Glycated albumin and diabetes mellitus

Background

Diabetes is a growing worldwide problem that is strongly associated with atherosclerosis. Screening and intervention for diabetes in the earliest stages are advocated for the prevention of diabetic complications and cardiovascular disease.

Scope of review

This review gives a background of and discusses the potential clinical utility of glycated albumin (GA) in diabetes.

Major conclusions

GA is a ketoamine formed via a non-enzymatic glycation reaction of serum albumin and it reflects mean glycemia over two to three weeks. GA can be used for patients with anemia or hemoglobinopathies for whom the clinically measured hemoglobin A1c level may be inaccurate. Because both serum and plasma samples can be used, GA can be analyzed from the same samples as common biological markers. GA is a useful marker for the screening of diabetes in a medical evaluation. It can be also used to determine the effectiveness of treatment before initiating or changing medications for diabetic patients. GA is potentially an atherogenic protein in the development of diabetic atherosclerosis.

General significance

GA measurement is useful as part of a routine examination to screen for both diabetes and atherosclerosis. This article is part of a Special Issue entitled Serum Albumin.     

Genetic associations with coronary heart disease: Meta-analyses of 12 candidate genetic variants

Aims

The aim of this study was to evaluate the combined contribution of 12 genetic variants to the risk of coronary heart disease (CHD).

Methods

Through a comprehensive literature search for genetic variants involved in the CHD association study, we harvested a total of 10 genes (12 variants) for the current meta-analyses. These genes consisted of GPX1 (rs1050450), PPARD (rs2016520), ALOX15 (rs34210653), SELPLG (rs2228315), FCGR2A (rs1801274), CCL5 (rs2107538), CYP1A1 (rs4646903), TP53 (rs1042522), CX37 (rs1764391), and PECAM1 (rs668, rs12953, and rs1131012).

Results

A total of 45 studies among 23,314 cases and 28,430 controls were retrieved for the meta-analyses of 12 genetic variants. The results showed a significant association between the GPX1 rs1050450 polymorphism and CHD (odd ratio (OR) = 1.61, 95% confidence interval (CI) = 1.25–2.07, P = 0.0002). Other meta-analyses of the rest 11 variants suggested a lack of association with the risk of CHD.

Conclusion

Our results confirmed that GPX1 rs1050450 was associated with susceptibility to CHD in Chinese and Indian populations.     

Single nucleotide polymorphism of CD40 in the 5′-untranslated region is associated with ischemic stroke

Objectives

Ischemic stroke is influenced by both environmental and genetic factors. The CD40/CD40L system is related to proinflammatory and prothrombogenic responses, which are involved in the pathophysiology of ischemic stroke. The aim of this study was to evaluate association between the CD40 -1C/T single nucleotide polymorphism (SNP) and ischemic stroke in a Chinese population.

Methods

We conducted a case–control study including 286 ischemic stroke patients and 336 controls. CD40 -1C/T SNP was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods, and evaluated its relevance to ischemic stroke susceptibility.

Results

Significantly increased ischemic stroke risk was found to be associated with the T allele of CD40 -1C/T (OR = 1.273, 95% CI = 1.016–1.594). The frequencies of CT and TT/CT genotypes of CD40 -1C/T in ischemic stroke patients were significantly higher than those of controls, respectively (for CT: OR = 2.350, 95% CI = 1.601–3.449; for TT/CT: OR = 2.148, 95% CI = 1.479–3.119). And, similar results were obtained after adjusting non-matched variables. We found that the frequency of carried T genotypes (TT and TT/CT) was significantly increased in patients with history of stroke compared with patients without (for TT: OR = 6.538, 95%CI = 1.655–25.833; for TT/CT: OR = 3.469, 95%CI = 1.031–11.670), respectively.

Conclusions

The findings suggested that the CD40 -1C/T polymorphism might contribute to the susceptibility to ischemic stroke in the Chinese population, and might be associated with history of previous stroke.     

A combined LDL receptor/LDL receptor adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia

Familial hypercholesterolemia (FH) results from impaired catabolism of plasma low density lipoproteins (LDL), thus leading to high cholesterol, atherosclerosis, and a high risk of premature myocardial infarction. FH is commonly caused by defects of the LDL receptor or its main ligand apoB, together mediating cellular uptake and clearance of plasma LDL. In some cases FH is inherited by mutations in the genes of PCSK9 and LDLRAP1 (ARH) in a dominant or recessive trait. The encoded proteins are required for LDL receptor stability and internalization within the LDLR pathway. To detect the underlying genetic defect in a family of Turkish descent showing unregular inheritance of severe FH, we screened the four candidate genes by denaturing gradient gel electrophoresis (DGGE) mutation analysis. We identified different combinatory mixtures of LDLR- and LDLRAP1-gene defects as the cause for severe familial hypercholesterolemia in this family. We also show for the first time that a heterozygous LDLR mutation combined with a homozygous LDLRAP1 mutation produces a more severe hypercholesterolemia phenotype in the same family than a homozygous LDLR mutation alone.     

Relationship between chemokine (C–X–C motif) ligand 12 gene variant (rs1746048) and coronary heart disease: Case–control study and meta-analysis

The goal of our study is to evaluate the contribution of CXCL12 rs1746048 (hg19, chr10:44775574) to the risk of CHD in Han Chinese, and to summarize its role in CHD through meta-analysis of existing studies among various ethnic groups. Significant association is observed between rs1746048-C and an increased risk of CHD in Han Chinese (χ² = 5.41, df = 1, P = 0.02). Post hoc analysis reveals an even stronger association of rs1746048 with the risk of CHD for subjects aged 65 years or older (genotype: χ² = 8.39, df = 2, P = 0.015; allele: χ2 = 9.13, df = 1, P = 0.003, odd ratio (OR) = 1.91, 95% confidential interval (CI) = 1.25–2.91). A break down analysis by gender shows that rs1746048 is likely a CHD risk factor under the recessive model in males (CC + CT versus TT: P = 0.05, χ² = 3.59, df = 1, OR = 1.72, 95% CI = 1.00–3.04). In addition, a meta-analysis of ten studies among over 107,000 individuals confirms that rs1746048 is a risk factor of CHD (P < 0.0001, OR = 1.12, 95% CI = 1.09–1.15) and this agrees with the findings of our case–control study in Han Chinese.     

Impact of apolipoprotein A1- or lecithin:cholesterol acyltransferase-deficiency on white adipose tissue metabolic activity and glucose homeostasis in mice

High density lipoprotein (HDL) has attracted the attention of biomedical community due to its well-documented role in atheroprotection. HDL has also been recently implicated in the regulation of islets of Langerhans secretory function and in the etiology of peripheral insulin sensitivity. Indeed, data from numerous studies strongly indicate that the functions of pancreatic β-cells, skeletal muscles and adipose tissue could benefit from improved HDL functionality. To better understand how changes in HDL structure may affect diet-induced obesity and type 2 diabetes we aimed at investigating the impact of Apoa1 or Lcat deficiency, two key proteins of peripheral HDL metabolic pathway, on these pathological conditions in mouse models. We report that universal deletion of apoa1 or lcat expression in mice fed western-type diet results in increased sensitivity to body-weight gain compared to control C57BL/6 group. These changes in mouse genome correlate with discrete effects on white adipose tissue (WAT) metabolic activation and plasma glucose homeostasis. Apoa1-deficiency results in reduced WAT mitochondrial non-shivering thermogenesis. Lcat-deficiency causes a concerted reduction in both WAT oxidative phosphorylation and non-shivering thermogenesis, rendering lcat^?/? mice the most sensitive to weight gain out of the three strains tested, followed by apoa1^?/? mice. Nevertheless, only apoa1^?/? mice show disturbed plasma glucose homeostasis due to dysfunctional glucose-stimulated insulin secretion in pancreatic β-islets and insulin resistant skeletal muscles. Our analyses show that both apoa1^?/? and lcat^?/? mice fed high-fat diet have no measurable Apoa1 levels in their plasma, suggesting no direct involvement of Apoa1 in the observed phenotypic differences among groups.     

Discovery of the selective sphingomyelin synthase 2 inhibitors with the novel structure of oxazolopyridine

Sphingomyelin synthase (SMS) is a key enzyme in sphingomyelin biosynthetic pathway, whose activity is highly related to the atherosclerosis progression. SMS2 could serve as a promising therapeutic target for atherosclerosis. Based on the structure of lead compound D2, a series of oxazolopyridine derivatives were designed, synthesized, and their inhibitory activities against purified SMS1 and SMS2 enzymes were evaluated respectively. The representative molecules QY4 and QY16 possess micromolar inhibitory activities against SMS2 and excellent isoform preferences over SMS1, qualified to be selected as potential molecules in further discovery of specific SMS2 inhibitors.     

CHD7对发育和疾病的表观遗传调控研究进展

染色质重塑是指染色质通过其结构的动态变化影响基因组DNA的可接近性,进而影响DNA复制、转录、修复和重组的过程,属于表观遗传调控。染色质域解旋酶DNA结合蛋白7(CHD7)是一种ATP依赖的染色质重塑酶,能够调控发育过程中多种重要转录因子,广泛参与众多生理过程。本文对CHD7在发育和疾病当中的表观遗传调控作用进行简要概述。