Extraterritorial Effects of Foreign Tax Credit, Termination of Deferral and United States Tax Characterization

WOS: 00029324880011

The M235T Polymorphism in the AGT Gene and CHD Risk: Evidence of a Hardy-Weinberg Equilibrium Violation and Publication Bias in a Meta-Analysis

BACKGROUND: The M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease (CHD). METHODOLOGY/PRINCIPAL FINDINGS: A case-cohort study was conducted in 1,732 unrelated middle-age women (210 CHD cases and 1,522 controls) from a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model to study the association of the polymorphism with acute myocardial infarction (AMI) (n = 71) and CHD. In the case-cohort study, no increased risk for CHD was found under the additive genetic model (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.86 to 1.68; P = 0.28). This result was not changed by adjustment (HR = 1.17; 95% CI, 0.83 to 1.64; P = 0.38) nor by using dominant, recessive and pairwise genetic models. Analyses for AMI risk under the additive genetic model also did not show any statistically significant association (crude HR = 1.14; 95% CI, 0.93 to 1.39; P = 0.20). To evaluate the association, a comprehensive systematic review and meta-analysis were undertaken of all studies published up to February 2007 (searched through PubMed/MEDLINE, Web of Science and EMBASE). The meta-analysis (38 studies with 13284 cases and 18722 controls) showed a per-allele odds ratio (OR) of 1.08 (95% CI, 1.01 to 1.15; P = 0.02). Moderate to large levels of heterogeneity were identified between studies. Hardy-Weinberg equilibrium (HWE) violation and the mean age of cases were statistically significant sources of the observed variation. In a stratum of non-HWE violation studies, there was no effect. An asymmetric funnel plot, the Egger's test (P = 0.066), and the Begg-Mazumdar test (P = 0.074) were all suggestive of the presence of publication bias. CONCLUSIONS/SIGNIFICANCE: The pooled OR of the present meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remains uncertain because it may be due to various residual biases, including HWE-violation and publication biases

Novel mutations in TLR genes cause hyporesponsiveness to Mycobacterium avium subsp. paratuberculosis infection

<p>Abstract</p> <p>Background</p> <p>Toll like receptors (TLR) play the central role in the recognition of pathogen associated molecular patterns (PAMPs). Mutations in the TLR1, TLR2 and TLR4 genes may change the ability to recognize PAMPs and cause altered responsiveness to the bacterial pathogens.</p> <p>Results</p> <p>The study presents association between TLR gene mutations and increased susceptibility to <it>Mycobacterium avium </it>subsp. <it>paratuberculosis </it>(MAP) infection. Novel mutations in TLR genes (TLR1- Ser150Gly and Val220Met; TLR2 – Phe670Leu) were statistically correlated with the hindrance in recognition of MAP legends. This correlation was confirmed subsequently by measuring the expression levels of cytokines (IL-4, IL-8, IL-10, IL-12 and IFN-γ) in the mutant and wild type moDCs (mocyte derived dendritic cells) after challenge with MAP cell lysate or LPS. Further <it>in silico </it>analysis of the TLR1 and TLR4 ectodomains (ECD) revealed the polymorphic nature of the central ECD and irregularities in the central LRR (leucine rich repeat) motifs.</p> <p>Conclusion</p> <p>The most critical positions that may alter the pathogen recognition ability of TLR were: the 9^thamino acid position in LRR motif (TLR1–LRR10) and 4^thresidue downstream to LRR domain (exta-LRR region of TLR4). The study describes novel mutations in the TLRs and presents their association with the MAP infection.</p

GENETIC TESTING AND MOLECULAR BIOMARKERS

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by episodes of inflammation in the absence of high-titer autoantibodies or antigen-specific T cells. The Mediterranean fever (MEFV) gene located on chromosome 16p13.3, which encodes the 781-amino-acid protein pyrin, is the causative gene for this monogenic Mendelian disease. This study presents the molecular analysis of an MEFV gene mutation screen of 5518 Turkish individuals with clinical diagnoses of FMF. Patients were genetically diagnosed using the FMF StripAssay and DNA sequencing analysis. Contrary to the results achieved by the FMF StripAssay, DNA sequencing analysis identified large-scale coding and noncoding novel sequence variants, together with a significant group (76%) of individuals who were receiving colchicine and had a single heterozygous mutation, despite the recessive inheritance of FMF. In conclusion, sequence analysis, unlike other routine laboratory techniques, may enable screening for a broad range of nucleotide variations and may prevent less common, population-restricted, novel sequence variants from being overlooked

CLINICA CHIMICA ACTA

Background: The renin-angiotensin system (RAS) and endothelial nitric oxide (NO) affect the pathogenesis of atherosclerosis and prognosis of coronary artery disease (CAD). Previous epidemiologic data suggested that genetic factors are more likely to affect young rather than old people. Our objective was to investigate the association between the polymorphisms of eNOS (Glu298Asp) and the RAS genes and premature CAD in a Turkish population. Methods: A total of 115 Turkish patients with premature CAD and 83 controls were included in the study. ACE I/D, AT1R A/C, AGT T/M and eNOS Glu298Asp gene polymorphisms were analysed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results: It was found that increased premature CAD risk is associated with higher frequencies of the ACE DD [OR: 2.600 (CI 95% 1.395-4.847,p=0.002)], AGT MM [OR=2.407 (Cl 95% 1.267-4.573,p=0.007)] and eNOS 894TT [OR-17.000 (CI 95% 3.952-73.125,p<0.001)] genotypes. Carriers of ACE DD+eNOS 894TT (p=0.002), AGT MM+eNOS 894TT (p=0.001), ATIR AA+eNOS 894TT and ATIR non-AA+eNOS 894TT (p=0.002) genotypes were significantly associated with the risk of premature CAD

BIOCHEMICAL GENETICS

Angiotensin converting enzyme (ACE) plays an essential role in the renin-angiotensin system. It converts angiotensin I to angiotensin II and inactivates bradykinin and tachykinins. Numerous studies have been published investigating associations of the ACE gene I/D polymorphism with various pathophysiological conditions. We examined the prevalence of the ACE I/D polymorphism in a sample of healthy volunteers from western Turkey, including 1063 healthy Turkish controls. Analysis of the ACE I/D gene polymorphisms by polymerase chain reaction found frequencies of 16.1% for the II genotype, 47.7% for the ID genotype, and 36.2% for the DD genotype. The allele frequency was 39.9% for the I alleles and 60.1% for the D allele. This study demonstrates that the allele and genotype frequency values for the Turkish population are similar to previously published frequencies for Caucasian populations