Serum fetuin-a and risk of thoracic aortic aneurysms: a two-sample mendelian randomization study.

Background: Recent studies have revealed a significant decrease in serum fetuin-A levels in atherosclerotic aneurysms, indicating that fetuin-A may play a protective role in the progression of arterial calcification. However, the specific mechanism behind this phenomenon remains unclear. We aimed to examine the association between fetuin-A levels in thoracic aortic aneurysms (TAAs) and risk of TAAs and to evaluate whether this association was causal. Methods: A total of 26 SNPs were selected as instrumental variables for fetuin-A in 9,055 participants of European ancestry from the CHARGE consortium, and their effects on thoracic aortic aneurysm and decreased descending thoracic aortic diameter were separately estimated in 353,049 and 39,688 individuals from FinnGen consortium. We used two-sample Mendelian randomization (MR) analysis to examine the causal association. At the same time, we employed various methods, including random-effects inverse variance weighting, weighted median, MR Egger regression, and MR PRESSO, to ensure the robustness of causal effects. We assessed heterogeneity using Cochran's Q value and examined horizontal pleiotropy through MR Egger regression and retention analysis. Results: Fetuin-A level was associated with a significantly decreasing risk of thoracic aortic aneurysm (odds ratio (OR) 0.64, 95% CI 0.47 - 0.87, P = 0.0044). Genetically predicted fetuin-A was also correlated with the decreased descending thoracic aortic diameter (ß = -0.086, standard error (SE) 0.036, P = 0.017). Conclusions: Serum fetuin-A level was negatively associated with risk of TTAs and correlated with the decreased descending thoracic aortic diameter. Mendelian randomization provides support for the potential causal relationship between fetuin-A and thoracic aortic aneurysm.

Fetuin-A and its genetic association with cardiometabolic disease.

Fetuin-A acts as both an inhibitor of calcification and insulin signaling. Previous studies reported conflicting results on the association between fetuin-A and cardiometabolic diseases. We aim to provide further insights into the association between genetically predicted levels of fetuin-A and cardiometabolic diseases using a Mendelian randomization strategy. Genetic variants associated with fetuin-A and their effect sizes were obtained from previous genetic studies. A series of two-sample Mendelian randomization analyses in 412,444 unrelated individuals from the UK Biobank did not show evidence for an association of genetically predicted fetuin-A with any stroke, ischemic stroke, or myocardial infarction. We do find that increased levels of genetically predicted fetuin-A are associated with increased risk of type 2 diabetes (OR = 1.21, 95%CI 1.13-1.30, P = < 0.01). Furthermore, genetically predicted fetuin-A increases the risk of coronary artery disease in individuals with type 2 diabetes, but we did not find evidence for an association between genetically predicted fetuin-A and coronary artery disease in those without type 2 diabetes (P for interaction = 0.03). One SD increase in genetically predicted fetuin-A decreases risk of myocardial infarction in women, but we do not find evidence for an association between genetically predicted fetuin-A and myocardial infarction in men (P for interaction = < 0.01). Genetically predicted fetuin-A is associated with type 2 diabetes. Furthermore, type 2 diabetes status modifies the association of genetically predicted fetuin-A with coronary artery disease, indicating that fetuin-A increases risk in individuals with type 2 diabetes. Finally, higher genetically predicted fetuin-A reduces the risk of myocardial infarction in women, but we do not find evidence for an association between genetically predicted fetuin-A and myocardial infarction in men.

Alpha 2-Heremans-Schmid glycoprotein gene polymorphism (rs4918) is associated with coronary artery calcification in incident peritoneal dialysis patients.

AIM: Coronary artery calcification (CAC) is a common and severe complication in peritoneal dialysis (PD) patients, and it progresses in a majority of patients. Fetuin-A, encoded by the alpha 2-Heremans-Schmid glycoprotein (AHSG) gene, is a serum calcification inhibitor. The study aimed to examine the role of AHSG gene polymorphism rs4918 in CAC and CAC progression of PD patients. METHODS: Incident PD patients at Huashan Hospital Fudan University in China from August 2007 to July 2018 were recruited in this prospective study and followed up for 2 years. Patients underwent CAC measurements at recruitment and 2 years later. AHSG gene polymorphism rs4918 and serum fetuin-A were determined at baseline. The demographic characteristics, clinical data, and laboratory data were collected during the follow-up period. Binary logistic regression was performed to explore the association between rs4918 with CAC and CAC progression. RESULTS: A total of 202 PD patients (112 men, 55.4%) were recruited, with a mean age of 54 ± 16 years. The multivariate logistic regression identified genotype GG as an independent risk factor that correlates to CAC (odds ratio [OR] = 2.153; 95% CI: 1.182-3.925; p = .012) and CAC progression (OR = 2.482; 95% CI: 1.422-4.330; p = .001). The serum fetuin-A level was influenced by the rs4918 variants of AHSG, with a dose-dependent effect depending on the number of the G allele. CONCLUSION: AHSG gene polymorphism rs4918 affects serum fetuin-A levels and is significantly associated with both CAC and CAC progression in a cohort of patients receiving PD.

Alpha-2 Heremans Schmid Glycoprotein (AHSG) promotes the proliferation of bladder cancer cells by regulating the TGF-ß signalling pathway.

Bladder cancer (BC) is one of the most common urinary tract malignancies and is the tenth most common cancer globally. Alpha-2 Heremans Schmid Glycoprotein (AHSG) is a multifunctional protein that plays different roles in the progression of multiple tumors. However, the role and mechanism of AHSG in the development and progression of BC are unknown. AHSG expression was assessed in BC cells and tissues using western blot and immunohistochemistry. Using plasmid and siRNA, overexpressed and knocked down AHSG in BC cells were constructed. A series of functional experiments, including CCK8, plate clone formation, and flow cytometry, were performed to evaluate cell proliferation and cycle. AHSG was expressed higher in BC cells and tissues than in normal bladder epithelial cells and non-tumor tissues. Functionally, the overexpression of AHSG significantly increased the proliferation of BC cells and promoted the cell cycle from G1 to the S phase, whereas the knockdown of AHSG gave the opposite result.Additionally, western blot results revealed that AHSG expression level was negatively correlated with the phosphorylation level of Smad2/3 protein, a key downstream molecule of the traditional TGF-ß signaling pathway, suggesting that AHSG could antagonize the traditional TGF-ß signaling pathway. Finally, the expression level of AHSG in the urine of BC patients was significantly higher than that of healthy subjects by ELISA, with specificity. Our study concluded that AHSG might be a novel marker of BC that promotes the proliferation of BC cells by regulating the TGF-ß signaling pathway.

Serum Fetuin-A and Risk of Gestational Diabetes Mellitus: An Observational Study and Mendelian Randomization Analysis.

CONTEXT: Fetuin-A was reported to be associated with risk of type 2 diabetes, but its association with incident gestational diabetes mellitus (GDM) was less studied. OBJECTIVE: We aimed to examine the association between fetuin-A levels in early pregnancy and risk of incident GDM and to evaluate whether this association was causal. METHODS: A total of 332 pregnant women with GDM and 664 matched controls were included in this nested case-control study. Multivariable conditional logistic regression was applied to investigate the prospective association between serum fetuin-A in early pregnancy and subsequent risk of GDM. Two-sample Mendelian randomization (MR) analysis was used to examine the causal association, using summary statistics from the CHARGE Consortium and the FinnGen consortium. RESULTS: The mean age of the participants was 28.0 years, and the mean gestational age was 11.0 weeks (range 6-15) at enrollment. In the final model, the odds ratio (OR) for GDM comparing the extreme quartiles of fetuin-A levels was 1.78 (95% CI 1.06, 2.98; P for trend = 0.009), and the restricted cubic spline analysis indicated a linear association (P for nonlinearity = 0.83). This positive association was found in women with waist circumference <80 cm but not in those with waist circumference ≥80 cm (P for interaction = 0.04). However, MR analyses showed no evidence of a causal association with an OR of 0.91 (95% CI 0.67, 1.23) per unit increment of fetuin-A. CONCLUSIONS: Serum fetuin-A levels in early pregnancy were positively associated with risk of GDM, particularly in those with normal waist circumference. However, we found no genetic evidence for a causal association.

Fetuin-A excess expression amplifies lipid induced apoptosis and ß-cell damage.

Fetuin-A, a hepato-adipokine, is associated with lipid-mediated islet inflammation and inflicts ß-cell death but the underlying mechanisms are still unclear. In an earlier report, it was shown that fetuin-A promotes lipid-induced insulin resistance by acting as an endogenous ligand of toll like receptor 4. Recently, we have also reported that ß-cells secrete fetuin-A on stimulation by palmitate causing ß-cell dysfunction. The aim of this study was twofold: (a) screening the role of fetuin-A in survival of murine ß-cells, and (b) to validate the effect of fetuin-A release and lipid induced apoptosis in mouse insulinoma cell line MIN6. Excess of lipid and fetuin-A in circulation induced significant deterioration of islet histoarchitecture and impeded insulin secretion by 2.7 ± 0.5-folds in 20 weeks high fat diet mice. Administration of fetuin-A (0.7 mg/g) along with 4 weeks of HFD produced similar results as 20 weeks of high fat feeding. Treating high doses of palmitate alone (0.50 mM) as well as in combination with fetuin-A (100 µg/ml) for 24 h inflicted apoptosis in MIN6 through the mitochondrial pathway. Knockdown of fetuin-A gene partially inhibited palmitate inflicted apoptosis in MIN6 by 1.83 ± 0.25 times, however, fetuin-A when added in the medium caused re-emergence of apoptosis. Notably, apoptosis induced by palmitate conditioned media from MIN6, 3T3L1, and HepG2, was partially inhibited in fetuin-A KD MIN6. These results confirmed the critical role of circulatory fetuin-A and ß-cell secreted fetuin-A in ß-cell dysfunction and apoptosis under hyperlipidemic conditions.

Association of Fetuin-A with Thr256Ser exon polymorphism of α2-Heremans Schmid Glycoprotein (AHSG) gene in type 2 diabetic patients with overt nephropathy.

BACKGROUND: Circulatory Fetuin-A has been well reported to elevate the risk for Diabetic Nephropathy (DN) and is associated with many vascular complications. Compelling reports have well documented that the circulatory levels of Fetuin-A directly have an impact on its AHSG (α2- Heremans- Schmid Glycoprotein) gene single nucleotide polymorphisms (SNP). Thus, in this study among the South Indian T2DM population, we aim to explore the association of AHSG Thr256Ser (rs4918) SNP in subjects with DN and correlate with the circulatory levels of Fetuin-A at various stages of DN patients. METHODS: A total of 975 subjects were recruited, such as Group-I, consisting of Controls (n = 300), Group-II, with normoalbuminuria (n = 300), Group-IIIa, with incipient microalbuminuria (n = 195), Group-IIIb, with persistent macroalbuminuria (n = 180)] and were subjected for genotyping using PCR-Restriction Fragment Length Polymorphism (RFLP). Circulatory Fetuin-A was measured using sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The 'G' allele of AHSG exon-7 (C/G) SNP is significantly concomitant and conferred significant risk for normoalbuminuria subjects. In the DN subjects, the 'G' allele showed the risk for persistent macroalbuminuria. A noticeable stepwise decrease was evidenced in the circulatory Fetuin-A among persistent macroalbuminuria over incipient microalbuminuria from normoalbuminuria. Further, the circulatory Fetuin-A was lowered in DN subjects with mutant GG genotype than the wild CC. CONCLUSION: AHSG Thr256Ser (rs4918) SNP was associated with renal complications among South Indian T2DM subjects.

Molecular and pathobiological involvement of fetuin-A in the pathogenesis of NAFLD.

The liver acts as a manufacturing unit for the production of fetuin-A, which is essential for various physiological characteristics. Scientific research has shown that a moderate upward push in fetuin-A serum levels is associated with a confirmed non-alcoholic fatty liver disease (NAFLD) diagnosis. Fetuin-A modulation is associated with a number of pathophysiological variables that cause liver problems, including insulin receptor signaling deficiencies, adipocyte dysfunction, hepatic inflammation, fibrosis, triacylglycerol production, macrophage invasion, and TLR4 activation. The focus of the present review is on the various molecular pathways, and genetic relevance of mRNA expression of fetuin-A which is correlated with progression of NAFLD. The other major area of exploration in the present review is based on the new targets for the modulation of fetuin-A, like calorie restriction and novel pharmacological agents, such as rosuvastatin, metformin, and pioglitazone which are successfully implicated in the management of various liver-related complications.

Alopecia-mental retardation syndrome: Molecular genetics of a rare neuro-dermal disorder.

Alopecia-mental retardation syndrome (APMR) is a rare autosomal recessive neuro-dermal disorder. It is characterized by heterogeneous phenotypic features, that is, absence of hair on the scalp, eyelashes, and eyebrows and mild to severe intellectual disability. So far, approximately 14 families (i.e., Iranian, Pakistani, and Swiss) with APMR have been reported in the scientific literature. Its precise prevalence is still unknown, but according to a predictive estimate, it prevails with the ratio of 1 in 1,000,000 persons worldwide. Until now, only four loci (two characterized and two uncharacterized) have been reported to be involved in APMR. The pathogenic variants in alpha-2-HS-glycoprotein [AHSG; APMR1 (MIM#203650)] and lanosterol synthase [LSS; APMR4 (MIM#618840)] are the characterized genetic factors associated with APMR. Among them, AHSG was reported in a consanguineous Iranian family and LSS gene in a Swiss origin family, while the remaining two uncharacterized loci, that is, APMR2 and APMR3, are reported in the Pakistani population. The current mini-report discusses the molecular genetics and mutational spectrum of APMR syndrome, its differential diagnosis from related disorders, and prediction of plausible candidate genes in two uncharacterized loci.

Effects of fetuin-A-containing calciprotein particles on posttranslational modifications of fetuin-A in HepG2 cells.

Fetuin-A is an inhibitor of ectopic calcification that is expressed mainly in hepatocytes and is secreted into the circulation after posttranslational processing, including glycosylation and phosphorylation. The molecular weight (MW) of fully modified fetuin-A (FM-fetuin-A) is approximately 60 kDa in an immunoblot, which is much higher than the estimated MW by amino acid sequence. Under conditions of calcification stress such as advanced stage chronic kidney disease, fetuin-A prevents calcification by forming colloidal complexes, which are referred to as calciprotein particles (CPP). Since the significance of CPP in this process is unclear, we investigated the effect of synthetic secondary CPP on the level of FM-fetuin-A in HepG2 cells. Secondary CPP increased the level of FM-fetuin-A in dose- and time-dependent manners, but did not affect expression of mRNA for fetuin-A. Treatment with O- and/or N-glycosidase caused a shift of the 60 kDa band of FM-fetuin-A to a lower MW. Preincubation with brefeldin A, an inhibitor of transport of newly synthesized proteins from the endoplasmic reticulum to the Golgi apparatus, completely blocked the secondary CPP-induced increase in FM-fetuin-A. Treatment with BAPTA-AM, an intracellular calcium chelating agent, also inhibited the CPP-induced increase in the FM-fetuin-A level. Secondary CPP accelerate posttranslational processing of fetuin-A in HepG2 cells.

Fetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress.

Intrauterine growth restriction (IUGR) is associated with reduced kidney size at birth, accelerated renal function decline, and increased risk for chronic kidney and cardiovascular diseases in adults. Precise mechanisms underlying fetal programming of adult diseases remain largely elusive and warrant extensive investigation. Setting up a mouse model of hypoxia-induced IUGR, fetal adaptations at mRNA, protein and cellular levels, and their long-term functional consequences are characterized, using the kidney as a readout. Here, we identify fetuin-A as an evolutionary conserved HIF target gene, and further investigate its role using fetuin-A KO animals and an adult model of ischemia-reperfusion injury. Beyond its role as systemic calcification inhibitor, fetuin-A emerges as a multifaceted protective factor that locally counteracts calcification, modulates macrophage polarization, and attenuates inflammation and fibrosis, thus preserving kidney function. Our study paves the way to therapeutic approaches mitigating mineral stress-induced inflammation and damage, principally applicable to all soft tissues.

In vivo estrogenicity of p-phenoxyphenol and p-pentyloxyphenol.

p-Alkoxyphenols (AOPs) are a class of ethers that are widely used in industrial and agricultural productions and daily necessities. p-Phenoxyphenol (PhOP) and p-pentyloxyphenol (PeOP) belong to this class and have been reported to be estrogenic in vitro. However, their in vivo estrogenic activities have rarely been of concern. In this study, we performed an immature mouse uterotrophic assay and studied the estrogenic effects of these two compounds in mice. The results revealed that the uterine weights of the animals treated with PhOP significantly increased at doses of 30 and 300 mg kg-1 bw day-1 for 3 days (P < 0.05), while no significant uterotrophic effects were observed in the mice treated with PeOP. Using next-generation transcriptome sequencing (RNA-seq), we also analyzed the gene expression in the uterine tissue of mice treated with PhOP and PeOP. The observed gene regulation patterns of the PhOP- and PeOP-treated specimens were similar to those of the 17ß-estradiol (E2)-treated specimens. In particular, some estrogen-responsive genes, such as the Sprr2 gene family, Apoa1, Prap1, and Ahsg, displayed a regulation trend similar to that of E2. In addition, molecule docking analysis revealed that both PhOP and PeOP could be well docked into the active site of hERα, with potential of mean force (PMF) values of - 58.68 and - 52.67 kcal mol-1 for PhOP and PeOP, respectively. The results of this study indicate that PhOP exhibits relatively strong in vivo estrogenic activity, which could be of future concern.

Fetuin-a expression profile in mouse and human adipose tissue.

Fetuin-A (Fet-A) was one of the first hepatokines to be reportedly linked to metabolic diseases. Fet-A was also suggested to be an adipokine, but its expression in the adipose tissue remains debatable. Here we compared the expression of Fet-A between human and mice adipose tissue biopsies as well as among human subcutaneous tissue and visceral adipose tissue primary cells, and mouse 3 T3-L1 cells at various stages of differentiation. Fet-A was expressed in mice biopsies and cells but not in human biopsies and cells, except in visceral adipose tissue primary cells following differentiation. Although the marginal expression of Fet-A in human visceral adipose tissue, a major contribution of Fet-A expression in human adipose tissue to systemic Fet-A levels is discounted, but it could indicate specific local Fet-A action in the visceral adipose tissue.

Lumenal calcification and microvasculopathy in fetuin-A-deficient mice lead to multiple organ morbidity.

The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP)-rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore pathological mineralization (calcification). The mutant mouse strain D2,Ahsg-/- combines fetuin-A deficiency with the calcification-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue calcification. Here we studied mechanisms leading to soft tissue calcification, organ damage and death in these mice. We analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/- mice. Fetuin-A-deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature death. Importantly, early-stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the calcification was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis. Collectively, these results demonstrate that soft tissue calcification can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of calcified matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis.

Association of serum FGF-23, klotho, fetuin-A, osteopontin, osteoprotegerin and hs-CRP levels with coronary artery disease.

Environmental, genetic, oxidative and biochemical factors play an important role in the atherosclerotic process. We investigated the association of serum fibroblast growth factor (FGF-23), klotho, fetuin-A, osteoprotegerin (OPG), osteopontin (OPN) and high-sensitive-CRP (Hs-CRP) markers with coronary artery disease and whether one was superior to others or not. A study group of 52 patients with coronary artery disease (CAD) and a control group of 30 patients with angiographically normal epicardial coronary arteries were included in the study. Serum FGF-23, klotho, fetuin-A, OPN, OPG and Hs-CRP marker levels were studied. Patients with CAD were classified in two groups as low (SYNTAX ≤22, n = 29) and moderate-high (SYNTAX ≥ 23, n = 23) according to anatomic SYNTAX score. FGF-23 (p = .033), klotho (p < .001), fetuin-A (p = .005) and OPG (p = .001) serum marker levels were significantly lower in CAD patients than the control group. Serum levels of FGF-23 (p = .012), klotho (p = .001), fetuin-A (p = .015) and OPG (p = 0.002) were significantly different between SYNTAX tertiles and control group. Klotho (p = .025, odd ratio (OR) = 0.542, 95% confidence interval (CI): 0.317-0.926) and HT (p = .004, OR = 34.598, 95%CI:1.054-1135.657) were the independent predictors of CAD presence. Serum klotho levels of 91.48 pmol/L predicts the presence of CAD with 60% sensitivity and 96.55% specificity (p < .001, area under curve = 0.864, 95% CI = 0.768, 0.931). We found that serum klotho level is an independent predictor of presence, extent and severity of CAD.

Association of AHSG gene polymorphisms with serum Fetuin-A levels in individuals with cardiovascular calcification in west of Iran.

Fetuin-A (AHSG) is a multifunctional secretory protein and acts as an ectopic valve and artery calcification inhibitor. We assessed the correlation between serum levels of Fetuin-A and both exon 6 (248 C/T) and exon 7 (256 C/G) mutations in patients with coronary artery calcification (CAC), mitral annular calcification (MAC), and aortic valve calcification (AVC). 184 patients and 184 healthy individuals as control group were included. The genetic variants of rs4917 and rs4918 for the AHSG gene were determined by PCR-RFLP and T-ARMS PCR techniques. Fetuin-A levels, fasting blood sugar (FBS), urea, creatinine, calcium phosphorus, and lipid profile were measured. Fetuin-A levels were remarkedly lower in individuals with AVC, MAC, and CAC comparing to the control group (p < 0.001). The CT + TT genotypes and the T allele (AHSG Thr248Met) were associated with the risk of calcification of heart valves and coronary artery by 1.31 and 1.27 times in the patient group, respectively. The frequency of CT genotype and T allele was considerably higher in the patient group comparing to the control group. Patients with T allele (CT + TT) had higher levels of FBS, urea, low-density lipoproteins (LDL)-C, phosphorus, systolic blood pressure (SBP), diastolic blood pressure (DBP) while decreased levels of triglyceride, high-density lipoproteins (HDL)-C, calcium and fetuin-A in comparison to control group. Additionally, there was a positive correlation between serum FBS, urea, creatinine, HDL-C, calcium with fetuin-A, and a negative correlation between phosphorous level, SBP, and DBP with fetuin-A. T allele in rs4917 Single nucleotide polymorphism (SNP) is the risk allele of calcification of heart valves and coronary arteries and fetuin-A levels correlates negatively with the occurrence of the disease.

Fetuin-A Thr256Ser gene polymorphism as a mortality predictor in patients with chronic kidney disease on maintenance haemodialysis in Medan, Indonesia.

Aim To investigate an impact of Fetuin-A Thr256Ser gene polymorphism on the mortality rate of chronic kidney disease on maintenance haemodialysis patients in Indonesia. Methods This is an analytic-longitudinal observational study using survival analysis with nine-month follow up on 106 maintenance haemodialysis patients. The PCR-RFLP is used to determine Fetuin-A Thr256Ser gene polymorphism and Fetuin-A serum level measured by using ELISA methods. We use time-independent cox regression analysis to investigate factors that contribute to patient survival. Results The mean survival time of this study is 8.49±1.53 months, with a median survival of 9 months (range 1-9 months). Among 12 (11.3%) deceased patients, most of them carried GG genotype with 8.87 times risk of mortality compared to those with CC+CG genotype (p=0.005). The group of patients with IL-6 level ≥86.9 pg/mL had higher mortality with 3.64 times greater risk compared to those with IL-6 level, <86.9 pg/mL (p=0.03). Conclusion This study revealed a significant dominance independent impact of the Fetuin-A Thr256Ser gene polymorphism on the survival rate of maintenance haemodialysis patients. These results suggest that genotype variation of Fetuin-A gene could be a potential marker to identify high mortality risk in Indonesia's maintenance haemodialysis patients, especially in Medan.

Acute Hyperenergetic, High-Fat Feeding Increases Circulating FGF21, LECT2, and Fetuin-A in Healthy Men.

BACKGROUND: Hepatokines such as fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B, and selenoprotein P (SeP) are liver-derived proteins that are modulated by chronic energy status and metabolic disease. Emerging data from rodent and cell models indicate that hepatokines may be sensitive to acute nutritional manipulation; however, data in humans are lacking. OBJECTIVE: The aim was to investigate the influence of hyperenergetic, high-fat feeding on circulating hepatokine concentrations, including the time course of responses. METHODS: In a randomized, crossover design, 12 healthy men [mean ± SD: age, 24 ± 4 y; BMI (kg/m2), 24.1 ± 1.5] consumed a 7-d hyperenergetic, high-fat diet [HE-HFD; +50% energy, 65% total energy as fat (32% saturated, 26% monounsaturated, 8% polyunsaturated)] and control diet (36% total energy as fat), separated by 3 wk. Whole-body insulin sensitivity was assessed before and after each diet using oral-glucose-tolerance tests. Fasting plasma concentrations of FGF21 (primary outcome), LECT2, fetuin-A, fetuin-B, SeP, and related metabolites were measured after 1, 3, and 7 d of each diet. Hepatokine responses were analyzed using 2-factor repeated-measures ANOVA and subsequent pairwise comparisons. RESULTS: Compared with the control, the HE-HFD increased circulating FGF21 at 1 d (105%) and 3 d (121%; P ≤ 0.040), LECT2 at 3 d (17%) and 7 d (32%; P ≤ 0.004), and fetuin-A at 7 d (7%; P = 0.028). Plasma fetuin-B and SeP did not respond to the HE-HFD. Whole-body insulin sensitivity was reduced after the HE-HFD by 31% (P = 0.021). CONCLUSIONS: Acute high-fat overfeeding augments circulating concentrations of FGF21, LECT2, and fetuin-A in healthy men. Notably, the time course of response varies between proteins and is transient for FGF21. These findings provide further insight into the nutritional regulation of hepatokines in humans and their interaction with metabolic homeostasis. This study was registered at clinicaltrials.gov as NCT03369145.

Minor variant of AHSG gene 767C>G polymorphism may decrease the risk of gestational diabetes mellitus.

Insulin resistance plays a central role in the development of gestational diabetes mellitus (GDM). The fetuin A molecule, of which serum level increases during pregnancy, is an inhibitor of insulin receptor tyrosine kinase and it is associated with insulin resistance. The aim of this study is to research the relationship of -843A>T (rs2248690) and 767C>G (rs4918) polymorphisms in the alpha-2-Heremans Schmid glycoprotein (AHSG) gene which is responsible for the synthesis of fetuin A and its association with (GDM). In this study, 83 pregnant women with GDM who applied to the Obstetrics and Gynaecology Clinics and 100 normal pregnants enrolled as the control group. Genotyping of AHSG gene polymorphisms was performed by using the TaqMan allelic discrimination kit with real time PCR device. In our study, homozygous GG genotype which was polymorphic in the 767C>G polymorphism of AHSG gene was found significantly low in the patient group (p < .05). Genotype distribution of AHSG gene -843A>T polymorphism was not statistically significant between the patient and control groups (p > .05). Our results showed that homozygous GG variant of AHSG gene 767C>G polymorphism may have protective effect against the development of GDM.Impact statementWhat is already known on this subject? Insulin resistance has a central role in the development of gestational diabetes mellitus (GDM). The fetuin A molecule is an inhibitor of insulin receptor tyrosine kinase and it is associated with insulin resistance. The -843T>A and 767G>C polymorphisms of AHSG gene encoding fetuin A are affects serum fetuin A level. In a single study investigating the relationship between GDM and AHSG gene 767G>C polymorphism, there was no significant difference in genotype distribution but it was reported that the frequency of G allele increased in GDM group and this increase provided a weak risk or predisposition.What the results of this study add? The present study revealed that homozygous GG variant of AHSG gene 767C>G polymorphism may decrease the risk of GDM.What the implications are of these findings for clinical practice and/or further research? Protective effect of homozygous GG variant of AHSG gene 767C>G polymorphism, can be used as a molecular biomarker to predict the development of GDM. These results should be supported by further research in larger sample sizes.

Is there an association between alpha 2-Heremans-Schmid glycoprotein (AHSG) gene Thr256Ser polymorphisms with aortic calcification in regular hemodialysis patients in Medan, Indonesia.

Aim Alpha2-Heremans-Schmid glycoprotein (AHSG), a circulating plasma protein, plays an essential role in bone and vascular mineralization. The impact of AHSG gene polymorphisms on aortic calcification in haemodialysis patients was inconsistent. We performed this study to clarify precise association among AHSG gene Thr256Ser single-nucleotide polymorphisms and aortic calcification. Methods Patients on stable regular haemodialysis treatment for more than thirty months were included in a cross-sectional study at Rasyida Renal Hospital Medan. Lateral spine X-rays were performed to evaluate the aortic calcification. Genotyping for the polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques. Results Aortic calcification was detected in 69.8% of patients. From 106 patients, 49 patients (46.2 %) had CC (Thr/Thr), 54 (51.0%) had CG (Thr/Ser) and three (2.8%) patients had GG (Ser/ Ser) polymorphism. The proportion of patients with heterozygous or homozygous G allele (CG and GG genotypes) is more likely (91.2%) to have aortic calcification. The bivariate analysis showed that Thr256Ser polymorphism (G allele) was associated with increased risk for aortic calcification (PR=2.03; 95% CI 1.48-2.80; p<0.001). However, overall results from multivariate analysis showed that Fetuin-A level <204 pg/mL (PR=22.0; 95% CI 3.32-145.91; p=0.001) and IL-6 level ≥53.05 mg/dL (PR=19.50; 95% CI 2.87-132.41; p=0.002) were the major risk factors for the occurrence of aortic calcification. Conclusion AHSG Thr256Ser gene polymorphism showed an association with aortic calcification in regular haemodialysis patients, but Fetuin-A and IL-6 have a dominant role in the development of aortic calcification.