUA among a middle aged and elderly Chinese population. METHODS: We included 16, 063 participants who were free of CHD, stroke, cancer and renal diseases at baseline from Sep. 2008 to June 2010, and were followed until Oct. 2013. Cox proportional hazard model was used to estimate the hazard ratios (HR) and 95% confidence interval (95% CI) of CHD incidence in relation to SUA. RESULTS: The adjusted HR for incident CHD increased gradually with the increasing SUA levels (P for linear trend=0.005), and the HR across sex-specific SUA quartile was 1.26 (95% CI: 1.09, 1.47), 1.13 (95% CI: 0.97, 1.31), 1.23 (95% CI: 1.06, 1.43) and 1.00 (reference; P for trend=0.014), respectively. In particular, the association was more evident in individuals with normal-weight and those without hypertension or metabolic syndrome (all P for interactions<0. 05). CONCLUSIONS: These findings suggested that higher SUA levels were independently associated with a dose-response increased risk of CHD incidence.

Sleep Duration and Midday Napping with 5-Year Incidence and Reversion of Metabolic Syndrome in Middle-Aged and Older Chinese.

STUDY OBJECTIVES: Prospective evidence on the association of sleep duration and midday napping with metabolic syndrome (MetS) is limited. We aimed to examine the associations of sleep duration and midday napping with risk of incidence and reversion of MetS and its components among a middle-aged and older Chinese population. METHODS: We included 14,399 subjects from the Dongfeng-Tongji (DFTJ) Cohort Study (2008-2013) who were free of coronary heart disease, stroke, and cancer at baseline. Baseline data were obtained by questionnaires and health examinations. Odds ratios (ORs) and 95% confidence interval (CI) were derived from multivariate logistic regression models. RESULTS: After controlling for potential covariates, longer sleep duration (≥ 9 h) was associated with a higher risk of MetS incidence (OR, 1.29; 95% CI, 1.08-1.55) and lower reversion of MetS (OR, 0.80; 95% CI, 0.66-0.96) compared with sleep duration of 7 to < 8 h; whereas shorter sleep duration (< 6 h) was not related to incidence or reversion of MetS. For midday napping, subjects with longer napping (≥ 90 min) was also associated with a higher risk of MetS incidence and a lower risk of MetS reversion compared with those with napping of 1 to < 30 min (OR, 1.48; 95% CI, 1.05-2.10 and OR, 0.70; 95% CI, 0.52-0.94, respectively). Significance for incidence or reversion of certain MetS components remained in shorter and longer sleepers but disappeared across napping categories. CONCLUSIONS: Both longer sleep duration and longer midday napping were potential risk factors for MetS incidence, and concurrently exert adverse effects on MetS reversion.

Green tea consumption is associated with reduced incident CHD and improved CHD-related biomarkers in the Dongfeng-Tongji cohort.

Prospective studies on the association of green tea with risk of coronary heart disease (CHD) incidence were scarce. This study examined whether green tea can reduce CHD incidence and have a beneficial effect on CHD-related risk markers in middle-aged and older Chinese population. We included 19,471 participants who were free of CHD, stroke or cancer at baseline from September 2008 to June 2010, and were followed until October 2013. Cox proportional hazard models were used to examine the hazard ratios (HR) of CHD incidence in relation to green tea consumption. Linear regression models were used to evaluate the effect of green tea on 5-year changes of CHD-related biomarkers. Compared with non-green tea consumers, the multivariable-adjusted HR for CHD was 0.89 (95% CI, 0.81-0.98) in green tea consumers. Particularly, the reduced risk of CHD incidence with green tea consumption was more evident among participants who were male, more than 60 years old, overweight, or with diabetes mellitus. In addition, green tea consumption improved multiple CHD-related risk markers including total cholesterol, HDL-cholesterol, triglycerides, mean platelet volume, and uric acid. In conclusion, green tea consumption was associated with a reduced risk of CHD incidence in the middle-aged and older Chinese populations, and the association might be partly due to altered CHD-related biomarkers.

Sensitive determination of four camptothecins by solid-phase microextraction-HPLC based on a boronic acid contained polymer monolithic layer.

Camptothecin (CPT) and its derivative have been revealed to possess special anti-cancer activity, extraction methods are necessary for trace determination of CPTs in complex samples. In this work, we prepared a high efficient boronic acid-based polymer monolithic layer for microextraction of CPTs. A disposable membrane filter-based extraction device was developed, and boronic acid groups were co-polymerized into a polyporous polymer skeleton and served as the monolithic sorbent. The prepared poly(4-VB-MA-TRIM) showed good stability and great extraction efficiency toward four CPTs. After optimization of extraction conditions, poly(4-VB-MA-TRIM)-based solid-phase microextraction was coupled HPLC for determination of CPTs in biological samples. The method exhibited low limits of detection of 0.05-0.2 ng mL(-1), which is significantly more sensitive than reported HPLC methods. The method also showed wide linear range (0.1-100 and 0.5-200 ng mL(-1)), good linearity (R(2)≥0.9981) and good reproducibility (RSD ≤3.76%). The method has been applied in plasma samples, with good selectivity and good recoveries ranging from 85.1 to 104.7%.

A genome-wide association study identifies common variants influencing serum uric acid concentrations in a Chinese population.

BACKGROUND: Uric acid (UA) is a complex phenotype influenced by both genetic and environmental factors as well as their interactions. Current genome-wide association studies (GWASs) have identified a variety of genetic determinants of UA in Europeans; however, such studies in Asians, especially in Chinese populations remain limited. METHODS: A two-stage GWAS was performed to identify single nucleotide polymorphisms (SNPs) that were associated with serum uric acid (UA) in a Chinese population of 12,281 participants (GWAS discovery stage included 1452 participants from the Dongfeng-Tongji cohort (DFTJ-cohort) and 1999 participants from the Fangchenggang Area Male Health and Examination Survey (FAMHES). The validation stage included another independent 8830 individuals from the DFTJ-cohort). Affymetrix Genome-Wide Human SNP Array 6.0 chips and Illumina Omni-Express platform were used for genotyping for DFTJ-cohort and FAMHES, respectively. Gene-environment interactions on serum UA levels were further explored in 10,282 participants from the DFTJ-cohort. RESULTS: Briefly, we identified two previously reported UA loci of SLC2A9 (rs11722228, combined P = 8.98 × 10-31) and ABCG2 (rs2231142, combined P = 3.34 × 10-42). The two independent SNPs rs11722228 and rs2231142 explained 1.03% and 1.09% of the total variation of UA levels, respectively. Heterogeneity was observed across different populations. More importantly, both independent SNPs rs11722228 and rs2231142 were nominally significantly interacted with gender on serum UA levels (P for interaction = 4.0 × 10-2 and 2.0 × 10-2, respectively). The minor allele (T) for rs11722228 in SLC2A9 has greater influence in elevating serum UA levels in females compared to males and the minor allele (T) of rs2231142 in ABCG2 had stronger effects on serum UA levels in males than that in females. CONCLUSIONS: Two genetic loci (SLC2A9 and ABCG2) were confirmed to be associated with serum UA concentration. These findings strongly support the evidence that SLC2A9 and ABCG2 function in UA metabolism across human populations. Furthermore, we observed these associations are modified by gender.

A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk.

OBJECTIVE: Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. DESIGN: We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). RESULTS: The analyses showed association peaks on three genetic loci for CA19-9 (FUT6-FUT3 at 19p13.3, FUT2-CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10(-13)-3.30×10(-290)); four for CEA (ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10(-22)-5.81×10(-209)); and two for AFP (AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10(-18) and 1.28×10(-14)). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p<0.05). CONCLUSIONS: This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.

Higher carbohydrate antigen 125 levels are associated with increased risk of coronary heart disease in elderly chinese: a population-based case-control study.

BACKGROUND: High carbohydrate antigen 125 (CA-125) level was reported to be associated with some cardiac dysfunctions, such as chronic heart failure, but the relationship between CA-125 level and coronary heart disease (CHD) risk remains unclear. The aim of this study was to explore the potential association in a Chinese older population. METHODS: In a population-based case-control study conducted in a Chinese older population, serum CA-125 levels were measured in 1177 diagnosed CHD patients and 3531 age and sex matched control subjects without CHD. RESULTS: Serum CA-125 level was significantly higher in CHD patients than controls (P < 0.001) with adjustment for age, gender, smoking, drinking, BMI, physical activity, hypertension, dyslipidemia, diabetes mellitus, medication history and family history of CHD and myocardial infarction. CHD risk was doubled (OR: 2.10, 95%CI: 1.69-2.60) among subjects in the highest quartile compared to those in the lowest quartile of CA-125 level (P trend < 0.001). Furthermore, CA-125 levels were associated with CHD risks in subjects with age over 60 years (OR: 2.19, 95%CI: 1.75-2.73), current smokers (OR: 2.29, 95%CI: 1.50-3.49), current drinkers (OR: 2.35, 95%CI: 1.57-3.53) and subjects with hypertension (OR: 2.04, 95%CI: 1.71-2.43). CONCLUSIONS: Elevated serum CA-125 level might be associated with increased risk of coronary heart disease in the Chinese older population. Further investigations are needed to identify the possible biological role of CA-125 in CHD development in the future.

The g0/g1 switch gene 2 is an important regulator of hepatic triglyceride metabolism.

Nonalcoholic fatty liver disease is associated with obesity and insulin resistance. Factors that regulate the disposal of hepatic triglycerides contribute to the development of hepatic steatosis. G0/G1 switch gene 2 (G0S2) is a target of peroxisome proliferator-activated receptors and plays an important role in regulating lipolysis in adipocytes. Therefore, we investigated whether G0S2 plays a role in hepatic lipid metabolism. Adenovirus-mediated expression of G0S2 (Ad-G0S2) potently induced fatty liver in mice. The liver mass of Ad-G0S2-infected mice was markedly increased with excess triglyceride content compared to the control mice. G0S2 did not change cellular cholesterol levels in hepatocytes. G0S2 was found to be co-localized with adipose triglyceride lipase at the surface of lipid droplets. Hepatic G0S2 overexpression resulted in an increase in plasma Low-density lipoprotein (LDL)/Very-Low-density (VLDL) lipoprotein cholesterol level. Plasma High-density lipoprotein (HDL) cholesterol and ketone body levels were slightly decreased in Ad-G0S2 injected mice. G0S2 also increased the accumulation of neutral lipids in cultured HepG2 and L02 cells. However, G0S2 overexpression in the liver significantly improved glucose tolerance in mice. Livers expressing G0S2 exhibited increased 6-(N-(7-nitrobenz-2-oxa-1-3-diazol-4-yl) amino)-6-deoxyglucose uptake compared with livers transfected with control adenovirus. Taken together, our results provide evidence supporting an important role for G0S2 as a regulator of triglyceride content in the liver and suggest that G0S2 may be a molecular target for the treatment of insulin resistance and other obesity-related metabolic disorders.

A genome-wide association study for serum bilirubin levels and gene-environment interaction in a Chinese population.

Bilirubin is an effective antioxidant and is influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified multiple loci affecting serum total bilirubin levels. However, most of the studies were conducted in European populations and little attention has been devoted either to genetic variants associated with direct and indirect bilirubin levels or to the gene-environment interactions on bilirubin levels. In this study, a two-stage GWAS was performed to identify genetic variants associated with all types of bilirubin levels in 10,282 Han Chinese individuals. Gene-environment interactions were further examined. Briefly, two previously reported loci, UGT1A1 on 2q37 (rs6742078 and rs4148323, combined P = 1.44 × 10(-89) and P = 5.05 × 10(-69) , respectively) and SLCO1B3 on 12p12 (rs2417940, combined P = 6.93 × 10(-19) ) were successfully replicated. The two loci explained 9.2% and 0.9% of the total variations of total bilirubin levels, respectively. Ethnic genetic differences were observed between Chinese and European populations. More importantly, a significant interaction was found between rs2417940 in SLCO1B3 gene and smoking on total bilirubin levels (P = 1.99 × 10(-3) ). Single nucleotide polymorphism (SNP) rs2417940 had stronger effects on total bilirubin levels in nonsmokers than in smokers, suggesting that the effects of SLCO1B3 genotype on bilirubin levels were partly dependent on smoking status. Consistent associations and interactions were observed for serum direct and indirect bilirubin levels.