Role of PC-1 and ACE genes on insulin resistance and cardiac mass in never-treated hypertensive patients. Suggestive evidence for a digenic additive modulation

Background and aimInsulin resistance and increased left ventricular mass (LVM) characterize patients with essential hypertension. Some genetic polymorphisms play a role in the modulation of both insulin resistance and LVM. The aim of this work was to investigate whether the PC-1 and ACE genes exert a polygenic control of insulin resistance and LVM in hypertensive patients.Methods and resultsIn 158 never-treated hypertensive patients, we evaluated insulin resistance by HOMA index [insulin (μU/mL) × glucose (mmol/L)]/22.5 and LVM by echocardiograms. Genetic polymorphisms were obtained by polymerase chain reaction. PC-1 X121Q genotype carriers (K121Q + Q121Q, n = 46) had higher HOMA (3.14 ± 1.28 vs. 2.49 ± 1.25; p = 0.002) and LVM (137 ± 34 vs. 127 ± 24 g/m²; p = 0.02) than K121K patients (n = 112). Similarly, ACE DD carriers (n = 56) showed higher HOMA (3.94 ± 1.13 vs. 1.98 ± 0.72; p < 0.00001) and LVM (142 ± 26 vs. 123 ± 25 g/m²; p = 0.00004) than XI (ID + II, n = 102) patients. When considering both PC-1 and ACE polymorphisms, HOMA (p < 0.00001) and LVM (p = 0.00003) progressively increased from K121K/XI to X121Q/XI, K121K/DD and X121Q/DD patients. The association of both gene polymorphisms with LVM was no longer significant after adjusting for HOMA values. As compared to K121K/XI patients (i.e. no at risk alleles), X121Q/DD patients had a significantly increased risk (OR: 4.4, 95% C.I. 1.4–14.0, p = 0.011) to have left ventricular hypertrophy.ConclusionsIn hypertensive patients PC-1 K121Q and ACE I/D polymorphisms have an additive deleterious effect on insulin resistance and, consequently, on LVM, thus increasing the global cardiovascular risk. Identification of carriers of the at-risk genotypes may help set up prevention strategies to be specifically targeted at these patients.     

FADS gene polymorphisms in Koreans: association with ω6 polyunsaturated fatty acids in serum phospholipids, lipid peroxides, and coronary artery disease

ObjectiveWe investigated the association of polymorphisms in FADS genes with polyunsaturated fatty acids (PUFAs) in serum phospholipids, lipid peroxides, and coronary artery disease (CAD) in Koreans.MethodsIn this case–control study, CAD patients (n = 756, 40–79 years) and healthy controls (n = 890) were genotyped for rs174537 near FADS1 (FEN1 rs174537G > T), FADS2 (rs174575, rs2727270), and FADS3 (rs1000778). We calculated the odds ratios (ORs) for CAD risk and measured serum PUFA composition and lipid peroxide.ResultsAmong four SNPs, only rs174537G > T differed in allele frequencies between controls and CAD patients after adjustment for age, BMI, cigarette smoking, alcohol consumption, hypertension, diabetes mellitus, and hyperlipidemia (P = 0.017). The minor T allele was associated with a lower risk of CAD [OR 0.75 (95%CI 0.61–0.92), P = 0.006] after adjustment. rs174537T carriers had a significantly higher proportion of linoleic acid (LA, 18:2ω6), lower arachidonic acid (AA, 20:4ω6), and lower ratios of AA/dihomo-γ-linolenic acid (DGLA, 20:3ω6) and AA/LA than G/G subjects in both control and CAD groups. In the control group, 174537T carriers had significantly lower levels of total- and LDL-cholesterol, malondialdehyde, and ox-LDL. In CAD patients, rs174537T carriers showed a larger LDL particle size than G/G subjects. The proportion of AA in serum phospholipids positively correlated with LDL-cholesterol, ox-LDL, and malondialdehyde in controls and with 8-epi-prostaglandin F_2α in both control and CAD groups.ConclusionThe rs174537T is associated with a lower proportion of AA in serum phospholipids and reduced CAD risk, in association with reduced total- and LDL-cholesterol and lipid peroxides.     

ABCB1 haplotype is associated with major molecular response in chronic myeloid leukemia patients treated with standard-dose of imatinib

BackgroundImatinib mesylate (IM) is a selective tyrosine kinase inhibitor used for treating chronic myeloid leukemia (CML). IM has high efficacy, however some individuals develop a resistance due to impaired bioavailability. Polymorphisms in genes encoding membrane transporters such as ABCB1 have been associated with differences in protein expression and function that influence the response to several drugs.AimTo investigate the relationship of ABCB1 polymorphisms with markers of response to IM in patients with CML.MethodsOne hundred eighteen CML patients initially treated with a standard dose of IM (400 mg/day) for 18 months were selected at two health centers in Sao Paulo City, Brazil. The response criteria were based on the European LeukemiaNet recommendations. ABCB1 polymorphisms c.1236C > T (rs1128503), c.3435C > T (rs1045642) and c.2677G > T/A (rs2032582) were evaluated by PCR-RFLP.ResultsABCB1 polymorphisms were not related with a risk for CML in this sample population (p < 0.05). In the CML group, frequencies of ABCB1 SNPs were similar between responder and non-responder patients (p > 0.05). In the responder group, the frequency of ABCB11236CT/2677GT/3435CT haplotype was higher in patients with major molecular response (MMR) (51.7%) than in patients without MMR (8.3%, p = 0.010). Furthermore, carriers of this haplotype had increased the probability of reaching the MMR compared with the non-carriers (OR: 11.8; 95% CI: 1.43–97.3, p = 0.022).ConclusionsThe ABCB1 1236CT/2677GT/3435CT haplotype is positively associated with the major molecular response to IM in CML patients.     

Proinflammatory HLA-DRB1*01-haplotype predisposes to ST-elevation myocardial infarction

BackgroundMajor histocompatibility complex (MHC) gene region harbours haplotypes that associate with coronary artery disease (CAD). Their role in ST-elevation infarction (STEMI) or on the inflammatory level is not known.MethodsFour candidate MHC markers were analyzed by real-time quantitative PCR and constructed into haplotypes from patients with STEMI (n = 162), matched controls with no CAD (n = 319) and general population sample (n = 149). High sensitivity C-reactive protein (hsCRP) was assessed in a follow-up visit from patients (n = 86) and at inclusion from other study subjects.ResultsThe haplotype with one copy of HLA-DRB1*01, C4A, C4B but no HLA-B*35 doubled the risk of STEMI (OR = 2.15, 95%CI = 1.11–4.15, p = 0.020 for patients vs. controls, and OR = 2.26, 95%CI = 0.97–5.24, p = 0.052 for patients vs. population sample). The association between patients and controls persisted in multivariate analyses. The frequency of the haplotype was 5.86% (n = 19/324) in patients, 2.82% (n = 18/638) in controls and 2.68% (n = 8/298) in population sample. None of the individual MHC markers alone showed significant association with STEMI.In multivariate analyses, the haplotype carriers had higher hsCRP levels in patients (median 3.37 mg/L in carriers vs. 1.14 mg/L in non-carriers, p = 0.019) and in controls (median 2.90 mg/L vs. 1.21 mg/L, p = 0.009, respectively).ConclusionThe MHC haplotype associates with STEMI and elevated baseline hsCRP levels. The results are in concordance with previous data on non-STEMI patients, implying that a HLA-DRB1*01 – related haplotype increases the risk of CAD, possibly though increased inflammation.     

Gene-nutrient interactions and gender may modulate the association between ApoA1 and ApoB gene polymorphisms and metabolic syndrome risk

ObjectiveDyslipidemia is a key feature of the metabolic syndrome (MetS), which is determined by both genetic and dietary factors.MethodsWe determined the relationships between ApoA1 and ApoB polymorphisms and MetS risk, and whether dietary fat modulates this in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754).ResultsApoB rs512535 and ApoA1 rs670 major G allele homozygotes had increased MetS risk (OR 1.65 [CI 1.24, 2.20], P = 0.0006; OR 1.42 [CI 1.08, 1.87], P = 0.013), which may be, partly, explained by their increased abdominal obesity and impaired insulin sensitivity (P < 0.05) but not dyslipidemia. Interestingly these associations derived primarily from the male GG homozygotes (ApoB rs512535 OR 1.92 [CI 1.31, 2.81], P = 0.0008; ApoA1 rs670 OR 1.50 [CI 1.05, 2.12], P = 0.024). MetS risk was exacerbated among the habitual high-fat consumers (>35% energy) (ApoB rs512535 OR 2.00 [CI 1.14, 3.51], P = 0.015; OR 1.58 [CI 1.11, 2.25], P = 0.012 for ApoA1 rs670). In addition a high monounsaturated fat (MUFA) intake (>14% energy) increased MetS risk (OR 1.89 [CI 1.08, 3.30], P = 0.026 and OR 1.57 [CI 1.10, 2.40], P = 0.014 for ApoB rs512535 and ApoA1 rs670, respectively). MetS risk was abolished among the habitual low-fat consumers (<35% energy). Saturated and polyunsaturated fat intake did not modulate MetS risk.ConclusionApoB rs512535 and ApoA1 rs670 may influence MetS risk. Apparent modulation of these associations by gender and dietary fat composition suggests novel gene-gender-diet interactions.     

IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy

ObjectiveThe IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to type 1 diabetes (T1D), type 2 diabetes (T2D) and diabetic nephropathy (DN). Its protein functionally binds to 5’-UTR of the imprinting IGF2 gene. The present study aims to evaluate the IGF2BP2-IGF2 genetic effects in diabetes and DN.Materials and MethodsThree cohorts including T1D with and without DN (n = 1139) of European descents from the GoKinD study, Swedish T1D with and without DN (n = 303) and Czech control subjects without diabetes, T1D, T2D with and without DN (n = 1418) were enrolled in TaqMan genotyping experiments for IGF2BP2 rs4402960 and IGF2 rs10770125. Igf2bp2 gene expression in kidney tissues of db/db and control mice at the ages of 5 and 26 weeks was examined with real time RT-PCR and Western blot.ResultsAn association of IGF2BP2 rs4402960 with T2D in the Czech population was replicated. This IGF2BP2 polymorphism (P = 0.037, OR = 0.69 95% CI 0.49–0.98) was found to be associated with DN in male not in female patients with T1D selected from the GoKinD study. In the analyses of combined the GoKinD, Czech and Swedish populations, the association between IGF2BP2 polymorphism and DN in male patients with T1D was still significant (P = 0.030, OR = 0.73, 95% CI 0.54–0.97). IGF2 rs10770125 was also associated with DN in male T1D patients of the GoKinD population (P = 0.038, OR = 0.67 95% CI 0.46–0.98). There might be a genetic interaction between IGF2BP2 and IGF2 (P = 0.05). The Igf2bp2 gene expression levels were increased in the kidneys of db/db mice compared to controls at the age of 5 weeks but not at 26 weeks.ConclusionsThe present study has replicated the association of IGF2BP2 rs4402960 with T2D in the Czech population and provided data suggesting that IGF2BP2 may have genetic interaction with IGF2 with a protective effect against DN in male patients with T1D.     

CRP and CD14 polymorphisms correlate with coronary plaque volume in patients with coronary artery disease--IVUS substudy of the ENCORE trials

BackgroundSeveral proinflammatory single-nucleotide polymorphisms (SNPs) have been linked to the progression of atherosclerosis and coronary artery disease (CAD). Plaque size and its destabilization by inflammatory processes are major determinants of ischemia and acute coronary syndromes. Intravascular ultrasound (IVUS) allows for quantification of plaque size in vivo. We therefore investigated the relation of plaque size with mutations of proinflammatory genes in patients with CAD.MethodsIn 196 patients with stable CAD enrolled in the ENCORE trials coronary plaque and vessel volume was assessed by IVUS. 173 patients were successfully genotyped for polymorphisms of proinflammatory genes CD14 C(?260)T and CRP C(+1444)T using the single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach.ResultsBaseline characteristics were comparable for all genotype groups. Higher ratios of plaque volume/vessel volume were observed in patients with the CRP 1444TT (n = 11) and CD14 260TT (n = 33) genotypes (p = 0.016 and p = 0.026, respectively).ConclusionIn patients with stable coronary artery disease the CRP 1444TT and CD14 260TT variants are associated with larger coronary plaque volume independently of concomitant cardiovascular risk factors.     

Multicentre, randomised, controlled study of the impact of continuous sub-cutaneous glucose monitoring (GlucoDay) on glycaemic control in type 1 and type 2 diabetes patients

AimThis randomised study was designed to investigate the impact of continuous glucose monitoring (CGM) for 48 h on glycaemic control with a 3-month follow-up in patients with type 1 (T1D) or type 2 (T2D) diabetes.MethodsA total of 48 patients with poor glycaemic control (HbA_1c: 8–10.5%) underwent CGM for 48 h using the GlucoDay^® system (A. Menarini Diagnostics), after which they were randomly assigned to treatment adjustments based on either their CGM profile (CGM group) or their usual self-monitoring of blood glucose (SMBG group). HbA_1c measurement and 48-h CGM were repeated 3 months later.ResultsAltogether, 34 patients with either T1D (n = 9) or T2D (n = 25) completed the study; seven patients chose to leave the study, and seven patients in the CGM group were excluded because their baseline CGM graphs were not interpretable. HbA_1c levels decreased significantly in the CGM group (n = 14, –0.63 ± 0.27%; P = 0.023), but not in the controls (n = 20, –0.28 ± 0.21%; P = 0.30). In T2D patients, the improvement associated with CGM vs SMBG was due to HbA_1c decreases (mean: –0.63 ± 0.34%; P = 0.05 vs –0.31 ± 0.29%; P = 0.18, respectively). However, HbA_1c did not change significantly with CGM in T1D patients. Comparisons of CGM data at baseline and after 3 months showed no significant changes in glucose control, glucose variability or hypoglycaemia. No major adverse events related to the GlucoDay^® system were reported.ConclusionThis is the first randomised study showing that CGM improves glycaemic control in patients with T2D.     

Type 1 diabetes: Dealing with physical activity

AimFor patients with type 1 diabetes (T1D) using multiple insulin injections (MII), there are currently no guidelines for insulin dose adjustments in the event of physical activity (PA) and no simple algorithms that can be applied directly. Thus, the objective of this study was to assess the relevance of simple algorithms based on assessments of PA intensity by T1D patients themselves.MethodsThis 4-month observational study was conducted in 35 patients using the Diabeo software system. Algorithms for insulin dose adjustments aimed to reduce the insulin dose of the meal closest to PA by 30 and 50% for moderate and intense PA, respectively. A 50% reduction plus extra carbohydrates was proposed for intense PA of long duration. These algorithms were entered into the Diabeo system.ResultsThe mean blood glucose (BG) profile in the event of PA (n = 151 triple BG values) was compared with that when no PA was performed (n = 3606). The initial mean FBG values were similar in both groups (7.58 ± 2.70 mmol/L vs. 7.80 ± 3.49 mmol/L; P = 0.36), whereas there was a slight, but significant, increase in 2-hours postprandial BG (PPBG) values related to PA, with a return to similar values before the next meal. The incidence of mild hypoglycaemia was similar, whether PA was undertaken or not, for the 2-hour PPBG and the next fasting/premeal glucose values.ConclusionThis appears to be a pragmatic and efficient method for T1D patients using MII to adjust insulin doses in the event of PA that only requires an assessment of PA intensity by the patients themselves to anticipate the magnitude of the reduction in insulin doses.     

Urinary albumin excretion in latent autoimmune diabetes in adults (LADA) is more similar to type 2 than type 1 diabetes: Results of the Nord-Trøndelag Health Study 1995–1997

AimAs it is unclear, whether or not, urinary albumin excretion (UAE) differs between patients classified as latent autoimmune diabetes in adults (LADA) and other forms of diabetes, our study aimed to investigate the distribution of the albumin-to-creatinine ratio (ACR) in LADA compared with those in the “classical” types 1 (T1D) and 2 (T2D) diabetes.MethodsWe used data from the Nord-Trøndelag Health Study (HUNT) (n = 64,931) of 1995–1997. ACR (mg/mmol) was measured in three urine samples from all diabetic patients (n = 1525) and from 5% of the non-diabetic study population (n = 2104). We calculated the geometric means and 95% confidence intervals (CI) using a general linear model.ResultsThe unadjusted mean ACR in LADA was similar to that in T2D (1.45, CI: 1.23–1.71 vs 1.41, CI: 1.33–1.49, respectively) but was significantly higher than those in T1D (0.99, CI: 0.83–1.19; P = 0.002) and non-diabetics (0.72, CI: 0.69–0.74; P < 0.001). These results remained similar even after multiple adjustments.ConclusionIn this cross-sectional study, the ACR in LADA and in T2D were similar and higher than in T1D. This similarity between LADA and T2D makes it unlikely that the autoimmune processes that operate in LADA promote albuminuria.     

Akt2 Gene common allelic variants in insulin resistance and the metabolic syndrome

Background and aimSeveral lines of evidence indicate that glucose homeostasis may be under the control of Akt2 and it can therefore be seen as a candidate gene for human insulin resistance (IR) and related phenotypes. The aim of our study was the identification of Akt2 common allelic variants that might modulate susceptibility to IR and related metabolic abnormalities.Methods and resultsThe Akt2 gene (exons, 5′ and 3′ regulatory regions) was re-sequenced in samples of 50 blood donors from the Gargano region. Two single nucleotide polymorphisms (SNPs) in 5′ (rs11669332 and rs969531) and two in 3′ (rs2304186 and C1658T) regulatory regions were exploited in an association study using 661 healthy unrelated Caucasian individuals from the same region.Individuals being homozygous for the T allele of rs11669332 (an Akt2 promoter) showed lower systolic blood pressure (p = 0.04), total/HDL cholesterol ratio (p = 0.02) and the metabolic syndrome score (p = 0.04), while carriers of the A allele of rs969531 (in 5′-UTR) showed higher systolic blood pressure (p = 0.027). The association between phenotypic traits and possible haplotypes was tested as well. However, no haplotype affecting the risk of metabolic abnormalities was found.ConclusionsTwo variants in 5′ regulatory region of Akt2 gene are associated and may modulate susceptibility to IR and related metabolic abnormalities.     

Plasma profiling by a protein array approach identifies IGFBP-1 as a novel biomarker of abdominal aortic aneurysm

ObjectiveCytokines are important mediators of immune-inflammatory responses implicated in abdominal aortic aneurysm (AAA) pathogenesis. Our objective was to investigate the cytokine expression profile in plasma of AAA patients.MethodsCytokine protein expression was measured in plasma of 5 large AAA patients (aortic size >50 mm) and 5 controls (aortic size <30 mm) using a 20-cytokine antibody-based protein array. IGFBP-1 plasma concentrations were analyzed by ELISA. IGFBP-1 protein levels were analyzed in AAA thrombus by immunohistochemistry and Western blot. Platelet aggregation was assessed by conventional optical aggregometry.ResultsSeveral proteins including MIP-3alpha (CCL20), Eotaxin-2 and IGFBP-1 were increased in AAA patients compared to controls. Among them, IGFBP-1 concentrations were significantly higher in large AAA patients vs control subjects. These data were validated in plasma of patients with large AAA (n = 30) compared to matched controls (n = 30) [834(469–1628) vs 497(204–893) pg/ml, p < 0.01]. Furthermore, the potential association of IGFBP-1 with AAA size was analyzed in a second independent group of subjects [large AAA (n = 59), small AAA patients (aortic size = 30–50 mm, n = 54) and controls (n = 30)]. Interestingly, IGFBP-1 levels correlated with AAA size (r = 0.4, p < 0.001), which remained significant after adjusting for traditional risk factors. IGFBP-1 was localized in the luminal part of AAA thrombus and IGFBP-1 levels were increased in AAA thrombus conditioned media compared to media layer and healthy media. Interestingly, IGFBP-1 abrogated the potentiation of ADP-induced platelet aggregation triggered by IGF-1.ConclusionsIGFBP-1 has been identified by a protein array approach as a potential novel biomarker of AAA. The biological role of IGFBP-1 in AAA pathogenesis could be related to the modulation on the effect of IGF-1 on platelet aggregation.     

T-cadherin gene variants are associated with type 2 diabetes and the Fatty Liver Index in the French population

AimAdiponectin is an adipocyte-secreted protein associated with insulin sensitivity. T-cadherin is a receptor for high and medium molecular weight adiponectin. In GWAS, T-cadherin gene (CDH13) polymorphisms are associated with circulating adiponectin levels. This study investigated the associations between genetic variants of CDH13 and type 2 diabetes (T2D), and its related parameters, in a Caucasian population.MethodsTwo polymorphisms of CDH13 (rs11646213 and rs3865188) were genotyped in two French cohorts, a general population from the D.E.S.I.R. study (n = 5212) and people with T2D in the DIABHYCAR study (n = 3123). Baseline adiponectin levels were measured in D.E.S.I.R. participants who were normoglycaemic at baseline, but hyperglycaemic after 3 years (n = 230), and in controls who remained normoglycaemic (n = 226) throughout.ResultsIn a cross-sectional analysis, CDH13 genotype distributions differed between those with and without T2D, with T2D odds ratios (OR) of 1.11 (95% CI: 1.04–1.18; P = 0.001) and 0.92 (95% CI: 0.87–0.98; P = 0.01) for rs11646213 and rs3865188, respectively. The rs11646213 variant, associated with a higher OR for T2D, was also associated with higher BMI (P = 0.03) and HbA_1c (P = 0.006), and lower plasma adiponectin levels (P = 0.03) in the D.E.S.I.R. participants. Conversely, the rs3865188 variant, associated with a lower OR for T2D, was also associated with lower BMI (P = 0.03), HbA_1c (P = 0.02) and Fatty Liver Index (FLI; P ≤ 0.01), and higher plasma adiponectin levels (P = 0.002). Associations with HbA_1c, FLI and adiponectin levels persisted after adjusting for BMI.ConclusionCDH13 polymorphisms are associated with prevalent T2D in this French population study. The association may be mediated through effects on BMI and/or plasma adiponectin.     

QTc and autonomic neuropathy in diabetes: effects of acute hyperglycaemia and n-3 PUFA

Background and aimsAutonomic function is also regulated by glycaemia and exerts a crucial role in the control of blood pressure and cardiac function. The disruption of this physiological mechanism impacts deeply on cardiovascular mortality in diabetes. We investigated the influence of autonomic dysfunction on QTc interval and on sympatho-vagal balance (LF/HF), in response to acute hyperglycaemia and to membrane electrical stabilization (n-3 PUFA).Methods and resultsTwenty-four type 2 diabetic patients, without (N−: n = 13) or with (N+: n = 11) autonomic neuropathy and 13 healthy subjects (C) underwent BP and ECG monitoring during a 24-h period and during a 2-h hyperglycaemic clamp. ΔQTc during the night was blunted in diabetics (0.5 ± 2.5 vs. C: 2.9 ± 2.5%, p = 0.001), and ΔLF/HF was decreased in N+ (−2.8 ± 38.2 vs. C = 34.8 ± 28.1%, p = 0.02). During hyperglycaemia, QTc increased in C; LF/HF significantly increased in C and N−. A 6-month treatment with n-3 PUFA partially restored ΔLF/HF and ΔQTc (2.1 ± 1.40, p = 0.04 vs. basal) only in N−.ConclusionHyperglycaemia increases QTc interval and sympathetic activity; electrical membrane stabilization improves autonomic function only in the absence of overt autonomic neuropathy. Strategies to prevent the disruption of autonomic function with newer approaches, other than just glucose control, should be implemented.     

The epistasis between vascular homeostasis genes is apparent in essential hypertension

ObjectiveThe epistasis influence of vascular homeostasis genes is vital to multigenetic diseases. This study was designed to perceive the possible role of epistasis in the etiology of essential hypertension.MethodsWe investigated seven polymorphisms of ACE, CYP11B2 and NOS3 epistatically, and SBP, DBP, MAP, ACE activity, plasma aldosterone concentration (PAC) and NOx level in 860 age- and ethnicity-matched unrelated north-Indian subjects.ResultsThe hypertension risk in individuals with interacted-genotypes (IwIw + IwIc) + (4aa), (IcIc) + (4bb + 4ba) and IcIc + 4aa of the CYP11B2 and NOS3 was significantly higher with odds ratio 5.5 (95% CI = 2.9–10.6, P < 0.0001), 2.4 (95% CI = 1.4–4.1, P < 0.0008) and 7.5 (95% CI = 1.6–34.8, P = 0.010), respectively. The odds ratio for hypertension with interacted-haplotypes (?344T/Ic) + (?922A/?786T/4a/894G) and (?344T/Ic) + (?922G/?786C/4a/894G) of CYP11B2 and NOS3 was 5.3 (95% CI = 2.0–14.2, P = 0.005) and 3.9 (95% CI = 1.4–10.4, P = 0.04), respectively; whereas for the protective interacted-haplotypes (?344T/Iw) + (?922A/?786T/4b/894G), the odds ratio was 0.7 (95% CI = 0.5–0.9, P = 0.03). While the interacted-genotypes, IcIc + 4aa correlated with higher SBP and MAP (P = 0.006; P = 0.04), the interacted-haplotypes, (?344T/Ic) + (?922A/?786T/4a/894G) and (?344T/Ic) + (?922G/?786C/4a/894G) correlated with higher MAP and lower NOx level (P = 0.02 and P = 0.03, respectively), and the protective interacted-haplotypes (?344T/Iw) + (?922A/?786T/4b/894G) correlated with lower PAC and MAP (P = 0.024 and P = 0.018, respectively).ConclusionsThe epistasis between CYP11B2 and NOS3 and its correlation with varied clinical and biochemical parameters signify its possible contribution in the complex etiology of hypertension.     

Sensitivity of A1C to diagnose diabetes is decreased in high-risk older Southeast Asians

ObjectiveTo determine the effect of ageing on the performance of glycosylated haemoglobin A1C (A1C) for the diagnosis of diabetes mellitus (DM) in Southeast Asians.MethodsA1C was measured in 511 subjects (mean age of 52.4 years; range 14–93) undergoing the 75-g oral glucose tolerance test (OGTT). Using receiver operating curve (ROC) analysis, the performance of A1C for the diagnosis of diabetes (using different standard criteria) was compared between 4 groups: < 45 (n = 156), 45–54 (n = 132), 55–64 (n = 122), ≥ 65 years (n = 101).ResultsSubjects aged ≥ 65 years had the highest false-negative rates with fasting plasma glucose (60.8%) and A1C (35.1%), the smallest area under ROC curve (0.723, 95% CI 0.627–0.820), the lowest sensitivity (58.7%, 95% CI 50.4–65.7) and specificity (71.1%, 95% CI 57.3–82.6) of A1C 6.5%, compared to the younger age groups.ConclusionOGTT is preferable for diagnosis of DM in older Southeast Asian adults.     

Chronic granulomatous disease in pediatric patients: 25 years of experience

IntroductionChronic granulomatous disease (CGD) is an uncommon primary immune deficiency (affecting 1/200,000 newborn infants) caused by a defect in phagocyte production of oxygen metabolites, and resulting in bacterial infections produced by catalase-positive microorganisms and fungal diseases that occasionally may prove fatal.MethodsA review is made of the clinical records of 13 pediatric patients diagnosed with CGD between 1980 and 2005.ResultsAll patients were males. The mean age at diagnosis was 36 months. The clinical manifestations at the time of diagnosis comprised the following: Abscesses or abscessified adenopathies 4/13 (Staphylococcus aureus (2), Serratia liquefaciens, S. marcescens and Klebsiella sp.), pneumonia 3/13 (Rhodococcus equi, Salmonella typhimurium plus Pneumocystis jiroveci), osteomyelitis 1/13 (Aspergillus sp.), sepsis 1/13 (S. aureus), urinary infection 1/13 (Klebsiella sp.), severe gastroenteritis 1/13, oral aphthae 1/13 and Crohn-like inflammatory bowel disease 1/13. The diagnosis was initially established by the nitroblue tetrazolium test, and confirmed by flow cytometry 10/13 and genetic techniques (gp91) 9/13. In the course of these disease processes there were 88 infections: abscesses (n = 26), lymphadenitis (n = 12), pneumoniae (n = 10), gastroenteritis (n = 7), sepsis (n = 6), osteomyelitis (n = 3) and others (n = 24). As to the germs isolated, the frequency distribution was as follows (n = 49): Aspergillus sp. (n = 10), Staphylococcus sp. (n = 7), Salmonella sp. (n = 6), Serratia sp. (n = 5), Pseudomonas aeruginosa (n = 4), Klebsiella sp. (n = 4), Proteus sp. (n = 3), Leishmania sp. (n = 2) and others (n = 8). IFN-γ was administered in 7/13 cases, and itraconazole in 9/13; all received cotrimoxazole. There were four deaths, with one case each of sepsis due to gramnegative bacterial infection; disseminated aspergillosis; visceral leishmaniasis and hemophagocytosis; and post-kidney transplant complications.ConclusionsClinical suspicion and flow cytometry are the keys for diagnosis of CGD and detection of carrier relatives. Specific prophylactic measures and medical controls are required to prevent serious infections. IFN-γ has been used intermittently, though its effectiveness is controversial.     

Long-term use of oral nicorandil stabilizes coronary plaque in patients with stable angina pectoris

ObjectiveThe Impact of Nicorandil in Angina (IONA) trial demonstrated that the use of nicorandil, an anti-anginal drug, reduced future cardiovascular events in patients with stable angina. We hypothesized that nicorandil has beneficial effects on coronary arterial plaque characteristics and atherosclerogenesis.Methods and ResultsPreintervention intravascular ultrasound-virtual histology was performed prospectively in 65 consecutive patients with stable angina pectoris. There were no differences in coronary risk factors between the nicorandil (n = 16) and non-nicorandil (n = 49) groups. However, the nicorandil group demonstrated a larger %fibrous tissue (68 ± 10 vs. 62 ± 11%, P = 0.049) and a smaller %necrotic core tissue (11 ± 7 vs. 16 ± 10%, P = 0.049) compared with the non-nicorandil group. Multiple regression analysis showed that %necrotic core tissue (P = 0.045) was negatively and %fibrous tissue (P = 0.026) was positively associated with the use of nicorandil independent of statin use. We also analyzed the effect of nicorandil on atherosclerotic lesion formation in a mouse model of atherosclerosis. Lipid profiles were unaffected, but the area of atherosclerotic lesion and plaque necrosis were significantly reduced following 8-week nicorandil treatment in ApoE-deficient mice fed an atherogenic diet. Nicorandil significantly reduced the expression levels of endoplasmic reticulum stress markers, C/EBP homologous protein (CHOP) and glucose regulated protein/BiP (GRP78) in atherosclerotic lesions. Nicorandil significantly attenuated tunicamycin-induced CHOP upregulation in cultured THP-1 macrophages.ConclusionsNicorandil exerts its anti-atherogenic effect by mechanisms different from those of statins. Long-term nicorandil treatment is a potentially suitable second-line prevention therapy for patients with coronary artery disease.     

Protein and glutamine kinetics during counter-regulatory failure in type 1 diabetes

Background and aimsHealthy individuals counteract insulin-induced hypoglycaemia by increasing glutamine utilization but not proteolysis. Glucagon is important to this response because it increases glutamine uptake. In type 1 diabetes (T1DM) glucagon and epinephrine responses to hypoglycaemia are defective. We investigated whether glutamine and amino acid utilization during hypoglycaemia is altered in T1DM with defective counter-regulatory responses.Methods and resultsEight T1DM patients (duration of diabetes 14 ± 4 years and therefore with presumed defective counter-regulatory response) and eight controls (CON) received a 3 h hypoglycaemic hyperinsulinaemic (0.65 mU/kg per min) clamp coupled to [6,6-²H₂]glucose, [1-¹³C]leucine and [2-¹⁵N]glutamine to trace the relative kinetics.Post-absorptive plasma glucose and glucose uptake were increased in T1DM (9.09 ± 0.99 vs 5.01 ± 0.22 mmol/l and 19.5 ± 0.9 vs 12.6 ± 0.8 μmol/kg per min, p < 0.01). During the clamp T1DM but not CON required exogenous glucose (4.4 ± 1.7 μmol/kg per min) to maintain the hypoglycaemic plateau because the endogenous glucose production was significantly suppressed (p < 0.01). In T1DM the leucine and phenylalanine concentrations were less suppressed from basal (p < 0.05) despite a similar insulin suppression of proteolysis (−16 ± 2 vs −20 ± 4%, p = ns) indicating a defective stimulation of leucine metabolic clearance from basal (+18 ± 3% vs +55 ± 9%, p < 0.01). Glutamine concentration remained unchanged from basal (−7 ± 3% vs −35 ± 3%, p < 0.01) and the clearance of glutamine was markedly defective in T1DM (+6 ± 2%) in comparison with controls (+22 ± 4%; p = 0.02).ConclusionsIn T1DM, the counter-regulatory failure to hypoglycaemia seems to be associated with a defective glutamine utilization. The failure to clear circulating amino acids, specifically glutamine, during hypoglycaemia may adversely affect gluconeogenesis.     

Urine α-Glutathione S-transferase, systemic inflammation and arterial function in juvenile type 1 diabetes

BackgroundDespite marked improvement in therapy and monitoring of patients with insulin-dependent (type 1) diabetes, diabetic nephropathy remains a serious complication, with subsequent end-stage renal disease in about 20% of cases.ObjectiveTo investigate in young patients with type 1 diabetes whether urine α-Glutathione S-transferase to creatinine ratio (α-GST:crea) relates to markers of systemic inflammation and subclinical vasculopathy.DesignChildren and adolescents (median age and diabetes duration 14 and 6 years, respectively) with type 1 diabetes screened in a previous study for proximal tubular (urine α-GST:crea ratio) and renal (plasma creatinine, cystatin C glomerular filtration rate (GFR), and timed urine albumin excretion rate (AER)) function were, within the same timeframe, also investigated for vascular (blood pressure, carotid artery intima–media thickness (IMT) and compliance (CAC), brachial artery flow-mediated dilatation (FMD) and plasma cyclic guanosine monophosphate (cGMP) and inflammatory (C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α)) profiles. Exposure to environmental tobacco smoke (ETS) was assessed through questionnaire (n = 67 respondents).ResultsNone of the patients (n = 69) had overt renal insufficiency. AER correlated with age (p = 0.01, r = 0.3), diabetes duration (p = 0.02, r = 0.3), FMD (p = 0.04, r = ? 0.3, n = 52), CAC (p = 0.03, r = ? 0.3, n = 62) and cGMP (p = 0.01, r = ? 0.3, n = 59). α-GST:crea was lower (p = 0.03) in patients than in controls. α-GST:crea appeared to be particularly lower in older patients (p = 0.004, r = ? 0.34 vs age), in those with worse diabetic control (p = 0.03, r = ? 0.26 vs HbA1c), and in those with lower carotid artery elasticity (p = 0.017, r = 0.3 vs CAC). Although ETS had no direct significant impact on α-GST:crea, α-GST:crea correlated with FMD only in patients with ETS (r = 0.5, p = 0.009, n = 13). α-GST:crea showed positive association with TNF-α (p = 0.01, r = 0.3).ConclusionIn children and adolescents with type 1 diabetes, lower levels of urine excretion of α-GST:crea appear to be associated with decreasing elasticity and endothelial vasomotor function of peripheral arteries, especially in patients with ETS. In contrast, higher levels of α-GST:crea are more common in patients with elevated markers of systemic inflammation. Large scale prospective studies are needed to clarify the meaning and mechanisms of this association.