Effects and plasma proteomic analysis of GLP-1RA versus CPA/EE, in combination with metformin, on overweight PCOS women: a randomized controlled trial.

PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS. METHODS: In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-µg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2-1.8 mg/day) +Met (1500 mg/day) for 12 weeks. The clinical effectiveness and adverse effects were evaluated, followed by plasma proteomic analysis and verification of critical biomarkers by ELISA. RESULTS: Eighty(80%) patients completed the study. Both interventions improved menstrual cycle, polycystic ovaries, LH(luteinizing hormone) and HbA1c(hemoglobin A1c) levels after the 12-week treatment. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI (Body Mass Index), and waist circumference, FBG(fasting blood glucose), AUCI(area under curve of insulin),TC (Total Cholesterol), IL-6(Interleukin-6) and improving insulin sensitivity, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in improving hyperandrogenemia, including T(total testosterone), LH, LH/FSH(Luteinizing hormone/follicle-stimulating hormone), SHBG(sex hormone-binding globulin) and FAI (free androgen index). By contract, GLP-1RA+Met group only improved LH. Plasma proteomic analysis revealed that the interventions altered proteins involved in reactive oxygen species detoxification (PRDX6, GSTO1, GSTP1, GSTM2), platelet degranulation (FN1), and the immune response (SERPINB9). CONCLUSIONS: Both CPA/EE+Met and GLP-1RA + Met treatment improved reproductive functions in overweight PCOS women. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI, and waist, and improving metabolism, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in reducing hyperandrogenemia. The novel plasma biomarkers PRDX6, FN1, and SERPINB9, might be indicators and targets for PCOS treatment. TRIAL REGISTRATION CLINICALTIALS. GOV TRIAL NO: NCT03151005. Registered 12 May, 2017, https://clinicaltrials.gov/ct2/show/NCT03151005 .

Differences in Clinical Characteristics and Surgical Outcomes of Patients with Ischemic and Hemorrhagic Pituitary Adenomas.

OBJECTIVE: Ischemia and hemorrhage of pituitary adenomas (PA) caused important clinical syndrome. However, the differences on clinical characteristics and surgical outcomes between these two kinds apoplexy were less reported. METHODS: A retrospective analysis was made of patients with pituitary apoplexy between January 2013 and June 2018. Baseline and clinical characteristics before surgery were reviewed. All patients underwent transsphenoidal surgery and were followed up at least 1 year. RESULTS: Total 67 cases (5.8%) among 1147 pituitary tumor patients were enrolled, which consisted of 28 (~2.4%) ischemic PA and 39 (~3.4%) hemorrhagic PA. There were more male patients in the ischemic group compared with hemorrhagic group (78.6% vs 53.8%, p=0.043). However, the mean age, tumor size and functional tumor ratio were significant higher in the hemorrhagic group. Headache was more common in ischemic PA (82.1%) than that of hemorrhagic PA (51.3%, p=0.011). Magnetic resonance imaging findings found that mucosal thickening and enhancement of the sphenoid sinus was observed in 15 ischemic PA patients (n=27, 55.6%), but none in patients with hemorrhagic PA (n=38, p<0.0001). It was worth noting that the rate of pre-surgical hypopituitarism in ischemic PA patients were seemed higher than that in hemorrhagic PA patients, but not significant. The two groups got a total tumor resection rate at 94.1% and 92.9%, independently. No significant difference on the operative time, blood loss in operation and complications in perioperative period was observed in two groups. After operation, cranial nerve symptoms recovered to normal at 81.8% of ischemic PA patients and 82.6% of hemorrhagic PA patients. Importantly, the incidence of postoperative hypopituitarism partially decreased in both groups, among which the rate of hypothyroidism in ischemic PA patients significantly decreased from 46.4% to 18.5% (p=0.044). CONCLUSION: Patients with ischemic PA presented different clinical characteristics to the hemorrhagic ones. Transsphenoidal surgery should be considered for the patients with neuro-ophthalmic deficits and might benefit for pituitary function recovery of the apoplectic adenoma patients, especially pituitary thyroid axis in ischemic PA patients.

Pleiomorphism plurihormonal Pit-1-positive macroadenoma with central hyperthyroidism: a rare case report and literature review.

BACKGROUND: Thyrotropin-secreting pituitary neuroendocrine tumors (PitNETs) are rare pituitary adenomas that are occasionally accompanied by hypersecretion of other anterior pituitary hormones, such as growth hormone (GH) and prolactin (PRL). The clinical, biochemical, and pathological characteristics may represent diverse circumstances. CASE PRESENTATION: In this report, a 33-year-old female diagnosed with a TSH PitNET co-secreting GH presented no obvious clinical symptoms. The main characteristics were elevated thyroid-stimulating hormone (TSH), free tri-iodothyronine (FT3), and free thyroxine (FT4) levels accompanied by slightly elevated GH and insulin-like growth factor-1 (IGF-1) levels. Magnetic resonance imaging (MRI) detected a pituitary macroadenoma (18 × 16 × 16 mm) with cavernous sinus and suprasellar invasion. Immunohistochemistry revealed diffuse positivity for TSH, strong immunoreactivity for GH, and sporadic positivity for PRL. The electron microscope and double immunofluorescence staining confirmed a plurimorphous plurihormonal adenoma producing TSH, GH, and PRL. After preoperative somatostatin receptor ligand (SRL) treatment and transsphenoidal surgery, the patient achieved temporary clinical and biochemical remission. However, 3 months after surgery, the patient was suspected of having Hashimoto's thyroiditis due to higher thyroglobulin antibody (TGAb), thyroid peroxidase antibody (TPOAb), and thyroid receptor antibody (TRAb) and an enlarged thyroid nodule. During follow-up, thyroid function and TSH slowly transformed from transient hyperthyroidism to hypothyroidism. They were maintained in the normal range by L-T4. CONCLUSION: In the TSH PitNET, the positive immunohistochemistry for TSH, GH, and PRL translated into hormonal overproduction with TSH and GH.

An Asian case of combined 17α-hydroxylase/17,20-lyase deficiency due to homozygous p.R96Q mutation: A case report and review of the literature.

Background: Combined 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a very rare form of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene. Almost 100 different mutations of the CYP17A1 gene have been reported, including p.R96Q mutation, but no case of p.R96Q mutation has been described in Asian populations. Case presentation: We describe a 22-year-old female patient of 46,XY karyotype, who presented with pseudohermaphrodism, primary amenorrhea, underdeveloped secondary sexual characteristics, delayed epiphyseal healing, hypertension, and hypokalemia. The diagnosis of 17-OHD was reached by measurement of steroid hormones and abdominal CT scan and confirmed by genetic sequencing, which revealed a homozygous p.R96Q missense mutation in the CYP17A1 gene. The patient received treatment with dexamethasone and estradiol, and 4 months of follow-up showed that both blood pressure and potassium were well controlled. Conclusions: This is the first Asian case of CAH caused by a homozygous p.R96Q missense mutation in the CYP17A1 gene. Herein, we highlight the role of inguinal hernia in the early diagnosis of female 17-OHD and the necessity of removing the ectopic testis.

Clinical Characteristics and Associated Factors of Colonic Polyps in Acromegaly.

PURPOSE: To investigate the clinical characteristics and associated factors of colonic polyps in patients with acromegaly. METHODS: Clinical characteristics and colonoscopy findings of 86 acromegaly patients who received treatment were retrospectively reviewed, and colonoscopy findings and the correlation with growth hormone (GH)-secreting pituitary adenoma (GHPA) volume and hormonal/metabolic levels were analyzed. RESULTS: The prevalence of colonic polyps in acromegaly patients was 40.7% and increased significantly with advanced age, especially in those ≥50 years. Multiple polyps (62.8%) and colonic polyps in the left colon (54.2%) were detected more frequently. Compared to acromegaly patients without polyps, those with polyps displayed higher insulin-like growth factor-1 × upper limit of normal (IGF-1×ULN) levels (P=0.03). IGF-1 levels and GHPA volumes in patients with polyps showed increasing trends, although the differences were not significant. GH levels were higher in patients with polyps of diameter ≤5 mm than those with polyps of diameter >5 mm (P=0.031). The univariate and multivariate logistic regression analysis revealed that GHPA volumes (OR: 1.09, 95% CI: 1.01-1.20; P=0.039) and IGF-1×ULN Q2 levels (OR: 6.51, 95% CI: 1.20-44.60; P=0.038) were independent factors for predicting the risk of colonic polyp occurrence in acromegaly patients. A nomogram was prepared to evaluate the risk of colonic polyps in acromegaly patients. CONCLUSION: The acromegalic patients are a population with a high prevalence of colonic polyps. GHPA volumes and IGF-1×ULN levels may be predictors of colonic polyp occurrence.

Identification of Key Genes and Pathways in Peripheral Blood Mononuclear Cells of Type 1 Diabetes Mellitus by Integrated Bioinformatics Analysis.

BACKGROUND: The onset and progression of type 1 diabetes mellitus (T1DM) is closely related to autoimmunity. Effective monitoring of the immune system and developing targeted therapies are frontier fields in T1DM treatment. Currently, the most available tissue that reflects the immune system is peripheral blood mononuclear cells (PBMCs). Thus, the aim of this study was to identify key PBMC biomarkers of T1DM. METHODS: Common differentially expressed genes (DEGs) were screened from the Gene Expression Omnibus (GEO) datasets GSE9006, GSE72377, and GSE55098, and PBMC mRNA expression in T1DM patients was compared with that in healthy participants by GEO2R. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) network analyses of DEGs were performed using the Cytoscape, DAVID, and STRING databases. The vital hub genes were validated by reverse transcription-polymerase chain reaction using clinical samples. The disease-gene-drug interaction network was built using the Comparative Toxicogenomics Database (CTD) and Drug Gene Interaction Database (DGIdb). RESULTS: We found that various biological functions or pathways related to the immune system and glucose metabolism changed in PBMCs from T1DM patients. In the PPI network, the DEGs of module 1 were significantly enriched in processes including inflammatory and immune responses and in pathways of proteoglycans in cancer. Moreover, we focused on four vital hub genes, namely, chitinase-3-like protein 1 (CHI3L1), C-X-C motif chemokine ligand 1 (CXCL1), matrix metallopeptidase 9 (MMP9), and granzyme B (GZMB), and confirmed them in clinical PBMC samples. Furthermore, the disease-gene-drug interaction network revealed the potential of key genes as reference markers in T1DM. CONCLUSION: These results provide new insight into T1DM pathogenesis and novel biomarkers that could be widely representative reference indicators or potential therapeutic targets for clinical applications.

Case Report: A Deletion Variant in the DCAF17 Gene Underlying Woodhouse-Sakati Syndrome in a Chinese Consanguineous Family.

Woodhouse-Sakati syndrome (WSS, MIM 241080) is a rare neuroendocrine disease characterized by hair loss, hypogonadism, diabetes, hearing loss, and extrapyramidal syndrome, and is usually caused by mutations in the DCAF17 gene as an inherited disease. DCAF17 plays an important role in mammalian gonadal development and infertility. So far, there have been no WSS reports in China. The patient introduced in this case is from a consanguineous family. The main symptoms of the patient were alopecia and gonadal agenesis. Other symptoms such as hearing loss, intellectual disability, and hyperglycemia were remarkable, and these symptoms are often observed in WSS patients. We found a nonsense mutation in the 11th exon of the gene DCAF17 (Refseq: NM_025000) in the patient and her younger brother, which confirmed the diagnosis of WSS. The genetic results also showed that the mutation was inherited from their healthy first-cousin parents.

Adrenal artery ablation for primary aldosteronism without apparent aldosteronoma: An efficacy and safety, proof-of-principle trial.

Primary aldosteronism (PA) is associated with resistant hypertension and cardiovascular events. There are some limitations of current medical and surgical therapies for PA. To determine the efficacy and safety of catheter-based adrenal artery ablation for treatment of PA patients who refused both surgery and medical therapy, we performed this prospective cohort study. Thirty-six PA patients without apparent aldosteronoma were treated by adrenal artery ablation. Primary outcome was postoperative blood pressure and defined daily dose (DDD) of antihypertensive medications after adrenal ablation. Secondary outcome was biochemical success. We assessed outcomes based on Primary Aldosteronism Surgical Outcome (PASO) criteria. Adrenal CT scan, biochemical evaluation, adrenal artery ablation and adrenal venous sampling (AVS) were underwent. After adrenal ablation, complete clinical success (normotension without antihypertensive medication) was achieved in 9/36 (25.0%) patients and partial clinical success (reduction in blood pressure or less antihypertensive medication) in 13/36 (36.1%) patients. Complete biochemical success (correction of hypokalemia and normalization of aldosterone-to-renin ratio) was achieved in 16/36 (44.4%) patients. Office-based and ambulatory blood pressures were reduced by 17/7 and 11/2 mmHg at 6 months after ablation, respectively. The plasma cortisol level in the ablation group decreased slightly, but no patient developed hypoadrenocorticism. Catheter-based adrenal ablation appears to produce substantial and sustained blood pressure reduction and biochemical improvement, with only minor adverse events in PA patients without apparent aldosteronoma. This therapy could be an important supplement for current PA treatments.

Short-Term Versus 6-Week Prednisone In The Treatment Of Subacute Thyroiditis: A Randomized Controlled Trial.

OBJECTIVE: Moderate-to-severe subacute thyroiditis is clinically managed with 6 to 8 weeks of glucocorticoid therapy. However, no studies have evaluated short-term prednisone treatment for subacute thyroiditis. METHODS: This 24-week, prospective, single-blind, randomized controlled study enrolled patients (aged 18 to 70 years) with subacute thyroiditis who were hospitalized between August, 2013, and December, 2014. Patients with moderate-to-severe symptoms were randomly assigned to receive either 30 mg/day prednisone for 1 week, followed by 1 week of nonsteroidal anti-inflammatory drugs, or the conventional 6-week prednisone therapy. The primary endpoint was intergroup differences in treatment efficacy at the end of the treatment course. Secondary endpoints included between-group differences in post-withdrawal adverse effect parameters and thyroid function at weeks 6, 12, and 24. RESULTS: We screened 96 patients, randomized 52 participants, and 50 participants completed the study. Efficacy and recurrence rates were not significantly different at withdrawal in both groups (P = .65). At treatment discontinuation, parathyroid hormone (28.8 versus 38.9 pg/mL; P = .011) and systolic blood pressure (113.9 versus 122.4mm Hg; P = .023) were significantly lower in the experimental group than in the control group. There were no significant intergroup differences in other secondary endpoints at withdrawal and in thyroid function at weeks 6, 12, and 24. CONCLUSION: Fewer side effects of glucocorticoids and similar efficacy and recurrence rates were observed with short-term prednisone compared with the 6-week treatment for subacute thyroiditis. Short-term prednisone, with a better safety profile, may be an alternative strategy for ameliorating moderate-to-severe symptoms of subacute thyroiditis. ABBREVIATIONS: BPPG = breakfast postprandial plasma glucose; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; FPG = fasting plasma glucose; FT3 = free triiodothyronine; FT4 = free thyroxine; GA = glycated albumin; NSAIDs = nonsteroidal anti-inflammatory drugs; OC = osteocalcin; PINP = type I procollagen amino-terminal peptide; PTH = parathyroid hormone; RCT = randomized controlled trial; SAT = subacute thyroiditis; SBP = systolic blood pressure; TC = total cholesterol; TSH = thyroid-stimulating hormone; TBG = thyroid-binding globulin; TG = triglyceride; TGAb = antithyroglobulin antibody; TPOAb = antithyroid peroxidase antibody; TRAb = antithyroid-stimulating hormone receptor antibody.

Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis.

BACKGROUND: Increasing evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. However, little is known about the effects of commonly used antidiabetic agents on the gut microbiota. In this study, we investigated the roles of dipeptidyl peptidase-4 inhibitors (DPP-4i) and α-glucosidase inhibitor in modulating the gut microbiota. METHODS: 16S-rDNA sequencing was performed to analyse the effects of DPP-4i and acarbose on the gut microbiota in mice fed a high-fat diet (HFD). Fecal microbiota transplantation (FMT) from type 2 diabetes patients to germ-free mice was performed to investigate the contribution of the altered microbiome to antidiabetic effects of the drugs. Fecal metabolomics was also analysed by untargeted and targeted GC-MS systems. FINDINGS: Although DPP-4i and α-glucosidase inhibitor both altered the gut microbial composition, only the microbiome modulation of DPP-4i contributed to its hypoglycemic effect. Specifically, the changes of 68.6% genera induced by HFD were rescued by DPP-4i. FMT showed that the DPP-4i-altered microbiome improved glucose tolerance in colonized mice, while acarbose did not. Moreover, DPP-4i increased the abundance of Bacteroidetes, and also promoted a functional shift in the gut microbiome, especially increasing the production of succinate. INTERPRETATION: Our findings demonstrate an important effect of DPP-4i on the gut microbiota, revealing a new hypoglycemic mechanism and an additional benefit of it. Furthermore, modulating the microbial composition, and the functional shift arising from changes in the microbiome, might be a potential strategy for improving glucose homeostasis. FUND: This work was supported by grants from the National Natural Science Foundation of China (No. 81700757, No. 81471039, No. 81700714 and No. 81770434), the National Key R&D Program of China (No. 2017YFC1309602, No. 2016YFC1101100, No. 2017YFD0500503 and No. 2017YFD0501001), and the Natural Science Foundation of Chongqing (No. cstc2014jcyjjq10006, No. cstc2016jcyjA0093 and No. cstc2016jcyjA0518).

Plasma Asprosin Levels Are Associated with Glucose Metabolism, Lipid, and Sex Hormone Profiles in Females with Metabolic-Related Diseases.

Asprosin is a white adipose tissue-derived hormone that increases abnormally in mammals with insulin resistance. However, the role of asprosin in polycystic ovary syndrome (PCOS), a disease partly characterized by insulin resistance, and its potential connection with type 2 diabetes mellitus (T2DM) and PCOS has not been thoroughly elucidated to date. To investigate the association of asprosin with metabolic profiles, sex-related hormones, or inflammation in females with T2DM or PCOS, plasma asprosin and metabolic indicators were measured in 66 healthy females, 53 female patients with T2DM, and 41 patients with PCOS. Spearman's correlation analysis and binary logistic regression analysis models were used. Plasma asprosin was significantly higher in T2DM females than in healthy subjects (P < 0.001) and was positively correlated with fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and HOMA-IR (P < 0.05). Asprosin in PCOS subjects was also higher than in healthy subjects (P < 0.001) but lower than in T2DM subjects (P < 0.05), and it was positively correlated with FBG, HbA1c, HOMA-IR, LDL-c, APOB, APOE, and testosterone (P < 0.05). The BMI-categorized subgroups of PCOS subjects also showed correlations of asprosin with metabolic profiles and sex-related hormones. Binary logistic regression analysis revealed that plasma asprosin level acted as an independent risk factor for T2DM or PCOS. These findings suggest the correlation of plasma asprosin level with glucose metabolism, lipid metabolism, sex-related hormones, and inflammation in females, supporting asprosin as a potential predictive factor for females with metabolic-related diseases. This trial is registered with ChiCTR-ROC-17010719.

A novel chimeric CYP11B2/CYP11B1 combined with a new p.L340P CYP11B1 mutation in a patient with 11OHD: case report.

BACKGROUND: 11ß-Hydroxylase deficiency (11OHD) is a common form of congenital adrenal hyperplasia that has been shown to result from inactivating CYP11B1 mutations, and pathogenic CYP11B2/CYP11B1 chimeras contribute to a minority of cases. Heterozygote cases (chimeras combined with missense mutation) are very rare, and genetic analysis of these cases is difficult. CASE PRESENTATION: We describe an 11OHD patient presenting with precocious pseudopuberty and hypokalemia hypertension who harbored a chimeric CYP11B2/CYP11B1 with a novel breakage point located at g.9559-9742 of CYP11B2. Interestingly, the other allele exhibited a new mutation, p.L340P, in CYP11B1. Bioinformatics and molecular dynamics simulation indicated that p.L340P decreased the stability and changed the surface configuration of 11ß-hydroxylase, indicating a disease-causing mutation. Further pedigree study, PCR and next-generation sequencing indicated that the proband carried both the chimera and p.L340P, and coexistence of the two increased the severity of 11OHD in this family. After treatment with combined medications, blood pressure and clinical parameters improved. CONCLUSIONS: Our results suggest that chimera screening and CYP11B1 mutation screening should be simultaneously conducted, and pedigree study is necessary.

DPP-4 Inhibitors as Treatments for Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

OBJECTIVE: Several clinical studies have reported the application of dipeptidyl peptidase-4 (DPP-4) inhibitors as treatments for type 1 diabetes mellitus (T1DM). This study aims to review the outcomes of these existing studies and to discuss the therapeutic effects of DPP-4 inhibitors on T1DM. METHODS: We thoroughly searched the Medline, Embase, PubMed, and Cochrane Library databases and ClinicalTrials.gov for studies concerning the use of DPP-4 inhibitors in patients with T1DM. RESULTS: In preclinical trials, DPP-4 inhibitors improved the pathogenesis of T1DM. However, only a portion of the studies showed potential efficacy regarding clinical glycemic control and other clinical parameters. From this meta-analysis, pooled data from 5 randomized controlled trials revealed that the additional use of DPP-4 inhibitors resulted in a greater decrease in glycated hemoglobin A1c (HbA1c) levels (0.07%, 95% CI (-0.37%-0.23%)) than insulin monotherapy, although the decrease was not significant. A small decrease in postprandial glucose or insulin consumption was confirmed. CONCLUSION: Although DPP-4 inhibitors may be beneficial for T1DM, existing studies do not strongly support these positive effects in clinical practice. Further optimized clinical trials are needed.

Metformin inhibits proliferation and growth hormone secretion of GH3 pituitary adenoma cells.

Metformin is an anti-hyperglycemic agent used to treat diabetes, and recent evidence suggests it has antitumor efficacy. Because growth hormone-secreting pituitary adenoma (GH-PA) patients have a high incidence of diabetes frequently treated with metformin, we assessed the antitumor effect of metformin on GH-PA. We found that metformin effectively inhibited proliferation and induced apoptosis in the GH-PA cell line GH3. We detected a decrease in mitochondrial membrane potential (MMP), an increase in expression of pro-apoptotic proteins, and a decrease in expression of an anti-apoptotic protein in metformin-treated GH3 cells, which suggests involvement of the mitochondrial-mediated apoptosis pathway. Inhibition of AMPK, which is activated by metformin, failed to reverse the antiproliferative effect. ATF3 was upregulated by metformin, and its knockdown significantly reduced metformin-induced apoptosis. In addition, GH secretion was inhibited by metformin through suppression of STAT3 activity independently of AMPK. Metformin also significantly suppressed cellular proliferation and GH secretion in primary human GH-PA cells. Metformin also significantly inhibited GH3 cell proliferation and GH secretion in vivo. ATF3 upregulation and p-STAT3 downregulation were confirmed in xenografts. These findings suggest metformin is a potentially promising therapeutic agent for the treatment of GH-PA, particularly in patients with diabetes.

Identification and association of RAC1 gene polymorphisms with mRNA and protein expression levels of Rac1 in solid organ (kidney, liver, heart) transplant recipients.

The activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) is critical in the renal, hepatic and cardiac diseases that lead to the requirement for transplantation, however, no investigations have been performed in Chinese populations to determine the association between RAC1 genotypes and the activation of Rac1. In the present study, 304 solid organ transplant recipients (SOTRs), consisting of 164 renal transplantations, 85 hepatic transplantations and 55 cardiac transplantations, and 332 Chinese healthy control subjects were recruited to investigate whether differences existed in the mRNA and protein expression levels of Rac1 in the different groups. Furthermore, the present study identified and investigated associations of the RAC1 (rs702482, rs10951982, rs702483 and rs6954996) genotypes with the mRNA expression levels of RAC1, and the protein expression levels of total Rac1 and active Rac1­guanosine triphosphatase (GTP). It was identified that the healthy population had significantly higher levels of Rac1 and Rac1­GTP, compared with the kidney, liver and heart transplantation populations (P<0.001 for all comparisons). Significant associations (P<0.05) were observed between the RAC1 genotypes and the expression levels of mRNA, Rac1 and Rac1­GTP. However, the changes in the mRNA expression levels of RAC1 with genotypes were different from those of the proteins. The results of the present study represent the first, to the best of our knowledge, to report that Rac1 and Rac1­GTP proteins can be downregulated in SOTRs, and that RAC1 genetic polymorphisms can potentially affect the mRNA expression of RAC1, and the protein expression of Rac1 and Rac1­GTP. These results provide a foundation for further functional investigations to determine the biological and molecular functions of the RAC1 gene in SOTRs.

Decreased Peripheral Mitochondrial DNA Copy Number is Associated with the Risk of Heart Failure and Long-term Outcomes.

Mitochondrial DNA (mtDNA) copy number variation (CNV), which reflects the oxidant-induced cell damage, has been observed in a wide range of human diseases. However, whether it correlates with heart failure, which is closely related to oxidative stress, has never been elucidated before. We aimed to systematically investigate the associations between leukocyte mtDNA CNV and heart failure risk and prognosis. A total of 1700 hospitalized patients with heart failure and 1700 age- and sex-matched community population were consecutively enrolled in this observational study, as well as 1638 (96.4%) patients were followed prospectively for a median of 17 months (12-24 months). The relative mtDNA copy number of leukocyte of peripheral blood or cardiac tissue was measured in triplicate by quantitative real-time PCR method. Patients with heart failure possessed much lower relative mtDNA copy number compared with control subjects (median 0.83, interquartile range [IQR] 0.60-1.16 vs median 1.00, IQR 0.47-2.20; P < 0.001), especially for the patients with ischemic etiology (median, 0.77 for ischemic and 0.91 for non-ischemic, P < 0.001). Patients with lower mtDNA copy number exhibited 1.7 times higher risk of heart failure (odds ratio 1.71, 95% confidence interval [CI] 1.48-1.97, P < 0.001). Long-term follow-up (median of 17 months) showed that decreased mtDNA copy number was significant associated with both increased cardiovascular deaths (hazard ratio [HR] 1.58, 95% CI 1.16-2.16, P = 0.004) and cardiovascular rehospitalization (HR 1.48, 95% CI 1.21-1.82, P < 0.001). After adjusting for the conventional risk factors and medications, lower mtDNA copy numbers were still significantly associated with 50% higher cardiovascular mortality (P = 0.035). In conclusion, mtDNA copy number depletion is an independent risk factor for heart failure and predicts higher cardiovascular mortality in patients with heart failure.

ADAMTS7 locus confers high cross-race risk for development of coronary atheromatous plaque.

Genome-wide association studies of coronary artery disease (CAD) have recently identified a new susceptibility locus, ADAMTS7, in subjects of European ancestry. However, the significance of this locus in Chinese populations has not been identified. Therefore, this study was designed to evaluate the effect of rs3825807, a non-synonymous variant in the prodomain of the ADAMTS7 protease, on CAD risk and atherosclerosis severity in a Chinese population. We performed genetic association analyses in two independent case-control cohorts, which included a total of 8154 participants. Additionally, the association between the ADAMTS7 rs3825807 genotype and the proportion of CAD patients with 3- and 1-vessel disease was tested. We found that ADAMTS7 rs3825807 was associated with susceptibility to CAD in a Chinese population [odds ratio (OR) = 1.15, 95 % confidence interval (CI) = 1.05-1.26, P = 0.002]. The association remained significant after adjusting for clinical covariates (adjusted OR = 1.12, 95 % CI = 1.02-1.24, P = 0.02). Among 3741 angiographically documented CAD patients, the rs3825807 risk allele showed a significant association with disease severity (P = 0.04, trend P = 0.02). Additionally, 3-vessel disease demonstrated a strong and direct association with ADAMTS7 rs3825807 gene dosage (P = 0.02). Overall, our findings indicate that the significant associations observed between this coding variant in ADAMTS7 and the risk of CAD development are cross-ethnic, and the gene dosage is consistent with the degree of coronary atheromatous burden.