Association of Insulin Receptor Substrate-1 Gly972Arg Polymorphism with Dyslipidemia in Iraqi Type 2 Diabetic patients: A case-control Study

Double trouble: T2DM genetic risk factors play a causal role in CAD.

BSMI single nucleotide polymorphism in vitamin D receptor gene is associated with decreased circulatory levels of serum 25-hydroxyvitamin D among micro and macrovascular complications of type 2 diabetes mellitus

Objective To study the level of urinary 8-hydroxy deoxyguanosine (8-OHdG) in type 2 diabetic patients with or without coronary heart disease.Methods 150 cases were selected from hospitalized patients and the physical examination center in the General Hospital of Tianjin Medical University and were divided into diabetic group (n =50,male 25,female 25),diabetic patients with coronary heart disease group (n =50,male 25,female 25) and healthy control group (n =50,male 25,female 25).24 hours urine were collected,then urinary 8-OHdG was tested with enzyme linked immunosorbent assay,and urine creatinine was tested with trinitrophenol method.Blood glucose,creatinine,uric acid and blood urea nitrogen with enzymatic method,and HbA1 c with HPLC method,and fibrinogen (FIB) with Clauss method were also tested.Results Compared with normal control group [(6.97 ± 2.13) ng/mgCr],urinary 8-OHdG was increased in diabetes group [(12.26 ± 3.57) ng/mgCr] and diabetic coronary heart disease group [(14.41 ± 2.84) ng/mgCr].While compared with diabetes group,urinary 8-OHdG was significantly elevated in diabetic coronary heart disease group.Compared with healthy control group,the level of systolic blood pressure,body mass index,HbAlc,fasting blood glucose,2 hour postprandial blood glucose,triglyceride and fibrinogen were significantly higher in diabetic group and diabetic coronary heart disease group (all P ＜ 0.01),and the level of high density lipoprotein-cholesterol was lower (P ＜ 0.05).Compared with diabetes group,the level of HbA1c,2 h postprandial blood glucose and fibrinogen were significantly higher in diabetic coronary heart disease group (all P ＜ 0.01).Urinary 8-OHdG was positively related to systolic blood pressure,waist circumference,body mass index,triglyceride,fibrinogen,HbA1 c,fasting plasma glucose and 2 h postprandial blood glucose.After stepwise regressive analysis,HbA1c had significant effect on the levels of urinary 8-OHdG (P ＜ 0.001).Conclusions The level of urinary 8-OHdG is increased in patients with type 2 diabetes mellitus and diabetic patients with coronary heart disease.Urinary 8-OHdG might be a new marker for evaluating diabetic atherosclerosis. Key words: 8-Hydroxy-2'-deoxyguanosine ; Diabetes mellitus ; Coronary heart disease ; Atherosclerosis ; Oxidative stress

226: Relationship between intima-media thickness and diabetic dyslipidemia in patients with ischemic heart disease and type 2 diabetes mellitus

Type 2 diabetes mellitus is a complex disorder with a strong genetic component. Inherited complex disease susceptibility in humans is most commonly associated with single nucleotide polymorphisms. The mechanisms by which this occurs are still poorly understood. Here we focus on analyzing the effect of a set of disease-causing missense variations of the monogenetic form of Type 2 diabetes mellitus and a set of disease-associated nonsynonymous variations in comparison with that of nonsynonymous variations without any experimental evidence for association with any disease. Analysis of different properties such as evolutionary conservation status, solvent accessibility, secondary structure, etc. suggests that disease-causing variations are associated with extreme changes in the value of the parameters relating to evolutionary conservation and/or protein stability. Disease-associated variations are rather moderately conserved and have a milder effect on protein function and stability. The majority of the genes harboring these variations are clustered in or near the insulin signaling network. Most of these variations are identified as potential sites for post-translational modifications; certain predictions have already reported experimental evidence. Overall our results indicate that Type 2 diabetes mellitus may result from a large number of single nucleotide polymorphisms that impair modular domain function and post-translational modifications involved in signaling. Our emphasis is more on conserved corresponding residues than the variation alone. We believe that the approach of considering a stretch of peptide sequence involving a polymorphism would be a better method of defining the role of the polymorphism in the manifestation of this disease. Because most of the variations associated with the disease are rare, we hypothesize that this disease is a "mosaic model" of interaction between a large number of rare alleles and a small number of common alleles along with the environment, which is little contrary to the existing common disease common variant model.

Background Blood pressure (BP) is acutely regulated by the sympathetic nervous system through the action of vasoactive hormones (epinephrine, norepinephrine, and dopamine). Renalase, a recently discovered enzyme with monoamine oxidase activity is implicated in the degradation of catecholamines with a possible role in BP maintenance and cardiac protection against hypertension (HTN) and cardiovascular (CV) events. Objectives The aim of this study was to identify the potential involvement of renalase gene polymorphisms in patients with type 2 diabetes mellitus (T2DM) with or without HTN in the absence of diabetic nephropathy and to illustrate the role of renalase gene single-nucleotide polymorphisms (rs2576178 and rs10887800) in CV events. Study design This was a cross-sectional study. Patients and methods A total of 180 patients with T2DM attending the diabetes and cardiology clinics of Mansoura Hospital were recruited in the study: 100 patients with T2DM with HTN and 80 patients with T2DM who were normotensive. Further, 50 apparently healthy individuals matched in age and sex were included as a reference group. Clinical and laboratory examinations stressing on symptoms and signs of diabetes and HTN complications and ECG and Holter ECG monitoring stressing on QTc and QTd were performed; BMI, lipograms, microalbumin levels, and serum creatinine levels were also determined. Patients with renal disease, hepatic disease, and heart failure, those with previous or present renal or suprarenal lesions or endocrinopathies, and those with secondary HTN were excluded from the study. Genotype determination for two single-nucleotide polymorphisms (rs2576178 and rs10887800) in the renalase gene was carried out using the PCR method. Results The frequency of the GG allele of rs2576178 and rs10887800 was insignificantly higher in the diabetic hypertensive group than in the diabetic normotensive group. Both diabetic groups showed higher levels of GG alleles than the control group. The frequency of the GA allele of rs2576178 was significantly higher in the diabetic hypertensive group in comparison with the normotensive diabetic group. The allele frequency of G and A alleles of both studied renalases was also higher in the diabetic hypertensive group in comparison with the diabetic normotensive group; however, the differences were insignificant. The genotype distribution and allele frequencies did not show any statistically significant association with BMI, neuropathy, retinopathy, myocardial ischemia, QTc, or QTd. Conclusion The renalase gene can be potentially involved in BP regulation in T2DM. Further large-scale studies on the relationship between renalase and acute coronary syndrome and CV events are warranted.

Adiponectin, an adipocyte-secreted protein, is known to have anti-atherogenic, anti-inflammatory and anti-diabetic properties and its serum levels are decreased in obesity, type 2 diabetes, and coronary artery disease. Several studies have been performed to investigate the association of genetic variations in the adiponectin with obesity, insulin resistance, and type 2 diabetes, but few studies were performed in association with coronary artery disease. Therefore we examined the associations between two single nucleotide polymorphisms (SNPs), +45T>G and +276G>T of the adiponectin gene, and coronary artery diseases (CAD). One hundred and fifty six subjects (mean age 57.4 yrs) were enrolled in which coronary angiograms were performed due to chest pain. Genotypings were done for two SNPs in the adiponectin gene by Taqman polymerase chain reaction (PCR) method. The presence of CAD was defined as a >50% reduction of coronary artery diameter. Among 156 subjects, the allele frequencies were 0.683 for G allele and 0.317 for T allele in SNP +276G>T and 0.705 for T allele and 0.295 for G allele in SNP +45T>G. Both genotypes were in compliance with Hardy-Weinberg equilibrium. No association with the presence of CAD was observed for adiponectin gene SNP276 and SNP45 (p = 0.954, p = 0.843). Also, no significant association was observed between the severity of CAD and either SNPs (p = 0.571, p = 0.955). Our study showed that SNP +276G>T and +45T>G in adiponectin gene were not associated with the presence of CAD. Further studies will be necessary to confirm the role of SNP 276G>T and 45T>G in the development of CAD.

Genetic and environmental factors have been implicated in etiopathogenesis and progression of type 1 diabetes mellitus (T1DM) and diabetic nephropathy (DN). Genetic association between interleukin-10 (IL-10) single nucleotide polymorphisms (SNPs) with T2DM and DN was recently established. We aimed to explore the potential genetic risk of IL-10 gene rs1518111 and rs3021094 SNPs in susceptibility to T1DM and DN. Cross-sectional study included 140 T1DM children, of whom 74 had DN and 90 controls. IL-10 gene rs1518111 and rs3021094 SNP were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique of the extracted genomic DNA from participants. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to explore the association between IL-10 gene polymorphisms and the risk of T1DM and DN. For rs1518111 SNP, AA genotype was associated with high risk of T1DM (OR = 4.53; CI = 2.11-9.74; p < 0.001), while A allele was associated with high risk of both T1DM (OR = 3.35; CI = 2.20-5.09; p < 0.001) and DN (OR = 2.36; CI = 1.27-4.38; p = 0.006). For rs3021094 SNP, AC genotype displayed lower risk to develop T1DM (OR = 0.35; CI = 0.13-0.94; p = 0.037), while A allele displayed higher risk to develop T1DM (OR = 1.69; CI = 1.11-2.56; p = 0.013). GA and AC haplotypes of rs1518111 and rs3021094 had lower ORs for having T1DM and DN, while GC had lower OR for having T1DM. AA genotype and A allele of IL-10 rs1518111 SNP could be linked to increased risk for T1DM and DN among Egyptian children. None of rs3021094 genotypes or alleles displayed significant association with DN. GA and AC haplotypes could be protective against T1DM and DN susceptibility.

Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of insulin receptor substrate 1 (IRS-1) contribute to insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against insulin resistance in the brain by elevating IRS-1 expression.

Recent studies have demonstrated that CD36 is involved in the progression of atherosclerosis. Associations between rs1761667 polymorphisms of the CD36 gene and susceptibility to coronary artery disease (CAD) are not obvious. We studied the relationship between single nucleotide polymorphisms (SNPs), rs1761667 of CD36 gene and the risk of coronary atherosclerosis in a case-control study composed of 71 CAD patients and 76 healthy controls by assessment of allele frequencies and genotype distributions using real-time polymerase chain reaction (PCR) and the allele discrimination technique. Additionally, we detected CD36 expression by flow cytometry. The distribution of rs1761667 genotypes between the two groups was significantly different (P<0.001), with the frequency of the AG genotype being significantly higher in the CAD group than in the control group (P<0.001). The expression level of CD36 in the CAD group was significantly higher than that in the control group (P<0.001), with significant differences in the CAD patients with an AG genotype compared with those with an AA and GG genotype (P<0.001). The plasma levels (mg/dL) of low-density lipoprotein (LDL) in the CAD group were much higher than that in the control group (P<0.001). On the other hand, the plasma LDL levels in CAD patients with the AG genotype were remarkably higher than those with the GG and AA genotypes (P=0.046) and AG genotype was significantly more prevalent among type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) patients (P<0.05). After adjusted logistic regression analysis, the AG genotype of rs1761667 was associated with an increased risk of CAD (OR=17.97, 95% CI, 3.19-87.85, P=0.001). The AG genotype of the rs1761667 polymorphism in the CD36 gene may be involved in CAD pathogenesis as well as increased body mass index (BMI), T2DM and MetS in the Sohag population of Egypt.

Betaine-homocysteine S-methyltransferase (BHMT) uses betaine to catalyze the conversion of homocysteine (Hcy) to methionine. There are common genetic polymorphisms in the BHMT gene in humans that can alter its enzymatic activity. We generated the first Bhmt(-/-) mouse to model the functional effects of mutations that result in reduced BHMT activity. Deletion of Bhmt resulted in a 6-fold increase (p < 0.01) in hepatic and an 8-fold increase (p < 0.01) in plasma total Hcy concentrations. Deletion of Bhmt resulted in a 43% reduction in hepatic S-adenosylmethionine (AdoMet) (p < 0.01) and a 3-fold increase in hepatic S-adenosylhomocysteine (AdoHcy) (p < 0.01) concentrations, resulting in a 75% reduction in methylation potential (AdoMet:AdoHcy) (p < 0.01). Bhmt(-/-) mice accumulated betaine in most tissues, including a 21-fold increase in the liver concentration compared with wild type (WT) (p < 0.01). These mice had lower concentrations of choline, phosphocholine, glycerophosphocholine, phosphatidylcholine, and sphingomyelin in several tissues. At 5 weeks of age, Bhmt(-/-) mice had 36% lower total hepatic phospholipid concentrations and a 6-fold increase in hepatic triacyglycerol concentrations compared with WT (p < 0.01), which was due to a decrease in the secretion of very low density lipoproteins. At 1 year of age, 64% of Bhmt(-/-) mice had visible hepatic tumors. Histopathological analysis revealed that Bhmt(-/-) mice developed hepatocellular carcinoma or carcinoma precursors. These results indicate that BHMT has an important role in Hcy, choline, and one-carbon homeostasis. A lack of Bhmt also affects susceptibility to fatty liver and hepatocellular carcinoma. We suggest that functional polymorphisms in BHMT that significantly reduce activity may have similar effects in humans.

BackgroundGenome wide association studies (GWAS) have detected a considerable number of rheumatoid arthritis (RA) susceptibility loci [1]. Some RA loci have also been found to be associated with psoriatic arthritis...

Background: Type 2 Diabetes Mellitus (T2DM) is a common problem that is accompanied by disturbed metabolic homeostasis, oxidative stress and increase in proinflammatory cytokines.On the other hand, normal body metabolism is essential for the testicular function.Also, nesfatin-1 is a peptide hormone produced by numerous tissues, including the testes and shared in regulation of metabolic homeostasis and had antioxidant and anti-inflammatory properties.Aim: To investigate the effects of T2DM on testicular functions and the effects of exogenous treatment with nesfatin-1 on modulation of those effects, and, to declare the possible involved mechanisms.Material and Methods: 24-healthy adult male albino rats with a weight of 180-200gm, were divided into three groups of 8 rats each; control, type 2 diabetic (T2DM) and nesfatin-1 treated type 2 diabetic (T2DM + Nesfatin) groups.The control group received a standard diet, while, the diabetic groups (T2DM and T2DM + Nesfatin) received a High Fat Diet (HFD).Five weeks after beginning HFD, rats were fasted for 12h and received streptozotocin, in a dose of 35mg/kg, dissolved in 0. 1M sodium citrate buffer (pH 4.5) intraperitoneally (i.p.).Then, rats of the control and T2DM groups received normal saline i.p. in a dose of 1ml/kg/day for more 4 weeks and they continued to be fed with their corresponding diet, while, those of T2DM + Nesfatin group were treated with nesfatin-1 in a dose of 2 µ g/kg/day i.p. for more 4 weeks and they continued to be fed with HFD.The serum levels of testosterone, Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), tumor necrosis factor alpha (TNF α ) and interleukin-1 beta (IL-1 β ) were measured in the studied groups.Also, epididymal sperm motility and count, testicular histopathology and antioxidant enzymes Superoxide Dismutase (SOD) and catalase (CAT) activities were examined.Results: A significant (p<0.001)increase in the final Body Mass Index (BMI), Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) index, serum levels of glucose, insulin, Total Cholesterol (TC), Triglycerides (TG), Low Density Lipoprotein (LDL), TNFα and IL-1 β was found in the T2DM group in comparison to the control group.On the other hand, a significant (p<0.001)decrease in serum levels of High Density Lipoprotein (HDL), FSH, LH, and testosterone was

BackgroundHigh LDL-cholesterol (LDL-C) is a well-known risk factor for coronary artery disease (CAD). PCSK9, HMGCR, NPC1L1, ACLY, and LDLR gene have been reported as lipid lowering drug genes related to LDL-C lowering. However relevant Asian studies were rare.MethodsWe examined the causality between LDL-c drug target genes and CAD using Korean and Japanese data using the two sample Mendelian Randomization (MR) method. We conducted two-sample MR analysis of LDL-c lowering drug target genes (7 Single-nucleotide polymorphisms (SNP) in PCSK9, 6 SNPs in HMGCR, 5 SNPs in NPC1L1, 9 SNPs in ACLY, 3 SNPs in LDLR) and CAD. We used summary statistics data from the Korean Genome Epidemiology Study (KOGES) for LDL-C data, and Biobank of Japan (BBJ) for CAD data.ResultsFor every 10 mg/dl decrease in LDL-C determined by four significant SNPs in the PCSK9 gene, the risk of CAD decreased by approximately 20% (OR = 0.80, 95% CI: 0.75–0.86). The risk of CAD decreased by 10% for every 10 mg/dl decrease in LDL-C due to the six significant SNPs in the HMGCR gene (OR = 0.90, 95% CI: 0.86–0.94). Due to the two significant SNPs in the gene LDLR, the risk of CAD decreased by approximately 26% for every 10 mg/dl decrease in LDL-C (OR = 0.74, 95% CI: 0.66–0.82). The combined effect on CAD showed the largest effect size for the PCSK9 gene and LDLR gene, and the reduced CAD risk induced by these two genes together was OR = 0.78 (95%CI, 0.74–0.83). Finally, the combined effect of all three genes (PCSK9, HMGCR, and LDLR) was OR = 0.85 (95%CI, 0.79–0.91).ConclusionLDL-C reduction estimated by SNPs in LDL-C lowering drug target genes significantly reduced the risk of CAD. We found the potential of using of proxy research design for clinical trials using LDL-C lowering drugs.

Joint Linkage and Association Analysis with Exome Sequence Data Implicates SLC25A40 in Hypertriglyceridemia