B2 Allele Research Articles

Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase.

The present study investigated in Tunisian renal transplant patients, genetic polymorphisms of CYP3A4 -392A>G and CYP3A5 6986A>G and their influence on tacrolimus (Tac) pharmacokinetics during early and late post-transplant (PT) phases and established customized ranges of Tac doses matching the C0 target levels according to CYP3A4 and CYP3A5 genotype combination and the PT phase. We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring of Tac by morning C0 monitoring during early (1 to 90 days) and late (over 90 days) PT phases. The genomic DNA was extracted from peripheral blood mononuclear cells using a salting-out procedure. CYP3A4 promoter (rs2740574; -392A>G) and CYP3A5 (rs776746; 6986A>G) SNP genotyping was analyzed using PCR-RFLP. Fifty-two patients were enrolled in the study. During the early PT phase, the CYP3A5 polymorphism but not that of CYP3A4, correlates significantly with Tac dose-normalized C0 (C0/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C0/D Tac. The mean daily doses (mg/kg) matching therapeutic C0, regardless of the CYP3A genotypes, were 0.16 ± 0.05 and 0.10 ± 0.05 during early and late PT phase, respectively. Carriers of the CYP3A4*1B allele require higher doses to maintain the C0 in the therapeutic range during the two PT phases. However, patients carrying the CYP3A5*1 require significant higher Tac doses, only during the early phase. Our data support a critical role of the CYP3A5 6986A>G and CYP3A4 -392A>G polymorphisms on the variation of Tac exposure during the early and the late PT phase, respectively. The establishment of customized Tac doses, according to CYP3A4/CYP3A5 genotype combination and the PT time, may allow preventing graft rejection and improving the safety profile of this drug. Further studies are needed to investigate this issue.

HLA B51 is associated with faster AIDS progression among newly diagnosed HIV-infected individuals in Manitoba, Canada.

Human leucocyte antigen (HLA) alleles influence the rate of CD4 decline among HIV-infected individuals. We investigated the association between HLA B35 and HLA B51 and the rate of CD4 decline and/or opportunistic infections, among 294 HIV-positive individuals from Manitoba, Canada. All individuals presenting with a CD4 count >200cellsμL(-1) , who had at least two CD4 counts, and no evidence of co-infection were included. Individuals bearing HLA B35 or HLA B51 were compared to controls. A multivariate model demonstrated that HLA B35 allele was associated with a hazard ratio of 2.05 (95% CI 1.31-3.18) for reaching AIDS and HLA B51 allele with HR of 2.03 (95% CI 1.18-3.49) for reaching the same end-point. High prevalence of HLA B35 was seen in the patient population receiving care in Manitoba. Our observations confirm the association of HLA B35 with rapid disease progression. We report, for the first time, faster CD4 decline among individuals with HLA B51 allele.

Cholesteryl ester transfer protein: ace of spades, queen of hearts, or the joker?

Cholesteryl ester transfer protein: ace of spades, queen of hearts, or the joker?

Polymorphism of Gly482Ser PPARGC 1A and Ala203Pro PPARGC 1B in the pathogenesis of Graves’ orbitopathy

Aim. To examine the association of polymorphisms Gly482Ser PPARGC 1A and Ala203Pro PPARGC 1B with the development of thyroid eye disease (TEO). Materials and methods. A total of 88 people: 52 patients with TEO, 36 - healthy individuals. Identified polymorphisms Gly482Ser PPARGC 1A and Ala203Pro PPARGC 1B by PCR. Results. When TEO detected differences in the frequency of allele and genotype SNPs investigated compared with the control. The prevalence of genotypes and alleles in patients with TEO (Gly/Gly - 38.5%, Gly/Ser - 34.6%, Ser/Ser - 26.9%, Gly-allele - 55.8%, Ser-allele - 44.2% gene PPARGC 1A; Ala/Ala - 19.2%, Ala/Pro - 55.8%, Pro/Pro - 25%, Ala-allele - 47.1%, Pro-allele - 52.9% gene PPARGC 1B). The prevalence of genotypes and alleles in the control group (Gly/Gly - 38.9%, Gly/Ser - 44.4%, Ser/Ser - 16.7%, Gly-allele - 61.1%, Ser-allele - 38.9% of the gene PPARGC 1A; Ala/Ala - 25%, Ala/Pro - 58.3%, Pro/Pro - 16.7%, Ala-allele - 54.2%, Pro-allele - 45.8% of the gene PPARGC 1B). Conclusion. At TEO more common genotypes Ser482Ser PPARGC 1A, Pro203Pro PPARGC 1B and Ser allele polymorphism Gly482Ser PPARGC 1A, Pro polymorphism Ala203Pro PPARGC 1B, as well as less common genotypes Gly482Ser PPARGC 1A, Ala203Ala PPARGC 1B and Gly allele polymorphism Gly482Ser PPARGC 1A, Ala polymorphism Ala203Pro PPARGC 1B. Polymorphisms and allele Gly482Ser PPARGC 1A gene and gene Ala203Pro PPARGC 1B do not modify the risk of TEO.

The BstUI and DpnII Variants of the COL5A1 Gene Are Associated With Tennis Elbow

Background: Tennis elbow entails pain and tenderness over the lateral epicondyle. The exact cause of the condition is not fully understood. Type V collagen is a minor fibrillar collagen that intercalates with type I collagen and forms collagen fibrils. It is encoded by the COL5A1 gene. Sequence variants within COL5A1 3′-UTR have been implicated in musculoskeletal diseases. Purpose: To determine whether rs12722 (BstUI C414T polymorphism) and rs13946 (DpnII C230T polymorphism) of the COL5A1 gene are associated with an increased risk of tennis elbow. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 152 patients with tennis elbow and 195 healthy participants were enrolled in this study. The rs12722 (BstUI C414T) and rs13946 (DpnII C230T) polymorphisms were investigated with the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. Results: There was a significant difference in both BstUI and DpnII genotype frequencies between patients with tennis elbow and healthy participants. The A2 allele of BstUI and the B1 allele of DpnII were significantly underrepresented in the patient group. Conclusion: Individuals with the BstUI A1 allele and DpnII B2 allele of the COL5A1 gene have a high likelihood of developing symptoms of the tennis elbow. This is the first study reporting that rs12722 and rs13946 SNPs (single nucleotide polymorphisms) are genetic risk factors for tennis elbow.

Ethnic differences in the association between lipid metabolism genes and lipid levels in black and white South African women

ObjectiveDyslipidaemia can lead to the development of atherosclerosis and cardiovascular disease (CVD), however its prevalence has been shown to differ between ethnic groups in South Africa (SA). Therefore the aim of this study was to investigate ethnic differences in the association between serum lipid levels and polymorphisms within genes involved in lipid metabolism in black and white SA women. MethodsIn a convenient sample of 234 white and 209 black SA women of Xhosa ancestry, body composition (DXA) and fasting serum lipids were measured. Participants were genotyped for the cholesteryl ester transfer protein (CETP, rs708272, B1/B2), lipoprotein lipase (LPL, rs328, S/X), hepatic lipase (LIPC, rs1800588, C/T) and proprotein convertase subtilisin/kexin type 9 (PCSK9, rs28362286, C/X) polymorphisms. ResultsCompared to white women, black women had lower concentrations of serum total cholesterol (TC, P < 0.001), low density lipoprotein cholesterol (LDL-C, P < 0.001), high density lipoprotein cholesterol (HDL-C, P < 0.001) and triglycerides (TG, P < 0.001). There were significant differences in the genotype and allele frequency distributions between black and white women for the LPL S/X (P < 0.001), PCSK9 C679X (P = 0.002) and LIPC 514C/T (P < 0.001) polymorphisms. In black women only, there were genotype effects on serum lipid levels. Specifically, women with the LPL SX genotype had lower TC and LDL-C and higher HDL-C concentrations than those with the SS genotype and women with the CETP B2 allele had lower LDL-C concentrations than those with the B1B1 genotype. ConclusionPolymorphisms within the LPL and CETP genes were associated with a more protective lipid profile in black, but not white SA women. This supports the hypothesis that the more favorable lipid profile of black compared to white SA women is associated with polymorphisms in lipid metabolism genes, specifically the LPL and CETP genes.

Circulating cholesteryl ester transfer protein and coronary heart disease: mendelian randomization meta-analysis.

The cholesteryl ester transfer protein (CETP) plays a central role in reverse cholesterol transport. Currently, it remains unresolved whether circulating CETP is causally associated with coronary heart disease (CHD). We aimed to investigate this causal association using CETP gene rs708272 polymorphism as an instrument in a Mendelian randomization meta-analysis. We searched PubMed and EMBASE before May 2014. Data and study quality were assessed in duplicate. Thirty-four articles (17 813 CHD patients and 22 203 controls) were qualified. Overall analyses revealed a significant association of rs708272-B1 allele with a reduced CHD risk compared with B2 allele under allelic (odds ratio and 95% confidence interval: 0.87 and 0.82-0.92; P<0.001), homozygous genotypic (0.74 and 0.66-0.83; P<0.001), and dominant (0.87 and 0.80-0.94; P<0.001) models. Carriers of rs708272-B1B1 genotype (weighted mean difference and 95% confidence interval: -0.21 and -0.41 to 0.00 μg/dL; P=0.052) or B1 allele (-0.15 and -0.30 to 0.00 μg/dL; P=0.056) had a marginally lower circulating CETP level compared with B2B2 genotype carriers. In Mendelian randomization analysis, there was a 25% (odds ratio and 95% confidence interval: 0.75 and 0.19-0.91) and a 17% (0.83 and 0.41-0.96) significantly reduced risk of CHD by a reduction of 0.2 μg/mL in circulating CETP for the comparison of B1B1 genotype and B1 allele with B2B2 genotype, respectively. There were low probabilities of publication bias. Our findings demonstrate that the long-term genetically reduced circulating CETP might be causally associated with the low risk of CHD.

TaqIB and severity of coronary artery disease in the Turkish population: a pilot study.

The cholesteryl ester transfer protein (CETP) plays a crucial role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration. In this case-control study, we analyzed the genotype frequencies of CETP Taq1B polymorphisms in coronary artery disease patients (CAD; n=210) and controls (n=100). We analyzed the role of the CETP Taq1B variant in severity of CAD, and its association with plasma lipids and CETP concentration. DNA was extracted from 310 patients undergoing coronary angiography. The Taq1B polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (RFLP) analysis. Lipid concentrations were measured by an auto analyzer and CETP level by a commercial enzyme-linked immunosorbent assay (ELISA) kit. In our study population, the B2 allele frequency was higher in control subjects than patients with single, double or triple vessel disease. B2B2 genotype carriers had a significantly higher high-density lipoprotein cholesterol (HDL-C) concentration than those with the B1B1 genotype in controls (51.93±9.47versus 45.34±9.93; p<0.05) and in CAD patients (45.52±10.81 versus 40.38±9.12; p<0.05). B2B2 genotype carriers had a significantly lower CETP concentration than those with the B1B1 genotype in controls (1.39±0.58 versus 1.88±0.83; p< 0.05) and in CAD patients (2.04±1.39versus 2.81±1.68; p< 0.05). Our data suggest that the B2 allele is associated with higher concentrations of HDL-C and lower concentrations of CETP, which confer a protective effect on coronary artery disease.

Taq1B CETP Polymorphism and Cardiovascular Risk in an Endogamous Pop-ulation of Diabetic Men: A Study in Santa Rosa Del Conlara, San Luis, Argentina

Objectives: Type 2 diabetes mellitus (T2DM) patients are at increased risk of cardiovascular dis- eases (CVDs). Several polymorphisms in the cholesterol ester transfer protein (CETP) gene have been reported. The aim of this study was to determine the distribution and effect of the Taq1B polymorphism in the CETP gene on clinical and biochemical indicators of CVD risk in a population of endogamous-T2DM men. Methods: 102 men (57.5 ± 9.3 years old) inhabitants of Santa Rosa del Conlara, San Luis, Argentina, were recruited and assigned into two groups (22 control and 80 T2DM). Further, these two groups were subdivided according to their Taq1B CETP gene genotypes (i.e., B1B1, B1B2 and B2B2). Clinical and fasting-plasma biochemical indicators of CVD risk were measured and their association with the B1 allele was determined. Results: Compared to control, T2DM men had more central obesity, hypertension, atherogenic index, insulin resistance and poorly controlled diabetes. Compared to T2DM men having the B2 allele, those T2DM men having the B1 allele have increased risk of CVD as assessed by systolic blood pressure (156 ± 16.0 vs 135.8 ± 19.2, p = 0.015), atherogenic index (6.15 ± 1.3 vs 4.4 ± 0.7, p = 0.0008), HDL-c levels (38.9 ± 5.3 vs 64.4 ± 8.2, p < 0.0001) and insulin resistance (HOMA-IR, 5.78 ± 3.0 vs 2.4 ± 0.78, p = 0.004). Interestingly, only body mass index (r = −0.559, p = 0.01) and HDL-c concentration (r = −0.492, p = 0.02) negatively correlated with CVD risk in the endogamous population of B1B1 and B1B2 T2DM men. Conclusion: The B1 allele of the CETP gene predicts cardiovascular complications in an * Corresponding author.

Surveillance for Toxoplasma gondii in California mussels (Mytilus californianus) reveals transmission of atypical genotypes from land to sea.

Coastal habitat contamination with Toxoplasma gondii is a health risk to humans and marine wildlife, with infections documented in both nearshore and pelagic marine mammals. Due to lack of sensitive methods for detection of T. gondii in water, this study utilized an alternative surveillance approach for evaluating marine habitat contamination using wild mussels. The objectives of this study were to (i) validate sensitive molecular tools for T. gondii detection in mussels and (ii) apply optimized methods in a surveillance study to determine the prevalence and genotype(s) of T. gondii in mussels. Simplex polymerase chain reaction screening and multiplex genotyping assays were validated and then applied on 959 wild-caught mussels collected from central California. Thirteen mussels (1.4%) had detectable T. gondii DNA and the presence of T. gondii in mussels was significantly associated with proximity to freshwater run-off and collection during the wet season. Molecular characterization revealed alleles from T. gondii types I, II/III, X at the B1 locus, and a novel atypical B1 allele that was recently documented in T. gondii-infected carnivores from California. Findings demonstrate higher than previously reported T. gondii contamination of California coastlines, and describe novel strains of the parasite that further link terrestrial sources with marine contamination.

Association of cholesteryl ester transfer protein (CETP) gene polymorphism, high density lipoprotein cholesterol and risk of coronary artery disease: a meta-analysis using a Mendelian randomization approach.

BackgroundRecent randomized controlled trials have challenged the concept that increased high density lipoprotein cholesterol (HDL-C) levels are associated with coronary artery disease (CAD) risk reduction. The causal role of HDL-C in the development of atherosclerosis remains unclear. To increase precision and to minimize residual confounding, we exploited the cholesteryl ester transfer protein (CETP)-TaqIB polymorphism as an instrument based on Mendelian randomization.MethodsThe Mendelian randomization analysis was performed by two steps. First, we conducted a meta-analysis of 47 studies, including 23,928 cases and 27,068 controls, to quantify the relationship between the TaqIB polymorphism and the CAD risk. Next, the association between the TaqIB polymorphism and HDL-C was assessed among 5,929 Caucasians. We further employed Mendelian randomization to evaluate the causal effect of HDL-C on CAD based on the findings from the meta-analysis.ResultsThe overall comparison of the B2 allele with the B1 allele yielded a significant risk reduction of CAD (P < 0.0001; OR = 0.88; 95% CI: 0.84–0.92) with substantial between-study heterogeneity (I2 = 55.2%; Pheterogeneity <0.0001). The result was not materially changed after excluding the Hardy-Weinberg Equilibrium (HWE)-violation studies. Compared with B1B1 homozygotes, Caucasian carriers of the B2 allele had a 0.25 mmol/L increase in HDL-C level (95% CI: 0.20–0.31; P <0.0001; I2 = 0; Pheterogeneity =0.87). However, a 1 standard deviation (SD) elevation in HDL-C levels due to the TaqIB polymorphism, was marginal associated with CAD risk (OR =0.79; 95% CI: 0.54–1.03; P =0.08).ConclusionsTaken together, our results lend support to the concept that increased HDL-C cannot be translated into a reduction in CAD risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0118-1) contains supplementary material, which is available to authorized users.

P038 : USE OF HLA-ALLELE PAIRS WHICH DIFFER ONLY IN BW4/BW6 FOR ANTIBODY ANALYSIS

Aim Bw4 and Bw6 are mutually exclusive HLA Class I “public” epitopes encoded by amino acids 77–83. We sought to explore selective reactivity patterns of sera with antigens which only differed for Bw4 or Bw6. Methods We tested 6726 sera from 2953 transplant candidates using Labscreen ® Single Antigen (One Lambda, Canoga Park, CA). We focused on target alleles B∗27:05(Bw4) vs B∗27:08(Bw6) and B∗53:01(Bw4) vs B∗35:01(Bw6). Reactions were called Positive (MFI > 3000) or Negative (MFI Results Table 1 shows the excellent correlation between the two sets of allele pairs we used to detect anti-Bw4/Bw6 antibody. Fig. 1 shows that the mean MFI against Bw4 or Bw6 on the other target alleles in the kit were strongly predicted based only on the deduction from the two B27 alleles. Similar predictive value was found for the B35/B53 allele pair. Conclusion Use of selective reactivity of sera with allele targets which only differ in the Bw4 or Bw6 epitopes is a definitive method for detecting such antibodies without presence of masking antibodies against private antigens. Table 1 Bw4 Bw6 B∗53:01posB∗35:01neg B∗53:01negB∗35:01pos Bw4 B∗27:05posB∗27:08neg 79 0 Bw6 B∗27:05negB∗27:08pos 1 37

CETP TaqIB genotype modifies the association between alcohol and coronary heart disease: The INTERGENE case-control study

Alcohol consumption at moderate levels has been associated with decreased risk of coronary heart disease (CHD). However, the cardio-protective effect of alcohol may be restricted to subjects with a particular genotype of the cholesteryl ester transfer protein (CETP) polymorphism. There is evidence for this from one study in men, but the finding has not been confirmed since. The present study specifically re-examines the potential modification of the association between alcohol consumption and CHD by the CETP TaqIB (rs708272) polymorphism in a sample including both men and women. The INTERGENE case-control study consists of 618 patients with CHD and 2921 control subjects, of whom 19% were homozygous for the CETP TaqIB B2 allele. Alcohol consumption was categorized into sex-specific tertiles of ethanol intake, with non-drinkers constituting a separate category. Logistic regression was used to determine the association between CHD with genotype, ethanol intake, and their interaction. Participants with intermediate ethanol intake (2nd tertile) had lower risk of CHD than those with low ethanol intake (odds ratio [OR] = 0.65; 95% confidence interval [CI] 0.50–0.85). The strongest protective association was seen in the CETP TaqIB B2 homozygotes for intermediate vs. low ethanol intake (odds ratio OR = 0.21; 95% CI 0.10–0.44). The interaction between ethanol intake and genotype was statistically significant (p = 0.008), and of similar size in men and women though significant only in men (p = 0.01). The effect modification could not be explained by differences in lifestyle, socioeconomics, or alcohol-related biological variables such as HDL–cholesterol. Our study is the first to replicate previous findings of an effect modification in men. It gives only suggestive results for women, possibly due to the small number of female cases (n = 165). The prevented fraction for the favorable combination of genotype and alcohol consumption is about 6%, a value suggesting that the cardio-protective effect of moderate alcohol consumption applies only to a small segment of the general population.

Association of cholesteryl ester transfer protein genotypes with paraoxonase-1 activity, lipid profile and oxidative stress in type2 diabetes mellitus: A study in San Luis, Argentina.

Aims/IntroductionDiabetic dyslipidemia is common in type 2 diabetes. The TaqIB polymorphism in cholesteryl ester transfer protein (CETP; B1 and B2 alleles; rs708272) is associated with changes in enzyme activity and lipid concentrations. The aim of the present study was to assess associations of CETP genotypes with lipoprotein profile, oxidant/anti-oxidant status and the plasma activity of paraoxonase-1 (PON-1) in a population of diabetic patients living in San Luis, Argentina.Materials and MethodsFor oxidative stress status parameters, thiobarbituric acid-reactive substances (TBARS) and nitric oxide (NO) levels, and catalase and PON-1 activity were assessed in 40 patients with type 2 diabetes mellitus and 30 healthy participants. CETP polymorphism was analyzed by polymerase chain reaction-based methods.ResultsType 2 diabetes mellitus had significantly higher concentrations of oxidative stress parameters: TBARS (P < 0.0001) and catalase activity (P < 0.0001). PON-1 activity and NO levels were significantly lower in diabetics (P = 0.0002 and P = 0.0008, respectively). The CETP genotypes distribution among study groups was not significantly different. The B2 carriers of the TaqIB CETP polymorphism are associated with higher high-density lipoprotein cholesterol levels and PON-1 activity in control and type 2 diabetes mellitus patients. Linear regression analysis showed that there was a significant and positive correlation between the changes of PON-1 activity and high-density lipoprotein cholesterol levels in non-B1B1 (B2 carriers) in controls (r = 0.83, P < 0.0001) and diabetic patients (r = 0.39, P = 0.0003).ConclusionsThe results of the current study show that type 2 diabetes mellitus is characterized by intense oxidative stress, and that the alterations observed in the lipoprotein profile and PON-1 activity might be related to the higher CETP activity in diabetic patients as a consequence of insulin resistance.

Genetic polymorphisms of glutathione S-transferases and cytochrome P450 enzymes as susceptibility factors to systemic lupus erythematosus in southern Brazilian patients.

Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease that presents several clinical manifestations, affecting multiple organs and systems. Immunological, environmental, hormonal and genetic factors may contribute to disease. Genes and proteins involved in metabolism and detoxification of xenobiotics are often used as susceptibility markers to diseases with environmental risk factors. Cytochrome P450 (CYP) enzymes activate the xenobiotic making it more reactive, while the Glutathione S-transferases (GST) enzymes conjugate the reduced glutathione with electrophilic compounds, facilitating the toxic products excretion. CYP and GST polymorphisms can alter the expression and catalytic activity of enzymes. This study aimed to investigate the role of genetic variants of CYP and GST in susceptibility and clinical expression of SLE, through the analysis of GSTM1 null, GSTT1 null, GSTP1*Ile105Val, CYP1A1*2C and CYP2E1*5B polymorphisms. 371 SLE patients from Hospital de Clínicas de Porto Alegre and 522 healthy blood donors from southern Brazil were evaluated. GSTP1 and CYP variants were genotyped using PCR-RFLP and GSTT1 and GSTM1 variants were analyzed by multiplex PCR. Among European-derived individuals, a lower frequency of GSTP1*Val heterozygous genotypes was found in SLE patients when compared to controls (p = 0.005). In African-derived SLE patients, the CYP2E1*5B allelic frequency was higher in relation to controls (p = 0.054). We did not observe any clinical implication of the CYP and GST polymorphisms in patients with SLE. Our data suggest a protective role of the GSTP1*Ile/Val heterozygous genotype against the SLE in European-derived and a possible influence of the CYP2E1*5B allele in SLE susceptibility among African-derived individuals.

The PXR rs7643645 polymorphism is associated with the risk of higher prostate-specific antigen levels in prostate cancer patients.

Levels of enzymes that determine testosterone catabolism such as CYP3A4 have been associated with prostate cancer (PCa) risk. Although some studies have related CYP3A4*1B allele, a gene polymorphism that modifies CYP3A4 expression level, with PCa risk, others have failed, suggesting that additional genetic variants may be involved. Expression of CYP3A4 is largely due to the activation of Pregnane X Receptor (PXR). Particularly, rs2472677 and rs7643645 PXR polymorphisms modify CYP3A4 expression levels. To evaluate whether PXR-HNF3β/T (rs2472677), PXR-HNF4/G (rs7643645), and CYP3A4*1B (rs2740574) polymorphisms are associated with PCa a case control-study was performed. The multiple testing analysis showed that the PXR-HNF4/G polymorphism was associated with higher levels of prostate-specific antigen (PSA) in patients with PCa (OR = 3.99, p = 0.03). This association was stronger in patients diagnosed at the age of 65 years or older (OR = 10.8, p = 0.006). Although the CYP3A4*1B/*1B genotype was overrepresented in PCa patients, no differences were observed in the frequency of this and PXR-HNF3β/T alleles between controls and cases. Moreover, no significant association was found between these polymorphisms and PSA, Gleason grade, or tumor lymph node metastasis.

Increased risk of premature coronary artery disease in Egyptians with ABCA1 (R219K), CETP (TaqIB), and LCAT (4886C/T) genes polymorphism.

Epidemiological studies have shown a strong inverse relationship between high-density lipoprotein (HDL) cholesterol (HDLc) levels and coronary artery disease (CAD), and a low concentration of plasma HDLc is considered an independent risk factor for premature atherosclerosis. Mutations in ATP-binding cassette A1 transporter (ABCA1), cholesteryl ester transfer protein (CETP), and lecithin: cholesterol acyltransferase (LCAT) reduce HDLc in humans. To date, no study had tested the association between these polymorphisms and premature CAD (PCAD) in the Egyptian population. Here we searched for ABCA1 (rs2230806), CETP (rs708272), and LCAT (rs5923) mutations in the Egyptian population and investigated the possible association between these gene polymorphisms and PCAD. We aimed to investigate the association between ABCA1, CETP, and LCAT gene polymorphisms and PCAD in Egyptians. A total of 235 Egyptians-116 with documented PCAD (PCAD group) and 119 controls-were enrolled in the study. Mutation carriers with low HDLc had an elevated risk of PCAD (odds ratio [OR] = 11.38 for ABCA1 mutation carriers, P = .000; OR = 5.41 for CETP mutation carriers, P = .000; OR = 5.92 for LCAT mutation carriers, P = .000). Moreover, mutations in ABCA1, CETP, and LCAT were significantly associated with hyperlipidemia in this study. These observations show that the R allele of ABCA1, the B1 allele of CETP, and the T allele LCAT genes are associated with PCAD in Egyptians. They have more considerable effect on patients with low HDLc.

CETP TaqIB Polymorphism, Serum Lipid Levels And Risk Of Atrial Fibrillation: A Case-Control Study.

The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high-density lipoproteins (HDL) to triglyceride (TG)-rich lipoproteins. A consistent number of investigations has suggested an association between the TaqIB polymorphism of the CETP gene, plasma HDL-C levels and the risk of cardiovascular disease, but the results are controversial. The aim of this study was to determine if the TaqIB polymorphism might be related to the presence of atrial fibrillation (AF). We conducted a case-control study, enrolling 109 Caucasian unrelated patients coming from Salento (Southern Italy) with documented AF and 109 controls selected from the same ward. The CETP TaqIB genotypes were determined by RFLP-PCR. The subjects with the B2B2 genotype seem to be more susceptible to AF development (OR=2.28, 95% CI 1.06-4.89, p=0.032). The AF incidence is higher if we consider only the female subgroup (OR=5.14, 95% CI 1.57-16.82, p=0.0061). In the AF female subgroup the B2B2 patients had a statistically significant decrease of HDL-C levels (1.50 ± 0.35 vs 2.07 ± 0.42; p=0.012) and statistically higher TG levels (1.34 ± 0.46 vs 0.77 ± 0.14; p=0.027) and TG/HDL-C ratio (2.14 ± 0.80 vs 0.88 ± 0.23; p=0.007) when compared to B2B2 female control subjects. When we analyzed the linkage between the TaqIB polymorphism and the promoter variant (-629C/A), we found that 100% of the B2 alleles of the TaqIB polymorphism were associated with the A alleles of the -629 promoter polymorphism in our subjects. This study suggests that in post-menopausal women atrial fibrillation could be promoted by the association of CETP B2B2/AA genotype with higher triglycerides values.

Ethnicity and association with disease manifestations and mortality in Behçet's disease.

BackgroundBehçet’s disease (BD) significantly increases morbidity and mortality. BD mainly affects young adults with a peculiar geographical distribution. It has been suggested that BD varies in its phenotypic expression in different ethnic groups.MethodsWe investigated potential ethnicity-related differences relative to phenotype and prognosis of BD patients in a French multiethnic country. We included 769 consecutive patients fulfilling the international criteria of classification for BD, in the 3 largest ethnic groups of our cohort [European (n = 369), North African (n = 350) and sub Saharan African (n = 50)]. Factors that affect prognosis were assessed by multivariate analysis.Results535 (69.6%) patients were male and the median (IQR) age at diagnosis was of 30.9 (24.9-37.2) years. Sub Saharan African BD patients had a higher frequency of CNS involvement (48% vs 32.3% vs 29.5%, p = 0 .035), a higher rate of death (12% vs 6% vs 3.5%, p = 0.029) and a lower frequency of HLA B51 allele (29.4% vs 49.2% vs 55.8%, p = 0.009) compared to those from North Africa and Europe, respectively. Multivariate analysis showed that male gender (HR: 5.01, CI: 1.51-16.65), cardiovascular involvement (HR: 2.24, CI: 1.15-4.36), and sub Saharan African origin (HR 2.62 (0.98-6.97) were independently associated with mortality. The 15-year mortality rate was of 19%, 9% and 6% in sub Saharan African, North African and European BD patients, respectively (p = 0.015).ConclusionWe reported ethnicity-related differences with respect to phenotype of BD. Sub Saharan Africans patients exhibited a worse prognosis.

7,12-Dimethylbenz(a)anthracene-Induced Myelotoxicity Differs in Mice Selected for High or Low Acute Inflammatory Response

Polycyclic aromatic hydrocarbons, such as 7,12-dimethylbenz(a)anthracene (DMBA), are environmental pollutants that exert multiple toxic and carcinogenic effects. Studies showed that these effects are mediated by activation of the aryl hydrocarbon receptor (AhR) and modulated by allelic variants of Ahr gene. Here, we investigated the effects of DMBA treatment in the inflammatory response and bone marrow (BM) hematopoietic function of maximal acute inflammatory response (AIRmax) and minimal acute inflammatory response (AIRmin) heterogeneous mouse lines selected for high and low acute inflammatory responsiveness, respectively. The phenotypic selection resulted in the segregation of the Ahr(d) and Ahr(b1) alleles that confer low and high receptor ligand-binding affinity, respectively, in AIRmax and AIRmin mice. We observed a reduction in BM mature granulocyte population in AIRmin mice 24 hours after DMBA treatment while both blast and immature myeloid cells were increased. Proliferation and differentiation of BM myeloid cells in response to in vitro granulocyte-macrophage colony-stimulating factor stimulus were impaired in AIRmin-treated mice. These DMBA effects on myeloid BM cells (BMCs) affected the in vivo leukocyte migration to an inflammatory site induced by polyacrylamide beads (Biogel P-100, Bio-Rad, France) injection in AIRmin mice. On the other hand, these alterations were not observed in DMBA-treated AIRmax mice. These data indicate that DMBA affects myeloid cell differentiation and inflammatory response and Ahr(b1) allele in the genetic background of AIRmin mice contributes to this effect.