9p21.3 coronary artery disease risk locus and interferon alpha 21: Association study in an Asian Indian population

IntroductionType I Interferons (INFαs and INF β) are known to be proinflammatory cytokines that promote atherosclerosis. IFNA21 is a member of alpha Interferon gene cluster on short arm of chromosome 9. We analyzed the potential link between 9p21 coronary artery disease (CAD) risk locus and IFNA21.Objectivesa) study of association between serum IFNA21 levels and 14 demographic/clinical variables, including age, gender, diabetes, hypertension, and duration of CAD, b) study of association between high serum IFNA21 levels and 30 9p21 SNP genotypes.MethodsTo estimate serum circulating levels of IFNA21, we performed sandwich ELISA in 184 controls and 167 CAD cases. The IFNA21 levels could be classified into two broad classes: a) Low-level group: ≤15.6 pg/ml b) High-level group: >15.6 pg/ml. We also performed SNP genotyping for 30 SNPs at 9p21 locus in all study subjects using Sequenom MassARRAY technology. Statistical software SPSS (Version 21) was used to analyze the data obtained.ResultsOur analysis indicates that there could be an association of high IFNA21 levels with variables – gender, age, and duration of CAD in the study population. SNPs rs10757272 (TT), rs10757274 (GG), rs10757283 (TT), rs1333045 (CC), rs1333048 (CC), rs1333049 (CC), and rs4977574 (GG) showed significant risk association with high-level IFNA21 group.ConclusionsIFNA21 may be involved in inflammatory processes in an age-dependent manner and in progression of CAD. This IFNA21-mediated mechanism may be more active in females. Several 9p21 SNPs may modulate inflammatory processes mediated by IFNA21 and may, therefore, contribute to pathophysiology of CAD.     

Codon 104 variation of p53 gene provides adaptive apoptotic responses to extreme environments in mammals of the Tibet plateau

Mutational changes in p53 correlate well with tumorigenesis. Remarkably, however, relatively little is known about the role that p53 variations may play in environmental adaptation. Here we report that codon asparagine-104 (104N) and glutamic acid-104 (104E), respectively, of the p53 gene in the wild zokor (Myospalax baileyi) and root vole (Microtus oeconomus) are adaptively variable, meeting the environmental stresses of the Tibetan plateau. They differ from serine-104 (104S) seen in other rodents, including the lowland subterranean zokor Myospalax cansus, and from serine 106 (106S) in humans. Based on site-directed mutational analysis in human cell lines, the codon 104N variation in M. baileyi is responsible for the adaptive balance of the transactivation of apoptotic genes under hypoxia, cold, and acidic stresses. The 104E p53 variant in Microtus oeconomus suppresses apoptotic gene transactivation and cell apoptosis. Neither 104N nor 104E affects the cell-cycle genes. We propose that these variations in p53 codon 104 are an outcome of environmental adaptation and evolutionary selection that enhance cellular strategies for surviving the environmental stresses of hypoxia and cold (in M. baileyi and M. oeconomus) and hypercapnia (in M. baileyi) in the stressful environments of the Qinghai-Tibet plateau.The regulatory mechanisms of p53 mutation related to tumorigenesis have been widely studied and elucidated (1, 2). Notably, however, p53 evolution and adaptation to environmental stresses have not attracted as much attention. Current studies show that p53 is a master sensor and regulator in response to various stressors, such as DNA damage and hypoxia (3–6). Activation of p53 by stresses results in cell-cycle arrest, DNA repair, senescence, or apoptosis in which a series of p53 target genes are involved to maintain genomic integrity (2). The p53 variations associated with environmental stresses have been described in the Mexican salamander axolotl Ambystoma mexicanum and the Israeli blind subterranean mole rat (Spalax judaei; hereafter, S.j.) (7–9).For animals existing on high plateaus, hypoxia and cold serve as strong environmental selective pressures generating adaptive complexes to cope with these stresses. Animals that have evolved on plateaus adopt various strategies involving multiple variations to regulate a series of genes (3, 7). The zokor (Myospalax baileyi, Thomas, 1911; hereafter M.b.) and root vole (Microtus oeconomus, Pallas, 1776; hereafter M.o.) are the dominant native mammals living on the alpine meadow of the Qinghai-Tibet Plateau of China at altitudes of 3,000–4,500 m (equivalent to 11.0–13.0% O₂ at sea level). M.b. is genetically close to Myospalax cansus (Lyon, 1907; hereafter, M.c.), which lives in subterranean burrows at a lower altitude of about 800 m in the lowland of western China. M.b. and M.c. spend their entire life cycle at 70–250 cm underground with significantly low O₂ and high CO₂ levels in their burrows (10). Since the collision of the Indian and the Eurasian plates during the Tertiary (40–50 Mya) formed the Tibet plateau (11), small mammals living in this region have been geographically and ecologically isolated from other species and have adapted to the stressful plateau environment, contributing to the East Asian biodiversity (12–15). Our previous work demonstrated that mammals of the Qinghai-Tibet plateau are well adapted to the hypoxic environment (16–19), with particular expression patterns of HIF-1α and IGF-I and its binding protein (IGFBP-1), which mediate protection against hypoxia (20–23). Cells exposed to hypoxia succumb to p53-dependent apoptosis (24–27); thus mutations in p53 are required for cell survival under selective pressures. We examined the hypothesis that plateau mammals are adapted to this environment with p53 alterations linked to hypoxia, hypercapnia (high CO₂), and cold.Here we report that the variations of p53 codon 104 in three rodent species during long-term evolution and adaptation at the Qinghai-Tibet plateau reflect diverse survival strategies. The present study provides insights into the contribution of p53 variations to native mammals’ adaptation to the diverse and extreme environmental stresses of their habitats.     

The longevity effect of cranberry extract in Caenorhabditis elegans is modulated by daf-16 and osr-1

Nutraceuticals are known to have numerous health and disease preventing properties. Recent studies suggest that extracts containing cranberry may have anti-aging benefits. However, little is known about whether and how cranberry by itself promotes longevity and healthspan in any organism. Here we examined the effect of a cranberry only extract on lifespan and healthspan in Caenorhabditis elegans. Supplementation of the diet with cranberry extract (CBE) increased the lifespan in C. elegans in a concentration-dependent manner. Cranberry also increased tolerance of C. elegans to heat shock, but not to oxidative stress or ultraviolet irradiation. In addition, we tested the effect of cranberry on brood size and motility and found that cranberry did not influence these behaviors. Our mechanistic studies indicated that lifespan extension induced by CBE requires the insulin/IGF signaling pathway and DAF-16. We also found that cranberry promotes longevity through osmotic stress resistant-1 (OSR-1) and one of its downstream effectors, UNC-43, but not through SEK-1, a component of the p38 MAP kinase pathway. However, SIR-2.1 and JNK signaling pathways are not required for cranberry to promote longevity. Our findings suggest that cranberry supplementation confers increased longevity and stress resistance in C. elegans through pathways modulated by daf-16 and osr-1. This study reveals the anti-aging property of widely consumed cranberry and elucidates the underpinning mechanisms.     

The APOB polymorphism rs1801701 A/G (p.R3638Q) is an independent risk factor for early-onset coronary artery disease: Data from a Spanish cohort

Background and aimsApoliprotein B (ApoB) has been associated with hypercholesterolemia and ischemic coronary disease. This study was aimed to determine the effect of two APOB gene variants in the risk of developing early-onset coronary artery disease (EO-CAD) in a Spanish population. The association of these polymorphisms with hypercholesterolemia was also analysed.Methods and resultsThe study involved a total of 889 healthy population controls (397 male) and 790 EO-CAD cases (636 male; EO-CAD was defined as male <60 years and women <65 years). All the patients had at least one vessel with angiography documented atherosclerotic lesion. Patients and controls were genotyped for the APOB variants rs1801701 A/G (p.R3638Q) and rs1367117 C/T (p.T98I). Allele and genotype frequencies were compared between the groups (patients vs. controls, hyper-vs. normo-cholesterolemia) by logistic regression.The rs1801701 was significantly associated with EO-CAD in male (OR = 1.44, 95%CI = 1.05–1.99) and female (OR = 2.22, 95%CI = 1.58–3.14). This SNP was significantly associated with hypercholesterolemia in female, with a trend in male. The association with EO-CAD was independent of hypercholesterolemia (multiple logistic regression).ConclusionA common APOB polymorphism (rs1801701) was an independent risk factor for EO-CAD in our population. The risk-effect was more significant in female than in male.     

Alagille syndrome and Wilson disease in siblings: a diagnostic conundrum

The authors describe two siblings, each with a different, rare genetic condition that affects liver function. The index case, the 18-year-old asymptomatic brother of a young man recently diagnosed with Wilson disease, presented for Wilson disease screening and was also found to have abnormal liver function suggestive of cholestasis. However, ceruloplasmin level, 24 h urine copper concentration and liver synthetic function were normal. Further hepatic investigations and genetic mutation analysis were performed, ultimately leading to a diagnosis of Alagille syndrome. He was treated with ursodiol, which resulted in normalization of his liver function tests. Subsequently, he was found to be a carrier for a mutation in the Wilson disease gene, ATP7B. In the present report, the potential implications of being a heterozygote for Wilson disease in the context of Alagille syndrome are discussed. Also stressed is that care must be exercised by the clinician when diagnosing family members who may present with two different disorders closely mimicking one another.     

Genetic variants of chromosome 9p21.3 region associated with coronary artery disease and premature coronary artery disease in an Asian Indian population

IntroductionAsian Indians have a propensity for premature, severe, and diffuse coronary artery disease (CAD). Several single-nucleotide polymorphisms (SNPs) in the ‘core CAD’ region of the chromosomal region 9p21.3 are known to be strongly associated with CAD.ObjectivesWe aimed to study SNPs in the 9p21.3 region associated with CAD and premature CAD and identify their association with demographic and clinical characteristics in an Asian Indian population.MethodsSNP genotyping was performed for 30 SNPs of the 9p21.3 region using MassARRAY^® technology. Along with demographic and SNP data analysis, we also performed multivariate logistic regression analysis and multifactor dimensionality reduction analysis to study SNP–SNP and SNP–demographic/clinical variable interactions.ResultsOur results suggest that females are at a higher risk of premature CAD. We found that SNPs rs1333045 (CC), rs16905599 (AA), rs2383206 (GG), rs2383208 (AG), and rs4977574 (GG) were significantly associated with premature CAD. When adjusted for covariates/confounders, we found that rs2383206 showed the strongest risk association with CAD followed by rs16905599 and rs2383208. Further, SNPs rs1333049 (CC) and rs4977574 (GG) were found to be exclusively associated with premature CAD cases, suggesting their potential as genetic markers for premature CAD in the local population. Upon gender-based stratification, it was found that rs10757272 (TT and TC) is significantly associated with eightfold to ninefold CAD risk specifically among females. SNP rs7865618 (GG) is significantly associated with more than 2.5-fold CAD risk specifically among males.ConclusionOur study suggests that SNPs at the 9p21 risk locus may be used to generate a reliable genetic risk score along with markers at other loci.     

CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There w     

The H19 locus acts in vivo as a tumor suppressor

The H19 locus belongs to a cluster of imprinted genes that is linked to the human Beckwith-Wiedemann syndrome. The expression of H19 and its closely associated IGF2 gene is frequently deregulated in some human tumors, such as Wilms' tumors. In these cases, biallelic IGF2 expression and lack of expression of H19 are associated with hypermethylation of the imprinting center of this locus. These observations and others have suggested a potential tumor suppressor effect of the H19 locus. Some studies have also suggested that H19 is an oncogene, based on tissue culture systems. We show, using in vivo murine models of tumorigenesis, that the H19 locus controls the size of experimental teratocarcinomas, the number of polyps in the Apc murine model of colorectal cancer and the timing of appearance of SV40-induced hepatocarcinomas. The H19 locus thus clearly displays a tumor suppressor effect in mice.     

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Dichloroacetic acid (DCA), a water disinfection by-product, has attained emphasis due to its prospect for clinical use against different diseases including cancer along with negative impact on organisms. However, these reports are based on the toxicological as well clinical data using comparatively higher concentrations of DCA without much of environmental relevance. Here, we evaluate cellular as well as organismal effects of DCA at environmentally and mild clinically relevant concentrations (0.02–20.0 μg/ml) using an established model organism, Drosophila melanogaster. Flies were fed on food mixed with test concentrations of DCA for 12–48 h to examine the induction of reactive oxygen species (ROS) generation, oxidative stress (OS), heat shock genes (hsps) and cell death along with organismal responses. We also examined locomotor performance, ROS generation, glutathione (GSH) depletion, expression of GSH-synthesizing genes (gclc and gclm), and hsps at different days (0, 10, 20, 30, 40, 50) of the age in flies after prolonged DCA exposure. We observed mild OS and induction of antioxidant defense system in 20.0 μg/ml DCA-exposed organism after 24 h. After prolonged exposure to DCA, exposed organism exhibited improved survival, elevated expression of hsp27, gclc, and gclm concomitant with lower ROS generation and GSH depletion and improved locomotor performance. Conversely, hsp27 knockdown flies exhibited reversal of the above end points. The study provides evidence for the attenuation of cellular and functional decline in aged Drosophila after prolonged DCA exposure and the effect of hsp27 modulation which further incites studies towards the therapeutic application of DCA.     

Single nucleotide polymorphism in RECQL and survival in resectable pancreatic adenocarcinoma

Background:

RECQL is a DNA helicase involved in DNA mismatch repair. The RECQL polymorphism, 3′ untranslated region (UTR) A159C, was previously associated with overall survival of patients with resectable pancreatic adenocarcinoma treated with neoadjuvant chemoradiation. In the present study, we examined RECQL for somatic mutations and other polymorphisms and compared these findings with the outcome in patients who received adjuvant or neoadjuvant chemoradiation. We hypothesized that RECQL (i) would be mutated in cancer, (ii) would have polymorphisms linked to the 3′UTR A159C and that either or both events would affect function. We also hypothesized that (iii) these changes would be associated with survival in both cohorts of patients.

Material and methods:

We sequenced RECQL''s 15 exons and surrounding sequences in paired blood and tumour DNA of 39 patients. The 3′UTR A159C genotype was determined in blood DNA samples from 176 patients with resectable pancreatic adenocarcinoma treated with adjuvant (53) or neoadjuvant (123) chemoradiation. Survival was calculated using the Kaplan–Meier method, with log rank comparisons between groups. The relative impact of genotype on time to overall survival was performed using the Cox proportional hazards model.

Results:

Somatic mutations were found in UTRs and intronic regions but not in exonic coding regions of the RECQL gene. Two single nucleotide polymorphisms (SNPs), located in introns 2 and 11, were found to be part of the same haplotype block as the RECQL A159C SNP and showed a similar association with overall survival. No short-term difference in survival between treatment strategies was found. We identified a subgroup of patients responsive to neoadjuvant therapy in which the 159 A allele conferred strikingly improved long-term survival.

Discussion:

The RECQL 3′UTR A159C SNP is not linked with other functional SNPs within RECQL but may function as a site for regulatory molecules. The mechanism of action needs to be clarified further.     

Acute stress modulates genotype effects on amygdala processing in humans

Probing gene–environment interactions that affect neural processing is crucial for understanding individual differences in behavior and disease vulnerability. Here, we tested whether the current environmental context, which affects the acute brain state, modulates genotype effects on brain function in humans. We manipulated the context by inducing acute psychological stress, which increases noradrenergic activity, and probed its effect on tonic activity and phasic responses in the amygdala using two MRI techniques: conventional blood oxygen level–dependent functional MRI and arterial spin labeling. We showed that only carriers of a common functional deletion in ADRA2B, the gene coding for the α2b-adrenoreceptor, displayed increased phasic amygdala responses under stress. Tonic activity, reflecting the perfusion of the amygdala, increased independently of genotype after stress induction. Thus, when tonic activity was heightened by stress, only deletion carriers showed increased amygdala responses. Our results demonstrate that genetic effects on brain operations can be state dependent, such that they only become apparent under specific, often environmentally controlled, conditions.     

Interactions between pork consumption,CagA status and IL-1B-31 genotypes in gastric cancer

AIM: To explore potential interactions among Helicobacter pylori (H. pylori), CagA status, interleukin (IL)-1B-31 genotypes, and non-cardiac gastric cancer (GC) risk.METHODS: A case-control study of non-cardia GC was performed at 3 hospitals located in Xi’an, China, between September 2008 and July 2010. We included 171 patients with histologically diagnosed primary non-cardia GC and 367 population based controls (matched by sex, age and city of residence). A standardized questionnaire was used to obtain information regarding potential risk factors, including pork consumption. H. pylori CagA status was assessed by enzyme-linked immunosorbent assay, and IL-1B-31 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Multivariate unconditional logistic regression was used to explore potential interactions among the factors.RESULTS: The CagA appeared to confer an increased risk of GC (OR = 1.81, 95%CI: 1.25-2.61). The main associations with IL-1B-31C allele here were 0.98 (95%CI: 0.59-1.63) for CC vs TT and 0.99 (95%CI: 0.64-1.51) for C Carriers vs TT. However, no associations were observed for CagA or IL-1B-31 genotype status among subjects who reported low pork consumption (P for interaction = 0.11). In contrast, high pork consumption and IL-1B-31C genotypes appeared to synergistically increase GC risk (P for interaction = 0.048) after adjusting for confounding factors, particularly among subjects with CagA (OR = 3.07, 95%CI: 1.17-10.79). We did not observe effect modification of pork consumption by H. pylori CagA status, or between H. pylori CagA status and IL-1B-31 genotypes after adjustment for pork consumption and other factors.CONCLUSION: These interaction relationships among CagA, IL-1B-31 and pork consumption may have implications for development of the preventive strategies for the early detection of non-cardiac GC.     

Understanding the pathophysiological mechanisms in the pediatric non-alcoholic fatty liver disease: The role of genetics

Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resistance, accompanying obesity, that leads to liver steatosis increasing the absolute non esterified fatty acids uptake in the liver and the esterification to form triacylglycerol. The oxidative stress is involved in the second hit leading to the progression to nonalcoholic steatohepatitis(NASH) because of its harmful action on steatosic hepatocytes. However, at the present time, the two hits hypothesis needs to be updated because of the discover of genetic polymorphisms involved both in the liver fat accumulation and progression to NASH that make more intriguing understanding the NAFLD pathophysiological mechanisms. In this editorial, we want to underline the role of PNPLA3 I148 M, GPR120 R270 H and TM6SF2 E167 K in the pediatric NAFLD development because they add new pieces to the comprehension of the NAFLD pathophysiological puzzle. The PNPLA3 I148 M polymorphism encodes for an abnormal protein which predisposes to intrahepatic triglycerides accumulation both for a loss-of-function of its triglyceride hydrolase activity and for a gain-of-function of its lipogenic activity.Therefore, it is involved in the first hit, such as TM6SF2 E167 K polymorphisms that lead to intrahepatic fat accumulation through a reduced very low density lipoprotein secretion. On the other hand, the GPR120 R270 H variant, reducing the anti-inflammatory action of the GPR120 receptor expressed by Kuppfer cells, is involved in the second hit leading to the liver injury.     

Differences in antimicrobial susceptibility in Escherichia coli from Canadian intensive care units based on regional and demographic variables

OBJECTIVES

Escherichia coli resistance to antimicrobials varies according to many factors. E coli isolates from Canadian intensive care units (ICUs) were studied to determine the distribution and demographics associated with antimicrobial resistance in this population.

METHODS

The Canadian National Intensive Care Unit (CAN-ICU) study characterized pathogens isolated in Canadian ICUs from July 2005 to June 2006. E coli susceptibility to 10 antimicrobials was determined and a multivariate logistic regression model was designed to determine whether region, sex, isolation from a sterile site and age (younger than 30 years) were significantly associated with susceptibility to the tested antimicrobials, to multidrug resistance or pan-susceptibility.

RESULTS

Four hundred ninety-three E coli isolates, representing 12.6% of all isolates collected in the CAN-ICU study were examined. Susceptibilities were highest for meropenem and tigecycline (100%), cefepime (98.2%), piperacillin-tazobactam (97.0%), ceftriaxone (93.1%) and gentamicin (92.3%), and lowest for cefazolin (76.7%), trimethoprim-sulfamethoxazole (75.7%) and the fluoroquinolones (ciprofloxacin, 78.3%; and levofloxacin, 78.9%). In the multivariate model, fluoroquinolone resistance was lowest in patients younger than 30 years of age. Cefazolin and ceftriaxone susceptibility was lowest in Nova Scotia. Susceptibility to all tested antimicrobials was lowest in Nova Scotia and British Columbia. Isolation from a sterile site was associated with trimethoprim-sulfamethoxazole, piperacillin-tazobactam and multidrug resistance.

CONCLUSIONS

E coli antimicrobial susceptibility varies across Canadian ICUs. Age, region and site of infection should be considered when prescribing empirical antimicrobial therapy. For infections caused by or suspected to be caused by E coli, fluoroquinolones, cefazolin and sulfonamides should be avoided due to low susceptibilities. Local antimicrobial prescribing practices, in particular the liberal use of fluoroquinolones and cephalosporins, and inadequate infection control practices are likely reducing susceptibility rates.     

Association between inherited monogenic liver disorders and chronic hepatitis C简

AIM: To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C.METHODS: This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing.RESULTS: The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087).CONCLUSION: Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail.     

24-hour antiplatelet effect of aspirin in patients with previous definite stent thrombosis

Objective

Once-daily aspirin is standard treatment, but recent studies point towards increased platelet function at the end of the dosing interval. Stent thrombosis (ST) has been linked with reduced antiplatelet effect of aspirin, so we investigated if platelet inhibition by aspirin declines through 24 h in patients with previous definite ST. Furthermore, we explored whether increased levels of immature platelets and thrombopoietin are associated with a particularly rapid recovery of platelet function.

Methods

This case–control study included 50 patients with previous definite ST matched with 100 patients with stable coronary artery disease and 50 healthy volunteers. All participants were on aspirin 75 mg/day mono antiplatelet therapy. Platelet aggregation was measured 1 and 24 h after aspirin intake using platelet aggregometry (Multiplate^® Analyzer). Cyclooxygenase-1 activity, platelet activation, immature platelets, and thrombopoietin were measured.

Results

Platelet aggregation increased by 109 ± 150 (arachidonic acid) and 47 ± 155 (collagen) aggregation units per minute from 1 to 24 h after aspirin intake (p-values < 0.0001) with corresponding increases in thromboxane B₂ (5.6 ± 5.1 ng/ml, p < 0.0001) and soluble P-selectin (6.2 ± 15.5 ng/ml, p < 0.0001). Platelet aggregation increased equally in all groups, but patients with previous ST displayed the highest levels of platelet aggregation at 24 h (p-values ≤ 0.05) and the highest levels of immature platelets (p < 0.01) and thrombopoietin (p < 0.0001).

Conclusions

Platelet inhibition declined significantly during the 24-hour dosing interval in aspirin-treated patients with previous definite ST or stable coronary artery disease and in healthy individuals. Increased levels of immature platelets and thrombopoietin were observed in patients with previous definite ST.     

Role of rs1466535 low density lipoprotein receptor-related protein 1 (LRP1) gene polymorphism in carotid artery disease

Objective

An association between rs1466535 low density lipoprotein receptor-related protein 1 (LRP1) gene polymorphism and abdominal aortic aneurysm (AAA) was recently demonstrated. It has not yet been defined if this association is specific for AAA or related to atherosclerosis per se. Therefore, we aimed to evaluate the role of the rs1466535 polymorphism in conferring genetic susceptibility for carotid artery stenosis (CAS).

Methods

The rs1466535 polymorphism was evaluated in n = 814 patients with CAS and n = 814 subjects without evidence of carotid atherosclerosis by TaqMan technology.

Results

The percentage of T allele rs1466535 carriers was significantly higher in CAS patients (49.3%) than in controls (43.9%, p = 0.032). At the multiple logistic regression analysis, the allele T carrier status did not remain a significant determinant of CAS.

Conclusions

The rs1466535 LRP1 polymorphism is not a significant and independent risk factor for CAS. Our result suggests this polymorphism in the LRP1 gene is not associated with atherosclerosis in general as it is not associated with CAS (this study), whereas it is strictly associated with AAA (our previous paper).