The association of myeloperoxidase promoter polymorphism with carotid atherosclerosis is abolished in patients with type 2 diabetes

ObjectivesType 2 diabetes mellitus (DM) enhances the development of atherosclerosis and reduces the activity of the oxidative myeloperoxidase (MPO) enzyme. MPO gene has a functional promoter polymorphism ?463G/A which leads to high- (GG) and low-expression (AG, AA) genotypes.Design and methodsWe studied the association of MPO polymorphism with carotid artery intima-media thickness (IMT) in 198 randomly selected Finnish men of Caucasian origin, 161 non-diabetics and 37 with type 2 DM. Their carotid IMT was measured by high-resolution ultrasonography, and the overall mean IMT value was calculated. MPO genotypes were determined by the PCR-RFLP method.ResultsWe found significant MPO genotype-by-study-group (control/DM) interactions with the overall mean IMT and internal carotid IMT (p = 0.05 and p = 0.04, respectively). Among non-diabetic subjects, the overall carotid IMT was 7.3% higher in subjects with the low-activity genotype when compared to the high-activity (G/G) group. The results remained significant after adjustment for total cholesterol and smoking (p = 0.015). No similar genotypic association was found for the subjects with type 2 DM.ConclusionsThis data suggests that in subjects with normal glucose metabolism, MPO gene variation may modify the carotid artery IMT.     

Association between the -2518G/A polymorphism in the monocyte chemoattractant protein-1 (MCP-1) gene and hypertension in Tunisian patients

ObjectivesMonocyte chemoattractant protein-1 (MCP-1:CCL2) has been demonstrated to be involved in the pathophysiology of atherosclerosis and hypertension. This study was aimed to investigate whether the single nucleotide polymorphism (SNP) at ?2518 of the MCP-1 gene promoter region is associated to hypertension in a sample of Tunisian population.Design and methodsA total of 290 Tunisian patients with hypertension and 390 normotensive controls were included in the study. The SNP of the MCP-1 gene was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.ResultsA significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with hypertension had a frequency of 7.2% for the GG genotype, 35.2% for the AG genotype and 57.6% for the AA genotype. Normotensive subjects had a frequency of 3.6% for the GG genotype, 29.7% for the AG genotype and 66.7% for the AA genotype (χ² = 8.02, p = 0.01). The hypertension patient group showed a significant higher frequency of the G allele compared to the controls [0.24 vs. 0.18; OR (95%CI), 1.46 (1.11–1.91), p = 0.004]. The association between the ?2518 G/A polymorphism of MCP-1 gene and hypertension remained significant after adjustment for other well-established cardiovascular risk factors.ConclusionThe present study showed a significant and independent association between the ?2518G/A polymorphism of the MCP-1 gene (presence of G allele) and hypertension in the Tunisian population.     

Matrix metalloproteinase (MMP)-9 genotypes and haplotypes in preeclampsia and gestational hypertension

BackgroundAbnormal production of matrix metalloproteinases (MMPs), especially MMP-9, may play a role in hypertensive disorders of pregnancy. These alterations may result from functional genetic polymorphisms in the promoter region of MMP-9 gene, which are known to change MMP-9 expression. We examined whether 2 MMP-9 polymorphisms (C^? 1562 T and (CA)n) and haplotypes are associated with preeclampsia and/or gestational hypertension.MethodsWe studied 476 pregnant women: 176 healthy pregnant (HP), 146 pregnant with gestational hypertension (GH), and 154 pregnant with preeclampsia (PE). Genomic DNA was extracted from whole blood and genotypes for C^? 1562 T and (CA)n polymorphisms were determined by PCR-RFLP. Haplotype frequencies were inferred using the PHASE ver. 2.1 program.ResultsFor the g.?90(CA)13–25 polymorphism, no significant differences were found in genotype and allele distributions when PE or GH groups were compared with HP group. However, the CT genotype and T allele for g.?1562C > T polymorphism were more commonly found in GH subjects compared with the HP group (both P < 0.05). Conversely, we found no differences in genotypes or allele distributions for the g.?1562C > T polymorphism when the PE and the HP groups were compared. No significant differences were found in overall distributions of haplotype frequencies when the GH or the PE group was compared with the HP group.ConclusionsThe C^? 1562 T polymorphism in MMP-9 gene is associated with gestational hypertension, but not with preeclampsia. These findings may help to explain the higher plasma MMP-9 levels previously reported in GH compared with HP.     

Matrix metalloproteinase-1 promoter genotypes and haplotypes are associated with carotid plaque presence

ObjectivesMatrix metalloproteinase (MMP)-1 degrades fibrillar collagens suggesting important role in vascular remodeling. Data about MMP-1 promoter polymorphisms and carotid atherosclerosis (CA) are scarce. The aim of this study was to evaluate association of MMP-1 genotypes/haplotypes with carotid plaque (CP) presence in Serbian population.Design and methodsStudy enrolled a total of 702 participants: 274 controls and 428 consecutive patients with CA who underwent carotid endarterectomy. MMP-1 polymorphisms ? 1607 1G/2G, ? 519 A/G and ? 340 T/C were genotyped by PCR and RFLP methods.ResultsIndividuals carrying MMP-1 ? 1607 2G allele had significantly increased allele dose-dependent risk for CP presence (1G1G vs. 1G2G vs. 2G2G; OR = 1; OR = 1.87 95% CI 1.29–2.07; OR = 3.49 95% CI 1.67–7.30, p = 0.0009, respectively). Compared to the referent haplotype 2G_? 1607-T_? 340-A_? 519, the haplotypes 1G_? 1607-T_? 340-A_? 519, 1G_? 1607-T_? 340-G_? 519 and 2G_? 1607-C_? 340-A_? 519 had statistically significant protective effect on CP presence (OR = 0.41, 95% CI 0.29–0.81, p = 0.01; OR = 0.56, 95% CI 0.44–0.89, p = 0.01; OR = 0.43, 95% CI 0.27–0.86, p = 0.02, respectively).ConclusionsMMP-1 ? 1607 G/2G polymorphism solely and specific haplotypes of three analyzed promoter polymorphisms are significantly and independently associated with occurrence of CP. Replication studies in other populations are needed.     

Synergistic effects of the polymorphisms in the PAI-1 and IL-6 genes with smoking in determining their associated risk with coronary artery disease

ObjectivesTo assess the relationship between IL-6 and PAI-1 polymorphisms and coronary artery disease (CAD) and to observe the interactions between these polymorphic variants and smoking in the CAD risk.Design and methodThe study population consisted of 178 patients with angiographically documented CAD and 202 blood donors. The analyses of genetic polymorphisms were performed using the PCR-RFLP method.ResultsThe frequency of PAI-1 5G allele was higher in the entire CAD group than in control group (p = 0.04, OR = 1.35). Also the 5G allele carriers (4G5G + 5G5G) were more frequent in patients than in controls (p = 0.03, OR = 1.93). The number of women carrying 5G allele was again significantly higher among patients (OR = 10.95 p = 0.0075). The IL-6 C allele frequency was higher only in the CAD male subgroup (p = 0.035, OR = 1.44). We found synergistic and cumulative effects between specific genotype patterns and smoking in determining the risk of CAD, especially between PAI-1(4G5G + 5G5G)+IL-6(CC) and smoking (SIM = 4.18 and p = 0.0005, OR = 9.20, respectively).ConclusionsThere are synergistic and cumulative effects of 5G allele of PAI-1 polymorphism and C allele of IL-6 polymorphism with smoking in determining their associated risk with CAD.     

Potential role of GABAA receptor subunit; GABRA6, GABRB2 and GABRR2 gene polymorphisms in epilepsy susceptibility and pharmacotherapy in North Indian population

BackgroundGABA_A receptors influence the susceptibility to seizures, and variations in the receptor genes can contribute to antiepileptic drug resistance also.MethodsWe investigated the possible associations of single nucleotide polymorphisms (SNPs) present in GABRA6 c. 1512 T>C, GABRB2 c. 1412 C>T, and GABRR2 c. IVS2C>G genes of GABA_A receptors in epilepsy susceptibility and drug resistance in northern Indian patients with epilepsy. After screening a total of 202 healthy controls and 401 epilepsy patients were enrolled in study. The genotyping was done by PCR-RFLP methods.ResultsThe GABRA6 c. 1512 T>C, polymorphism was conferring risk for epilepsy susceptibility for TC (P = 0.018), CC (P = 0.0001) genotype and for C allele (P = 0.0002). Another polymorphism GABRB2 c. 1412 C>T was also conferring high risk for epilepsy susceptibility CT (P = 0.012), TT (P = 0.778) genotype and for variant T allele (P = 0.034) but was not associated with drug resistance. No association was found with epilepsy susceptibility or with drug resistance in case of GABRR2 c. IVS2C>G gene polymorphism.ConclusionOverall, our findings suggest significant involvement of alpha (GABRA6) and beta (GABRB2) subunits of GABA_A receptor in epilepsy susceptibility in north Indian population.     

MMP-2 and TIMP-2 gene polymorphisms and susceptibility to atrial fibrillation in Chinese Han patients with hypertensive heart disease

BackgroundMMP-2 and TIMP-2 play important roles in the pathogenesis of arrhythmogenic atrial remodeling, and may contribute to the development and persistence of atrial fibrillation (AF). Functional polymorphisms in the promoter of MMP-2 and TIMP-2 gene may modulate an individual's susceptibility to AF.MethodsA total of 881 hypertensive heart disease patients from Chinese Han population (128 with and 753 without AF) were recruited in this study. The genotypes of the MMP2-1306C>T and -735C>T polymorphisms and TIMP-2 -418G>C polymorphisms were determined using PCR based method. The plasma concentration of TIMP-2 was measured by enzyme-linked immunosorbent assay in a subgroup with 81 patients.ResultsBoth genotype distribution and allele frequency of the TIMP-2 -418G>C polymorphism were significantly different between the AF and control group (P = 0.005 and P = 0.001, respectively). The C allele carriers (GC + CC) had a significantly increased risk of AF compared with the GG homozygotes (odds ratio,1.77, 95% CI 1.21–2.92, P = 0.009) in a logistic regression model after adjustment for age, left atrial dimension, left ventricular mass index, and antihypertensive drugs. The C allele carriers also had reduced levels of plasma TIMP-2 levels compared with GG homozygotes in both AF patients and control subjects. No relationship was found in this cohort between the presence of the MMP-2 -1306C>T and -735C>T polymorphism and AF.ConclusionsThe TIMP-2 -418G>C polymorphism is significantly associated with an increased susceptibility to AF in Chinese Han patients with hypertensive heart disease. The -418C allele, which is associated with a decreased expression of TIMP-2, might be a genetic risk for the development of AF in this cohort.     

Natriuretic peptide precursor B gene (TTTC)(n) microsatellite polymorphism in pre-eclampsia

BackgroundThere is a variable tandem repeat polymorphism in the 5′-flanking region of the natriuretic peptide precursor B gene (NPPB). A previous study showed association of the (TTTC) small tandem repeat (STR) variants of this gene and essential hypertension. Our aim was to identify this polymorphism in samples of pre-eclamptic patients and healthy controls. We also compared the natriuretic peptide B (BNP) concentrations.MethodsBlood samples were collected from healthy pregnant normotensive women (n = 235) and women with pre-eclampsia (n = 220). DNA was isolated and fluorescent PCR and DNA fragment analysis was performed for the detection of (TTTC) repeats. The plasma BNP concentration was measured by fluorescence immunoassay method.ResultsWe detected 12 different (TTTC) repeats on the NPPB gene in the studied population. The overall distribution of alleles and genotypes was significantly different between the control and pre-eclamptic groups. The number of 10-repeat genotype carriers showed significantly lower frequency in pre-eclamptics than in the healthy pregnant controls (p = 0.032). After adjustment for confounding factors pre-pregnancy BMI, maternal age, primiparity and smoking, the calculated odds ratio (OR) was 0.19 (95% CI: 0.04–0.87). Similarly, the 12-repeat genotype carriers showed significantly lower frequency in pre-eclamptics than in the healthy pregnants (p = 0.037; adjusted OR: 0.53 (95% CI: 0.29–0.96)). In contrast the 11-repeat genotype carrier frequency was significantly higher in the pre-eclamptic than in the healthy pregnant group (p < 0.001; adjusted OR 2.91 (95% CI: 1.75–4.84)).The concentration of the BNP was 9.75 pg/ml in the healthy controls and 32.40 pg/ml in the pre-eclamptic group (p < 0.0001). The 11/11 genotype carriers had significantly higher BNP levels in both groups.ConclusionsThe NPPB gene (TTTC) microsatellite polymorphism in the 5′-flanking region showed significant difference in the distribution of alleles and genotypes between healthy pregnant controls and pre-eclamptic patients in an ethnically homogeneous population. The concentration of the BNP was higher in pre-eclamptic women, and it showed association with the (TTTC) genotypes. We introduced an F-PCR and DNA fragment analysis method for the fast and reliable detection of this STR.     

Association between interleukin 23 receptor polymorphism and kidney transplant outcomes: a 10-year Taiwan cohort study

ObjectiveInterleukin 23 receptor (IL-23R) plays a role in the pathogenesis of multiple autoimmune processes. The relationship between allograft outcomes and the IL-23Rvariant genotypes has not been reported on previously. Therefore, we examined the relationship between this genetic polymorphism and kidney transplant outcomes.MethodsThis is an observational cohort study and 422 renal transplant recipients (RTRs) were enrolled. Polymerase chain reaction-restriction fragment length polymorphism was used for the measurement of IL-23R genetic polymorphisms. We used a composite end-point incorporating serum creatinine (SCr) doubling, graft failure and death as the primary outcome. Secondary outcomes included biopsy-proven acute rejection (BPAR), biopsy-proven interstitial fibrosis/tubular atrophy (IF/TA) and individual primary outcome. The risks of developing primary and secondary outcomes were compared between the different IL-23R genotypes and alleles.ResultsWith a mean follow-up of 79.3 ± 28.8 months, 26 patients in the IL-23R genotype AA group and 32 patients in the IL-23R genotype AC/CC group reached the primary outcome (p = 0.061). RTRs who carried the IL-23R AC/CC genotype (aHR 1.78; 95% CI. 1.01–3.12; p = 0.046) and C allele (aHR 1.48; 95% CI. 0.96–2.28; p = 0.075) had a higher risk of developing primary outcome as compared to those with IL-23R AA genotype and A allele, respectively. Moreover, RTRs who carried the IL-23R AC/CC genotype and C allele had a higher risk of developing biopsy-proven IF/TA (p = 0.012; p = 0.012) and SCr doubling (p = 0.024; p = 0.042) as compared to those with IL-23R AA genotype and A allele, respectively. The risk of BPAR, graft failure and death between the IL-23R genotypes and alleles were comparable.ConclusionIL-23R polymorphism may have a potential immuno-modulating role in long-term allograft outcome.     

Folate and choline metabolism gene variants and development of uterine cervical carcinoma

ObjectiveIt has been reported that aberrant DNA methylation can be associated with HPV infection and cervical tumorigenesis. The aim of this study was to evaluate the possibility that polymorphic variants of genes that may affect DNA methylation status are associated with the risk of cervical cancer in the Polish population.Design and methodEmploying PCR-RFLPs and HRM analyses, we examined the prevalence of BHMT Arg239Gln (rs3733890), MTR Asp919Gly (rs1805087), MTHFR Ala222Val (rs1801133), MTHFD1 Arg653Gln (rs2236225) and MTRR Ile22Met (rs1801394) genotypes and alleles in patients with advanced cervical cancer (n = 124) and controls (n = 168).ResultsThe odds ratio (OR) for BHMT Gln/Gln genotype was 0.433 (95% CI = 0.1780–1.054; p = 0.0602). The OR for patients having the BHMT Arg/Gln or Gln/Gln genotypes was 0.579 (95% CI = 0.3622–0.924; p = 0.0216). We also observed a significantly higher frequency of the BHMT 239Gln allele in controls than in patients, p = 0.0165. The genotype and allele frequencies of the MTR Asp919Gly, MTHFR Ala222Val, MTHFD1 Arg653Gln and MTRR Ile22Met gene variants did not display statistical differences between patients with cervical cancer and controls. We also did not find a significant association between the distribution of any genotypes or alleles and cancer characteristics.ConclusionOur results might suggest the protective role of the BHMT 239Gln variant in cervical cancer incidence.     

A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population

BackgroundLRP2 (also called megalin) plays a potential key role in the pathogenesis of Alzheimer's disease (AD). Recently, one genome-wide association study has revealed that the rs3755166 (G/A) polymorphism located in the LRP2 promoter is associated with development of AD in Caucasians, while there are no studies on the association LRP2 of with AD risk in Asians.MethodsTo evaluate the relationship between the rs3755166 polymorphism of the LRP2 gene and AD in the ethnic Chinese Han, we conducted a case-control study (n = 361, age > 50) to determine the prevalence of one common single-nucleotide polymorphism (SNP) of LRP2 (rs3755166) in patients with AD in Chinese population of Mainland China, and clarified whether this polymorphism is a risk factor for AD.ResultsThe prevalence of the minor allele (A) in the rs3755166 polymorphism was significantly different in AD patients and control subjects (P < 0.05). The rs3755166 polymorphism was associated with AD in the ethnic Chinese Han (OR = 1.378, 95% CI: 1.017-1.867, P = 0.039), and the results were not influenced by age, gender, or APOE status (P = 0.441, P = 0.94, P = 0.432, respectively).ConclusionOur data revealed the allele (A) of the rs3755166 polymorphism within LRP2 gene may contribute to AD risk in the Chinese Han Population.     

Association of GSTT1, GSTM1 and CYP1A1 polymorphisms with susceptibility to systemic lupus erythematosus in the Chinese population

BackgroundGSTT1, GSTM1, CYP1A1 are enzymes responsible for the detoxification of the toxicant which may be involved in the development of systemic lupus erythematosus (SLE). We examined the relationship between the risk of SLE and the polymorphisms of these genes in the Chinese population.MethodsSamples from 298 SLE patients and 284 healthy controls were collected. Polymerase chain reaction-restriction fragments length polymorphism (PCR–RFLP) was used to analyze the genotypes of CYP1A1 m2 and m4, while multiplex PCR was used to analyze the genotypes of GSTT1 and GSTM1.ResultsStatistically significant difference was observed in genotypes for GSTM1 (p = 0.003, OR 1.66 [95% CI 1.19–2.32]), but not for GSTT1 (p = 0.119, OR 0.77 [95% CI 0.56–1.07]), in the SLE patients as compared with the controls. Combinational analysis for double-null deletion of both GSTT1 and GSTM1 showed no significant difference (p = 0.863, OR 1.03 [95% CI 0.70–1.52]). Significant difference was observed in the genotype frequencies (p = 0.013), but not in the allele frequencies (p = 0.444, OR 0.90 [95% CI 0.70–1.17]), of CYP1A1 m2. All candidates have a wild-type genotype for CYP1A1 m4.ConclusionsPolymorphisms of GSTM1 are associated with SLE in the Chinese population.     

Haptoglobin (HP) polymorphisms and human longevity: A cross-sectional association study in a Central Italy population

BackgroundHaptoglobin (HP), which scavenges free, cell-toxic hemoglobin and has anti-inflammatory and immune-modulatory function in extravascular tissues, may represent an excellent candidate gene to investigate the life-span expectancy.MethodsHP 1/2 polymorphism has been determined for 1072 (569 females, 503 males) unrelated healthy individuals from Central Italy, 18–106 years old, divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes. HP*1F/S subtyping was also performed to check the possible existence for a preferential advantage of HP*1F or HP*1S allele.ResultsHP*1/*1 genotype results associated to increased probability of young subjects of attaining longevity (Comparison 1: O.R. 1.709, p = 0.0114) with a concomitant advantage of HP*1 allele (Comparison 1: O.R. 1.273, p = 0.0194). On the other side, carriers of HP*2 allele displayed an overall significant disadvantage in reaching Age Class 2 (O.R. 0.585, p = 0.0092). No significant differences were noticed between age groups either considering total HP*1F and HP*1S allele frequencies or according to HP 1/2 genotypes.ConclusionThe crucial role played by HP in aging process is warranted by its many established functions and its related phenotypes so that it may be considered an important gene involved in the determination of human survival.     

The association of ghrelin polymorphisms with coronary artery disease and ischemic chronic heart failure in an elderly Chinese population

ObjectiveTo investigate the association of coronary artery disease (CAD) and ischemic heart failure (IHF) with polymorphisms of the ghrelin gene in elderly Chinese patients.Design and methodsFifty-six patients with ischemic heart failure, sixty patients with coronary artery disease without heart failure, and one hundred healthy control subjects participated in the study. The polymorphisms were evaluated by polymerase chain reaction, sequencing, and fragment length polymorphism analysis.ResultsOnly one single nucleotide polymorphism (SNP), Leu72Met (408C/A), was observed across all samples. Gene frequencies of CC and allele frequencies of C were significantly greater in the CAD with IHF group than those in the CAD without IHF group (p = 0.025, p = 0.011). There was no significant association between the Leu72Met SNP with coronary artery disease risk factors.ConclusionOur results suggest that a C allele at position 408 of the ghrelin gene is associated with genetic susceptibility to ischemic heart failure in Chinese elders.     

The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest

IntroductionTreatment with hypothermia has been shown to improve outcome after cardiac arrest (CA). Current consensus is to rewarm at 0.25–0.5 °C/h and avoid fever. The aim of this study was to investigate whether active rewarming, the rate of rewarming or development of fever after treatment with hypothermia after CA was correlated with poor outcome.MethodsThis retrospective cohort study included adult patients treated with hypothermia after CA and admitted to the intensive care unit between January 2006 and January 2009. The average rewarming rate from end of hypothermia treatment (passive rewarming) or start active rewarming until 36 °C was dichotomized in a high (≥0.5 °C/h) or normal rate (<0.5 °C/h). Fever was defined as > 38 °C within 72 h after admission. Poor outcome was defined as death, vegetative state, or severe disability after 6 months.ResultsFrom 128 included patients, 56% had a poor outcome. Actively rewarmed patients (38%) had a higher risk for poor outcome, OR 2.14 (1.01–4.57), p < 0.05. However, this effect disappeared after adjustment for the confounders age and initial rhythm, OR 1.51 (0.64–3.58). A poor outcome was found in 15/21 patients (71%) with a high rewarming rate, compared to 54/103 patients (52%) with a normal rewarming rate, OR 2.61 (0.88–7.73), p = 0.08. Fever was not associated with outcome, OR 0.64 (0.31–1.30), p = 0.22.ConclusionsThis study showed that patients who needed active rewarming after therapeutic hypothermia after CA did not have a higher risk for a poor outcome. In addition, neither speed of rewarming, nor development of fever had an effect on outcome.     

Association of hsp70-2 (+1267A/G), hsp70-hom (+2437T/C), HMOX-1 (number of GT repeats) and TNF-alpha (+489G/A) polymorphisms with COPD in Croatian population

ObjectiveTo test for possible association of hsp70-2 (+ 1267A/G), hsp70-hom (+ 2437T/C), HMOX-1 (number of GT repeats) and TNF-α (+ 489G/A) polymorphisms with chronic obstructive pulmonary disease (COPD) in Croatian population.MethodsGenotyping of DNA isolated from whole blood of 130 COPD patients (as defined by spirometry) and 95 healthy controls was performed. Fragment size analysis upon restriction enzyme digestion and/or sequencing was used for genotype/allele definition. Significance of findings was tested using χ² test.Resultshsp70-2 (+ 1267A/G) polymorphism was significantly associated with COPD. Results of genotyping analysis indicated that a genotype carrying G allele was preferentially associated with COPD; odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.00–2.24 and P = 0.061. OR for the GG genotype was 3.47 with CI = 1.26–9.56 and P = 0.04. No association for hsp70-hom (+ 2437T/C), TNF-α (+ 489G/A) and HMOX-1 (number of GT repeats) polymorphisms were found. In addition, comparison of genotype frequencies among different stages of disease severity (GOLD II-IV) revealed no discrimination for any of the tested polymorphisms.ConclusionThis study is supporting the association of hsp70-2 (+ 1267A/G) polymorphism and COPD. Higher frequency of G allele and GG genotype in Croatian COPD patients was observed. There was no evidence for the association of hsp70-hom (+ 2437T/C), TNF-α (+ 489G/A) SNPs and HMOX-1 (number of GT repeats) polymorphism with COPD. Allele and genotype frequencies for all of the tested polymorphisms show no association with disease severity (GOLD II-IV).     

Identification of pharmacogenetic predictors of lipid-lowering response to atorvastatin in Chilean subjects with hypercholesterolemia

BackgroundStatins are normally the first-line therapy for hypercholesterolemia (HC); however, the lipid-lowering response shows high interindividual variation. We investigated the effect of four polymorphisms in CYP3A4, CYP3A5 and ABCB1 genes on response to atorvastatin and CYP3A4 activity in Chilean subjects with HC.MethodsA total of 142 hypercholesterolemic individuals underwent atorvastatin therapy (10 mg/day/1 month). Serum lipid levels before and after treatment were measured. Genetic variants in CYP3A4 (? 290A>G, rs2740574), CYP3A5 (6986A>G, rs776746) and ABCB1 (2677G>A/T, rs2032582 and 3435C>T, rs1045642) were analyzed by PCR-RFLP. CYP3A4 enzyme activity in urine samples was assessed through determination of 6β-hydroxycortisol/cortisol free ratio (6βOHC/FC).ResultsAfter 4 weeks of therapy, a significant reduction in total cholesterol (TC) and LDL-c was observed (P < 0.001). The G allele for ? 290A>G polymorphism was related to higher percentage of variation in TC and LDL-c (P < 0.001). Moreover, same allele was associated with higher HDL-c variation (P = 0.017). In addition, CYP3A4 enzyme activity was lower in subjects carrying this polymorphism (P = 0.009). No differences were observed for CYP3A5 and ABCB1 variants.ConclusionOur results suggest that presence of G allele for ? 290A>G polymorphism determines a better response to atorvastatin, being also associated with lower CYP3A4 activity in vivo, causing an increased atorvastatin activity.     

Chemokine CXC Ligand 16 serum concentration but not A181V genotype is associated with atherosclerotic stroke

BackgroundSerum chemokine CXC Ligand 16 (CXCL16) concentration is associated with atherosclerosis and CXCL16 expression may be influenced by the polymorphism, A181V. We established whether serum CXCL16 concentration or the A181V genotype is more strongly associated with atherosclerotic stroke and its associated risk factor, carotid atherosclerosis.MethodsPCR–RFLP was used to genotype 244 atherosclerotic stroke patients (AS group), 153 stroke-free controls (patient controls) and 167 healthy controls. Serum CXCL16 concentration was determined for a subset of patients (n = 135) and all controls. The same subset of patients was then examined using ultrasound to evaluate their carotid atherosclerotic lesions, including intima-media thickness (IMT), plaque stability and carotid plaque area (CPA).ResultsCompared with the patient controls and healthy controls, serum CXCL16 concentration was significantly increased in the AS group (P < 0.05, and 0.01). It was also strongly associated with increased IMT, vulnerable plaque and increased CPA (P < 0.05, < 0.001, and < 0.01). However, the CXCL16 A181V genotype distribution and allele frequencies showed no differences between AS and control groups, nor did it influence serum CXCL16 concentration.ConclusionSerum CXCL16 concentration is significantly associated with atherosclerotic stroke and carotid atherosclerosis, suggesting that this biochemical test may be useful to identify patients at increased risk of atherosclerosis.     

Cervicovaginal interleukin-6 as a predictor of preterm birth in African American women

BackgroundIdentification of women who will deliver preterm may reduce infant morbidity and mortality. In heterogeneous populations, fetal fibronectin (fFN) and interleukin-6 are excellent predictors of women who will not deliver within two weeks. African-Americans are at higher risk for preterm birth than Caucasians. This study compares the diagnostic utility of fFN and interleukin-6 in cervicovaginal fluid (CVF) to predict preterm birth within 14 days of sampling in African-American and Caucasian women.MethodsInterleukin-6 was measured in 667 CVF samples from 580 women with and without symptoms of labor. The utility of CVF interleukin-6 and fFN to predict delivery was determined in the total population and in African-Americans and Caucasians separately.ResultsfFN positive (≥ 50 μg/l) results were associated with delivery in ≤ 14 days in African-Americans (Odds Ratios (OR) 8.7; Likelihood Ratio (LR) 3.7) (p < 0.0001) and Caucasians (OR 11.9; LR 5.7) (p < 0.01). A positive interleukin-6 (≥ 250 ng/l) was associated with delivery in ≤ 14 days in African-Americans (OR 12.7; LR 5.25) (p < 0.0001), but not in Caucasians (OR 4.1; LR 3.2) (p = 0.13).ConclusionsCVF interleukin-6 and fFN have similar diagnostic utilities in a diverse population. Interleukin-6 more accurately predicts delivery within 14 days in African-Americans, while fFN is more accurate in Caucasians.