Association between the rs6950982 polymorphism near the SERPINE1 gene and blood pressure and lipid parameters in a high-cardiovascular-risk population: interaction with Mediterranean diet

The SERPINE1 (serpin peptidase inhibitor, clade E, member 1) gene, better known by its previous symbol PAI-1 (plasminogen activator inhibitor 1), has been associated with cardiovascular phenotypes with differing results. Our aim was to examine the association between the rs6950982 (G > A) near the SERPINE1 gene, blood pressure (BP) and plasma lipid concentrations as well as the modulation of the polymorphism effects by adherence to Mediterranean diet (AMD). We studied 945 high-cardiovascular-risk subjects. Biochemical, clinical, dietary and genetic data (rs6950982) were obtained. We also determined the common rs1799768 (4G/5G), for checking independent effects. AMD was measured by a validated questionnaire, and four groups were considered. rs6950982 (A > G) and rs1799768 (4G/5G) were only in moderate–low linkage disequilibrium (D′ = 0.719; r2 = 0.167). The most significant associations we obtained were with rs6950982 (A > G). In males, the G allele was nominally associated with higher diastolic BP (AA: 81.5 ± 10.9, AG: 82.1 ± 11.4, GG: 85.7 ± 10.5 mmHg; Padditive = 0.030) and systolic BP (AA + AG: 141.4 ± 6.9 mmHg vs. GG: 149.8 ± 8.0 mmHg; Precessive = 0.036). In the whole population, the rs6950982 was also associated with plasma lipids. Subject with the G allele presented higher total cholesterol (Padditive = 0.016, Precessive = 0.011), low-density lipoprotein cholesterol (Padditive = 0.032, Precessive = 0.031) and triglycerides (Padditive = 0.040, Precessive = 0.029). AMD modulated the effect of rs6950982 on triglyceride concentrations (P for interaction = 0.036). Greater AMD reduced the higher triglyceride concentrations in GG subjects. No significant interactions were found for the other parameters. The rs6950982 was associated with higher BP in men and higher triglycerides in the whole population, this association being modulated by AMD

Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study

The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments

Relationship of metabolic syndrome and its components with -844 G/A and HindIII C/G PAI-1 gene polymorphisms in Mexican children

<p>Abstract</p> <p>Background</p> <p>Several association studies have shown that -844 G/A and <it>HindIII </it>C/G <it>PAI-1 </it>polymorphisms are related with increase of PAI-1 levels, obesity, insulin resistance, glucose intolerance, hypertension and dyslipidemia, which are components of metabolic syndrome. The aim of this study was to analyze the allele and genotype frequencies of these polymorphisms in <it>PAI-1 </it>gene and its association with metabolic syndrome and its components in a sample of Mexican mestizo children.</p> <p>Methods</p> <p>This study included 100 children with an age range between 6-11 years divided in two groups: a) 48 children diagnosed with metabolic syndrome and b) 52 children metabolically healthy without any clinical and biochemical alteration. Metabolic syndrome was defined as the presence of three or more of the following criteria: fasting glucose levels ≥ 100 mg/dL, triglycerides ≥ 150 mg/dL, HDL-cholesterol < 40 mg/dL, obesity BMI ≥ 95^thpercentile, systolic blood pressure (SBP) and diastolic blood pressure (DBP) ≥ 95^thpercentile and insulin resistance HOMA-IR ≥ 2.4. The -844 G/A and <it>HindIII </it>C/G <it>PAI-1 </it>polymorphisms were analyzed by PCR-RFLP.</p> <p>Results</p> <p>For the -844 G/A polymorphism, the G/A genotype (OR = 2.79; 95% CI, 1.11-7.08; <it>p </it>= 0.015) and the A allele (OR = 2.2; 95% CI, 1.10-4.43; <it>p </it>= 0.015) were associated with metabolic syndrome. The -844 G/A and A/A genotypes were associated with increase in plasma triglycerides levels (OR = 2.6; 95% CI, 1.16 to 6.04; <it>p </it>= 0.02), decrease in plasma HDL-cholesterol levels (OR = 2.4; 95% CI, 1.06 to 5.42; <it>p </it>= 0.03) and obesity (OR = 2.6; 95% CI, 1.17-5.92; <it>p </it>= 0.01). The C/G and G/G genotypes of the <it>HindIII </it>C/G polymorphism contributed to a significant increase in plasma total cholesterol levels (179 vs. 165 mg/dL; <it>p </it>= 0.02) in comparison with C/C genotype.</p> <p>Conclusions</p> <p>The -844 G/A <it>PAI-1 </it>polymorphism is related with the risk of developing metabolic syndrome, obesity and atherogenic dyslipidemia, and the <it>HindIII </it>C/G <it>PAI-1 </it>polymorphism was associated with the increase of total cholesterol levels in Mexican children.</p

Neonatal Fc Receptor: From Immunity to Therapeutics

The neonatal Fc receptor (FcRn), also known as the Brambell receptor and encoded by Fcgrt, is a MHC class I like molecule that functions to protect IgG and albumin from catabolism, mediates transport of IgG across epithelial cells, and is involved in antigen presentation by professional antigen presenting cells. Its function is evident in early life in the transport of IgG from mother to fetus and neonate for passive immunity and later in the development of adaptive immunity and other functions throughout life. The unique ability of this receptor to prolong the half-life of IgG and albumin has guided engineering of novel therapeutics. Here, we aim to summarize the basic understanding of FcRn biology, its functions in various organs, and the therapeutic design of antibody- and albumin-based therapeutics in light of their interactions with FcRn

Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial

BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches