Association of ALOX5AP haplotypes with susceptibility to coronary artery disease in a Chinese Han population

BackgroundThe 5-lipoxygenase activating protein (FLAP), encoded by the activating 5-lipoxygenase (ALOX5AP) gene, is a crucial mediator of the biosynthesis of leukotrienes, which have been implicated in atherosclerosis. This study investigates whether ALOX5AP polymorphisms are associated with coronary artery disease (CAD) in a Chinese Han population.MethodsThe promoter, exons, splice site region and 3′-untranslated region of the ALOX5AP gene were sequenced in 48 subjects. Three polymorphic sites (? 1340T/G, + 8733T/C, + 20616G/C) found through sequencing were evaluated in 656 patients with angiographically proven CAD and 678 controls with normal coronary angiograms using a polymerase chain reaction and restriction fragment length polymorphism assay. Allelic, genotypic linkage disequilibrium and haplotypic association testing were performed using SHEsis and LDA software. Binary logistic regression was used to control for the presence of vascular risk factors.ResultsSeven single nucleotide polymorphisms (SNPs) were found through screening. No significant differences in allele carriers and genotype frequencies of the ALOX5AP polymorphisms were observed between the two groups. However, when the results of the three SNPs were combined, there was a significant association between two of the haplotypes and the risk of CAD. The haplotype GCG had a significantly greater frequency in patients than in controls (P < 0.001, OR = 1.728, 95%CI = 1.375–2.171), and the frequency of haplotype TCG was higher in controls (P < 0.001, OR = 0.623, 95%CI = 0.519–0.748).ConclusionThe data indicate that ALOX5AP gene variation is a genetic factor associated with interindividual differences in CAD risk.     

Postprandial hyperlipidemia in overt and subclinical hypothyroidism

Background and aimsLipid alterations in overt hypothyroidsm (OH) were well known, but its changes in subclinical hypothyroidism (SCH) and postprandial period were not clear. The aim of this study is to evaluate postprandial lipemia by oral lipid tolerance test (OLTT) in patients with OH and SCH.Materials and methodologyTwenty-five OH and 27 SCH, totally 52 hypothyroid patients [mean age 38.3 ± 12.8 year, body mass index (BMI): 29.0 ± 5.8 kg/m²] and 23 BMI- and age-matched healthy controls (mean age 36.7 ± 11.9 years; BMI: 27.1 ± 6.9 kg/m²) were included to the study. Anthropometric measurements and HOMA-IR levels were measured. Basal and postprandial lipid profile at 2nd, 4th, 6th and 8th hours were determined by oral lipid tolerance test.ResultsThere were not any statistical differences among three groups (control, OH and SCH) in terms of mean fasting levels of total cholesterol, LDL-cholesterol, VLDL-cholesterol, and triglyceride. On the contrary, mean triglyceride levels at postprandial 8th hour in both OH and SCH patients were higher than control subjects (p = 0.017 and p = 0.049, respectively). Again mean postprandial 8th hour VLDL-cholesterol levels in OH group were also higher than control subjects (p = 0.05). In addition mean HOMA-IR value of SCH and OH patients was similar with control subjects (1.5 ± 1.4 in OH; 1.3 ± 0.8 in SCH; 2.2 ± 2.2 in control group).ConclusionsAlthough total, LDL and VLDL-cholesterol, and triglyceride levels were not different from healthy controls, triglyceride and/or VLDL-cholesterol levels apparently increased with OLTT in both OH and SCH patients. Decreased lipid clearance may be responsible for this result.     

The effect of WNT5B IVS3C>G on the susceptibility to type 2 diabetes in UK Caucasian subjects

Background and aimsThe wnt signaling pathway regulates adipogenesis and insulin secretion. The WNT5B gene has been reported to confer susceptibility to type 2 diabetes (T2D) in the Japanese population, and we therefore evaluated this in Caucasian subjects with respect to obesity status.Methods and resultsTwo thousand seven hundred and one Caucasian middle-aged men from the prospective Northwick Park Heart Study II (NPHSII) of whom 153 developed T2D over 15 years and 1268 Caucasian middle-aged patients with T2D (60% male) were genotyped using a TaqMan assay for the IVS3C > G variant (rs2270031) in the WNT5B gene. The frequency of the G allele was 0.026 (0.022–0.031) in controls and 0.031 (0.025–0.039) in patients with diabetes, p = 0.24. In the prospective analysis, G allele carriers with BMI below 26 kg/m² had significantly higher T2D hazard risk [3.46 (1.34–8.96), p = 0.01]. Comparing T2D cases with NPHSII controls, the G allele was associated with a significantly higher T2D odds ratio (OR) of 1.50 (1.06–2.12), p = 0.02 in subjects with BMI lower than 30 kg/m². Increasing BMI had a smaller effect on risk in G allele carriers. The effect on risk was not explained by genotype being associated with any classical T2D risk factor. When the combined effect of this SNP and the TCF7L2 IVS3C > T SNP (rs7903146) was evaluated, a 2.07 (1.40–3.07), p < 0.0001 fold higher OR was observed in carriers of both the rare alleles.ConclusionVariation in WNT5B predisposes to T2D in the absence of obesity. The increase in risk conferred by the presence of both WNT5B and TCF7L2 variants strengthens the role of wnt signaling in T2D.     

IL1B genetic variation and plasma C-reactive protein level among young adults: the CARDIA study

ObjectiveInterleukin-1B (IL1B) modulates C-reactive protein (CRP) expression. However, whether IL1B genetic variation is associated with CRP level is unknown. Further, obesity, a state of low-grade inflammation that influences cellular IL-1 functions may modify this association.Methods and resultsStudy participants (N = 3289), 48% blacks and 52% whites, had CRP level measurements at year 7 and year 15 examinations as part of the CARDIA study. Ten tag single nucleotide polymorphisms (SNPs) that characterize common IL1B gene variation were genotyped. In SNP analysis, no significant associations with either level or change in time CRP were observed after multiple testing adjustments. However, global ILIB gene variation was associated with year 7 to year 15 change in CRP (global nominal p = 0.004, multiple testing corrected p = 0.048) among obese blacks. Compared to the commonest haplotype, a common haplotype that includes the SNP rs1143642 was associated with greater increases in CRP from year 7 to year 15 among obese blacks and whites while another common haplotype that includes the SNP rs3917356 was associated with decreased change in CRP from year 7 to year 15 among obese blacks. The rare alleles of ILIB SNPs, SNP 7114 (rs1143642) and SNP 3298 (rs3917356), were associated with greater increases and decreases in CRP from year 7 to year 15 among blacks, respectively, compared to their common variants.ConclusionIL1B genetic variation may have a role in CRP level regulation and this association may be modified by obesity.     

Arterial endothelial function and wall thickness in familial hypercholesterolemia and familial combined hyperlipidemia and the effect of statins. A systematic review and meta-analysis

BackgroundTo evaluate the impact of familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) on arterial properties and the effects of statins.MethodsWe meta-analyzed 51 studies providing data for 4,057 FH patients and 732 FCH patients with random-effects models, meta-regression analysis and publication bias analysis. The main outcomes of interest were (1) brachial artery flow-mediated dilation (FMD), (2) intima-media thickness (IMT), and (3) change of IMT and FMD after treatment with statins.ResultsCompared to normolipidemic controls, FH patients had lower FMD [pooled mean difference (MD): ?5.31%, 95% CI ?7.09 to ?3.53%, P < 0.001] and higher carotid IMT (pooled MD: 0.12 mm, 95% CI 0.09–0.15 mm, P < 0.001) and femoral IMT (pooled MD: 0.35 mm, 95% CI 0.18–0.51 mm, P < 0.001). FCH patients had lower FMD and increased IMT (pooled MD: ?3.60%, 95% CI ?6.69 to ?0.50%, P = 0.023; and 0.06 mm, 95% CI 0.04–0.08 mm, P < 0.001, respectively). Total and LDL-cholesterol was a significant determinant of FMD and carotid IMT in FCH patients and of FMD and femoral IMT in FH patients. In FH patients, statins improved FMD (pooled MD of change: 5.39%, 95% CI 2.86–7.92%, P < 0.001) and decreased carotid IMT (pooled MD of change: ?0.025 mm, 95% CI ?0.042 to ?0.009 mm, P = 0.003). Changes of both FMD and IMT with statins correlated with the duration × treatment intensity product in FH patients (both P < 0.01). Additionally, statins improved FMD in FCH patients (pooled MD of change: 2.06%, 95% CI 0.43–3.69%, P = 0.013). No significant publication bias was detected.ConclusionArterial properties are impaired in subjects with FH or FCH. Statins improve arterial function and structure in FH patients in a treatment intensity-related manner.     

Polymorphism in exons CpG rich regions of the cyp17-II gene affecting its mRNA expression and reproductive endocrine levels in female Japanese flounder (Paralichthys olivaceus)

Cytochrome P450c17-II (cyp17-II) gene is an important factor affecting the growth, gonad differentiation and development, and other reproductive traits of fish. There are three CpG rich regions in the coding region of cyp17-II gene in Japanese flounder (Paralichthys olivaceus). The aim of this study was to understand whether mutations in exons of the cyp17-II gene occured at CpG sites, and mutations and methylation status of those CpG sites were involved in regulation of the expression level of cyp17-II gene and the reproductive endocrine of Japanese flounder. The results showed that three single nucleotide polymorphisms (SNPs) were identified. SNP1 [(c. G594A (p.Gly 188Arg)] located in exon 4 of L1 locus, and SNP2 (c.A939G) and SNP3 (c.C975T) of L2 locus located in CpG rich region of the exon 6 of cyp17-II gene. Furthermore, the A to G transition at 939 bp position added a new methylation site to the cyp17-II coding region. According to multiple-comparison analysis, two loci (L1 and L2) were significantly associated with serum testosterone (T) level (P < 0.05) and the expression of cyp17-II in ovary (P < 0.01). Intriguingly, individuals with GG genotype of L2 locus containing eight CpG methylation sites had significantly lower serum testosterone level and cyp17-II mRNA expression than those with AA genotype containing seven CpG methylation sites. Moreover, the CpG site was highly methylated (?77.8%) at 938 bp position of individuals with GG genotype of L2 locus. These implied that the mutation and methylation status of the coding region of cyp17-II could influence the gene expression and the reproductive endocrine levels in female Japanese flounder and L2 locus could be regarded as a candidate genetic or epigenetic marker for Japanese flounder breeding programs.     

High-resolution melting analyses for genetic variants in ARID5B and IKZF1 with childhood acute lymphoblastic leukemia susceptibility loci in Taiwan

BackgroundChildhood acute lymphoblastic leukemia (ALL), a heterogeneous disease that includes multiple subtypes is defined by cell lineage and chromosome anomalies. Previous genome-wide association studies have reported several ARID5B and IKZF1 single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. High-resolution melting (HRM) analysis is a rapid and convenient technique to detect SNPs; we thereby detected SNPs in ARID5B and IKZF1 genes.MethodsWe enrolled 79 pediatric ALL patients and 80 healthy controls. Polymorphic variants of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) were detected by HRM, and SNPs were analyzed for association with childhood ALL.ResultsThe distribution of genotype rs7073837 in ARID5B significantly differed between ALL and controls (P = 0.046), while those of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs10740055 and rs7089424) did not. We analyzed the association for SNPs with B lineage ALL to find rs7073837 in ARID5B, conferring a higher risk for B lineage ALL (odds ratio, OR = 1.70, 95% confidence interval, CI = 1.01–2.87, P = 0.049).ConclusionHRM is a practical method to detect SNPs in ARID5B and IKZF1 genes. We found that rs7073837 in ARID5B correlated with a risk for childhood B lineage ALL.     

Chronic kidney disease, atherosclerosis, and cognitive and physical function in the geriatric group of the National Health and Nutrition Survey 1999-2002

BackgroundThis study was designed to elucidate the relationship between chronic kidney disease (CKD), atherosclerotic complications, and the effects on functional performance in the elderly.MethodsA total of 2431 subjects aged 65 and above from the National Health and Nutrition Survey (NHANES) 1999–2002 were included to formulate a population-based observational study. A structural equation model (SEM) was constructed to validate the relationship between renal impairment, atherosclerotic complications, and cognitive and physical function.ResultsThe results showed that renal impairment was independently associated with physical and cognitive function after adjustment of potential confounding factors (B = ?0.12, p = 0.02). Renal impairment was positively associated with atherosclerotic complications (B = 0.26, p < 0.001), which was in turn negatively associated with functional performance (B = ?0.24, p < 0.001). Variance analysis showed that 57% of the differences in physical and cognitive function could be attributed to CKD, CKD-associated atherosclerosis, and other cardiovascular risk factors.ConclusionsCKD may have impacts on the cognitive and physical function either directly or indirectly via atherosclerotic complications.     

Illustrating the roles of C-reactive protein in the development of the metabolic syndrome in women--a cross-racial validation

Background and aimsThis study was designed to elucidate the role of C-reactive protein (CRP) as an inflammatory marker in the development of the metabolic syndrome (MS).Methods and resultsA total of 333 women without current medication attended an obesity-screening programme held in Yun-Lin, Taiwan. Anthropometric measurements were obtained; biochemical profiles, lipid profiles and high-sensitivity CRP (hsCRP) were measured. A structural equation model (SEM) was constructed to demonstrate that obesity might initiate the sequential pathway that leads to a pro-inflammatory state and other metabolic derangements. The results of SEM in the Taiwanese women showed that obesity was positively associated with elevated CRP (B = 0.69, p < 0.001). The pro-inflammatory state could result in insulin resistance (B = 0.57, p < 0.001), which in turn could lead to dyslipidaemia (B = 0.46, p < 0.01). The association between obesity and hypertension was positive and direct (B = 0.43, p < 0.01) without the intermediation of inflammation or insulin resistance. The implications could be reproduced when the same model was applied to the metabolic profiles of the Caucasian participants in the National Health and Nutrition Examination Survey 1999–2002.ConclusionOur study has demonstrated that obesity plays the central role in leading to hypertension and a pro-inflammatory state, insulin resistance and dyslipidaemia. The SEM has provided a comprehensive view to illustrate the complex interplay of the main components in the development of the MS, and this approach can be generalized to different populations.     

Effects of obesity, physical activity, and cardiorespiratory fitness on blood pressure, inflammation, and insulin resistance in the National Health and Nutrition Survey 1999–2002

Background and aimsThis study was designed to elucidate the effects of obesity, self-reported physical activity and cardiorespiratory fitness on blood pressure, inflammation, and insulin resistance.Methods and resultsData from 950 Caucasian subjects ranging in age from 19 to 49 years from the National Health and Nutrition Survey (NHANES), 1999–2002, were included to construct a population-based observational study. Cardiorespiratory fitness (VO₂ max) was predicted from a submaximal exercise stress test. Self-reported physical activity was measured by metabolic equivalent score transformed from a questionnaire. A structural equation model (SEM) was developed to examine the relationship between obesity, cardiorespiratory fitness, self-reported physical activity, and hypertension, inflammation, and insulin resistance. The model showed that obesity was positively linked to hypertension (B = 0.50, P < 0.001) and C-reactive protein (CRP; B = 0.15, p < 0.05), which in turn led to insulin resistance (B = 0.44, P < 0.05). Increased cardiorespiratory fitness was negatively associated with CRP (Γ = ?0.23, P < 0.01), but not correlated to hypertension after adjustment for potential confounding factors. No significant association was found between self-reported physical activity and hypertension, insulin resistance, and CRP.ConclusionObesity contributes to the development of hypertension, inflammation, and insulin resistance. Improved cardiorespiratory fitness might lead to clinical and biochemical improvement in insulin resistance by reducing the inflammatory state.     

Effects of soybean D-LeciVita product on serum lipids and fatty acid composition in type 2 diabetic patients with hyperlipidemia

Background and aimHyperlipidemia is one of the major risk factors of cardiovascular complication in diabetes. High intake of soy product has been suggested to prevent cardiovascular disease. The purpose of this study was to evaluate if dietary supplement of soybean D-LeciVita product, rich in polyunsaturated phospholipids (with 12% lecithin, 35% soy protein) affects serum lipids and serum and erythrocyte phospholipid fatty acid composition in type 2 diabetic patients.Methods and resultsForty-seven patients (men and post-menopausal women) with isolated hypertriglyceridemia (IHTG) and combined hyperlipidemia (CHL), aged 43–70 years, were given 15 g of D-LeciVita powder as a water suspension in a single evening dose during the follow-up period of 12 weeks. Patients kept their diabetic diet relatively constant. Treatment was associated with a significant (p ≤ 0.001) decrease in serum total cholesterol and triglyceride levels by 12% and 22%, respectively. LDL-cholesterol decreased by 16% and HDL-cholesterol increased by 11% (p ≤ 0.001). Our study shows a 27% decrease in LDL-cholesterol (p ≤ 0.001) and a 12% increase in HDL-cholesterol (p ≤ 0.01) in CHL type 2 diabetic patients. Triglyceride levels decreased in type 2 diabetic patients with IHTG and CHL by 29% and 13%, respectively (p ≤ 0.01 and p ≤ 0.05). Our results show decrease in SFA and increase in n-6 and n-3 PUFA in serum and erythrocyte phospholipids. SFA decreased and n-3 PUFA increased in serum and erythrocyte phospholipids in IHTG and CHL groups.ConclusionThe present study indicated that added to a regular diet, soybean D-LeciVita product (combination of soy protein and lecithin) is associated not only with lipid-lowering effects but also with more favorable serum phospholipids fatty acid profile in type 2 diabetic patients with hyperlipidemia.     

Single polymorphism nucleotide rs1333049 on chromosome 9p21 is associated with carotid plaques but not with common carotid intima-media thickness in older adults. A combined analysis of the Three-City and the EVA studies

ObjectivesTo address the relationship of rs1333049, the 9p21 variant showing the strongest association with coronary heart disease (CHD), with carotid plaques and plaque-free common carotid artery intima-media thickness (CCA-IMT) in older adults from 2 French population-based cohorts.MethodsWe genotyped for rs1333049, 4097 CHD-free participants including 3191 aged 65–86 years from the Three-City (3C) Study and 906 aged 59–71 years from the Vascular Aging Study (EVA). Plaque-free mean CCA-IMT and the presence of carotid plaques were assessed.ResultsIn multivariate analysis, each C allele copy of rs1333049 was associated with baseline carotid plaques (odds ratio (OR) = 1.24; 95% confidence interval (CI) = 1.13–1.36; p < 0.001) but not with baseline CCA-IMT (p = 0.19). Among the EVA participants, the C allele was associated with 4-year plaques progression (p = 0.04) but not with CCA-IMT progression.ConclusionThe chromosome 9p21 locus might influence CHD risk through carotid plaques development.     

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.     

Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece

ObjectiveTo determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether this GRS also predicts incident stroke.MethodsGenotypes at nine CHD-relevant SNPs were determined in 494 cases of incident CHD, 320 cases of incident stroke and 1345 unaffected controls drawn from the population-based Greek component of the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. An additive GRS was calculated for each study participant by adding one unit for the presence of each high-risk allele multiplied by the estimated effect size of that allele in the discovery samples. Statistical analysis was performed using logistic regression.ResultsThe GRS was significantly associated with the incidence of CHD where the odds of CHD incidence in the highest quintile of the GRS were 1.74 times higher (95% confidence interval [CI] = 1.25–2.43, p for trend = 0.0004), compared to the lowest quintile. With respect to stroke, a weaker and non-significant positive association with GRS was apparent as the odds of stroke incidence in the highest quintile of the GRS were 1.36 times higher (95% CI = 0.90–2.06, p for trend = 0.188), compared to the lowest quintile.ConclusionA GRS relying on nine documented “CHD-specific” SNPs is significantly predictive of CHD but it was not found to be statistically significantly associated with incident stroke.     

Down regulation of CD11b and CD18 expression in children with hypercholesterolemia: a preliminary report

Background and aimCell adhesion molecules play an important role in the development of atherosclerosis mediating the attachment of monocytes to the endothelium. The aim of our study was to assess the cell surface expression of CD11b/CD18 integrin on the phagocytes of children affected by hypercholesterolemia.Methods and ResultsTwenty-six children with hypercholesterolemia (15 males, mean age 8.3, range 2–18) with a family history of early cardiovascular disease, as well as 26 children with normocholesterolemia matched for gender and age (15 males, mean age 8.3) were studied. Cell surface expression of CD11b/CD18 on peripheral blood mononuclear cells (PBMC) were analyzed by flow cytometry. The geometric mean percentages of CD11b and CD18 expression were significantly lower in the hypercholesterolemic group [52 (95% confidence intervals, 40–68) and 88 (84–93)] than in the control group [87 (83–91), P < 0.0001 and 93 (89–96), P < 0.05], respectively. After correction for age, gender, and pubertal status, CD11b cell surface expression on PBMC was inversely and independently correlated with total cholesterol concentrations (r = −0.395; P < 0.01) and LDL (r = −0.307; P < 0.05), as well as with triglycerides (r = −0.406; P < 0.01).ConclusionsIn children with hypercholesterolemia, cell surface expression of CD11b and CD18 on PBMC was significantly decreased. Follow-up studies are necessary to determine the clinical implications of these findings in the context of the natural course and progression of atherosclerosis in high risk children.     

Polymorphisms of LTA, LGALS2, and PSMA6 genes and coronary atherosclerosis: a pathological study of 1503 consecutive autopsy cases

ObjectiveRecent genome-wide association studies have identified polymorphisms of lymphotoxin-α (LTA), galectin-2 (LGALS2), and proteasome subunit a type 6 (PSMA6) genes as genetic risk factors for myocardial infarction (MI). However, their effects on coronary atherosclerosis, an intermediate phenotype of MI, remain largely unknown.MethodsWe investigated the correlation between polymorphisms of the LTA, LGALS2, and PSMA6 genes and the severity of pathological coronary stenosis index (CSI) and MI in 1503 consecutive autopsy cases of Japanese elderly patients.ResultsThe polymorphisms LTA rs1041981 and LGALS2 rs7291467 were associated with CSI with odds ratios of 1.54 (95% CI, 1.17–2.01; AA + CA over CC) and 1.62 (95% CI, 1.11–2.37; TT over CC + CT), respectively. PSMA6 rs1048990 was not associated with CSI. None of the SNPs was associated with MI in our sample.ConclusionOur findings indicate that the LTA and LGALS2 polymorphisms affect the subclinical phenotype of the coronary artery, which predisposes to the incidence of MI.     

Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels

Background and purposeThe endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension.Experimental approachET-1 levels were quantified by ELISA. PreproET-1, ET_A and ET_B receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ET_A (A-147627), ET_B (A-192621) and dual ET_A/B (bosentan) receptor antagonists.Key resultsIn rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced (p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ET_B receptor (p < 0.001) gene expressions were reduced, as were ET_B receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ET_A or the ET_B receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ET_A receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01).Conclusions and implicationsThe effectiveness of both selective ET_A and dual ET_A/B receptor antagonists is markedly increased in PAH. Down-regulation of pulmonary resistance arteries ET_B receptor may contribute to this finding.     

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.     

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.