Long QT syndrome — a cause of sudden death.

Sindrom dugog QT intervala (LQTS) je primarni aritmijski poremećaj koji može dovesti do pojave malignih ventrikularnih aritmija tipa torsades de pointe (TdP) i iznenadne srčane smrti. Obilježja u elektrokardiogramu (EKG) uključuju produljenje korigiranog QT intervala i abnormalnosti T-vala. Do danas identificirana genetska osnova za LQTS uključuje trinaest podložnih gena za LQTS: KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1, i KCNJ5. Najčešći genotip su mutacije KCNQ1 te gotovo polovica pacijenata ima tu vrstu mutacije. Navedeni geni kodiraju ionske kanale i regulatorne proteine koji su uključeni u modulaciju struja srčanog akcijskog potencijala. Stečeni oblici LQTS-a mogu također biti uzrokovani genetskim mutacijama, u tim slučajevima nositelji mutacija razvijaju aritmije isključivo u određenim uvjetima (npr. uporaba određenih lijekova). Trenutna terapija uključuje primjenu beta-blokatora, ugradnju implantabilnog kardioverter defibrilatora (ICD) te simpatičku denervaciju srca. LQTS mutacije povezane su s iznenadnom srčanom smrti kod mladih i veoma mladih; a post-mortem genetska testiranja LQTS gena mogu biti korisna kod procjene uzroka iznenadne neobjašnjive smrti (sudden unexplained death). Kaskadni probir koristan je za identificiranje asimptomatskih članova obitelji koji mogu biti pod povećanim rizikom od iznenadne smrti. U ovom preglednom članku prikazali smo gene povezane s LQTS-om zajedno s opisom povezanih patofizioloških mehanizama.Long QT syndrome (LQTS) is a primary arrhythmic disorder that may lead to the precipitation of torsades de pointe (TdP) and sudden death. Electrocardiogram (ECG) features include prolongation of the corrected QT interval and T-wave abnormalities. The genetic basis of LQTS identified to date includes thirteen susceptibility genes for LQTS: KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1, and KCNJ5. Mutations in KCNQ1 are by far the most frequent genotype with nearly half of the patients carrying KCNQ1 mutations. These genes code for ion channels and regulatory proteins that are involved in the modulation of the currents of the cardiac action potential (AP). Acquired forms of LQTS may also have underlying genetic mutations, in these cases mutation carriers develop arrhythmias only under certain conditions (e.g. use of certain medications). Current therapies include use of beta-blockers, implantable cardioverter defibrillators (ICD) and left cardiac sympathetic denervation. LQTS mutations have been associated with sudden death in the young and very young; and postmortem genetic testing in LQTS genes can be useful when assessing the cause of a sudden unexplained death. Cascade screening is also useful to identify asymptomatic family members that may be at risk of sudden death. Here we have reviewed the genes associated with LQTS along with the description of the related pathophysiological mechanisms

Long QT syndrome — a cause of sudden death.

Sindrom dugog QT intervala (LQTS) je primarni aritmijski poremećaj koji može dovesti do pojave malignih ventrikularnih aritmija tipa torsades de pointe (TdP) i iznenadne srčane smrti. Obilježja u elektrokardiogramu (EKG) uključuju produljenje korigiranog QT intervala i abnormalnosti T-vala. Do danas identificirana genetska osnova za LQTS uključuje trinaest podložnih gena za LQTS: KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1, i KCNJ5. Najčešći genotip su mutacije KCNQ1 te gotovo polovica pacijenata ima tu vrstu mutacije. Navedeni geni kodiraju ionske kanale i regulatorne proteine koji su uključeni u modulaciju struja srčanog akcijskog potencijala. Stečeni oblici LQTS-a mogu također biti uzrokovani genetskim mutacijama, u tim slučajevima nositelji mutacija razvijaju aritmije isključivo u određenim uvjetima (npr. uporaba određenih lijekova). Trenutna terapija uključuje primjenu beta-blokatora, ugradnju implantabilnog kardioverter defibrilatora (ICD) te simpatičku denervaciju srca. LQTS mutacije povezane su s iznenadnom srčanom smrti kod mladih i veoma mladih; a post-mortem genetska testiranja LQTS gena mogu biti korisna kod procjene uzroka iznenadne neobjašnjive smrti (sudden unexplained death). Kaskadni probir koristan je za identificiranje asimptomatskih članova obitelji koji mogu biti pod povećanim rizikom od iznenadne smrti. U ovom preglednom članku prikazali smo gene povezane s LQTS-om zajedno s opisom povezanih patofizioloških mehanizama.Long QT syndrome (LQTS) is a primary arrhythmic disorder that may lead to the precipitation of torsades de pointe (TdP) and sudden death. Electrocardiogram (ECG) features include prolongation of the corrected QT interval and T-wave abnormalities. The genetic basis of LQTS identified to date includes thirteen susceptibility genes for LQTS: KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1, and KCNJ5. Mutations in KCNQ1 are by far the most frequent genotype with nearly half of the patients carrying KCNQ1 mutations. These genes code for ion channels and regulatory proteins that are involved in the modulation of the currents of the cardiac action potential (AP). Acquired forms of LQTS may also have underlying genetic mutations, in these cases mutation carriers develop arrhythmias only under certain conditions (e.g. use of certain medications). Current therapies include use of beta-blockers, implantable cardioverter defibrillators (ICD) and left cardiac sympathetic denervation. LQTS mutations have been associated with sudden death in the young and very young; and postmortem genetic testing in LQTS genes can be useful when assessing the cause of a sudden unexplained death. Cascade screening is also useful to identify asymptomatic family members that may be at risk of sudden death. Here we have reviewed the genes associated with LQTS along with the description of the related pathophysiological mechanisms

Fc Gamma Receptor IIIB (FcɣRIIIB) Polymorphisms Are Associated with Clinical Malaria in Ghanaian Children

The original publication is available at http://www.plosone.orgPlasmodium falciparum malaria kills nearly a million people annually. Over 90% of these deaths occur in children under five years of age in sub-Saharan Africa. A neutrophil mediated mechanism, the antibody dependent respiratory burst (ADRB), was recently shown to correlate with protection from clinical malaria. Human neutrophils constitutively express Fc gamma receptor-FcɣRIIA and FcɣRIIIB by which they interact with immunoglobulin (Ig) G (IgG)-subclass antibodies. Polymorphisms in exon 4 of FCGR2A and exon 3 of FCGR3B genes encoding FcɣRIIA and FcɣRIIIB respectively have been described to alter the affinities of both receptors for IgG. Here, associations between specific polymorphisms, encoding FcɣRIIA p.H166R and FcɣRIIIB-NA1/NA2/SH variants with clinical malaria were investigated in a longitudinal malaria cohort study. FcɣRIIA-p.166H/R was genotyped by gene specific polymerase chain reaction followed by allele specific restriction enzyme digestion. FCGR3B-exon 3 was sequenced in 585 children, aged 1 to 12 years living in a malaria endemic region of Ghana. Multivariate logistic regression analysis found no association between FcɣRIIA-166H/R polymorphism and clinical malaria. The A-allele of FCGR3B-c.233C>A (rs5030738) was significantly associated with protection from clinical malaria under two out of three genetic models (additive: p = 0.0061; recessive: p = 0.097; dominant: p = 0.0076) of inheritance. The FcɣRIIIB-SH allotype (CTGAAA) containing the 233A-allele (in bold) was associated with protection from malaria (p = 0.049). The FcɣRIIIB-NA2*03 allotype (CTGCGA), a variant of the classical FcɣRIIIB-NA2 (CTGCAA) was associated with susceptibility to clinical malaria (p = 0.0092). The present study is the first to report an association between a variant of FcɣRIIIB-NA2 and susceptibility to clinical malaria and provides justification for further functional characterization of variants of the classical FcɣRIIIB allotypes. This would be crucial to the improvement of neutrophil mediated functional assays such as the ADRB assay aimed at assessing the functionality of antibodies induced by candidate malaria vaccines.European and Developing Countries Clinical Trials Partnership (www.edctp.org) (TA.2007.40200.012)European Vaccine Initiative (www.euvaccine.eu) (08-2007)African Malaria Network Trust (www.amanet-trust.org) (008/2008AIA)Publisher's versio

The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

The original publication is available at http://www.jnrbm.com/content/10/1/12Includes bibliographyAbstract Background The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic disease associated with an improper hypertrophic response. Results The coding regions of KCNE1, KCNE2, KCNE3, KCNE4, and KCNE5 were examined, by direct DNA sequencing, in a cohort of 93 unrelated HCM probands and 188 blood donor controls. Fifteen genetic variants, four previously unknown, were identified in the HCM probands. Eight variants were non-synonymous and one was located in the 3'UTR-region of KCNE4. No disease-causing mutations were found and no significant difference in the frequency of genetic variants was found between HCM probands and controls. Two variants of likely functional significance were found in controls only. Conclusions Mutations in KCNE genes are not a common cause of HCM and polymorphisms in these genes do not seem to be associated with a propensity to develop arrhythmiaPeer Reviewe

Hereditary Hemochromatosis (HFE) genotypes in heart failure: Relation to etiology and prognosis

<p>Abstract</p> <p>Background</p> <p>It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the <it>HFE </it>gene. In a large cohort of HF patients, we sought to determine the etiological role and the prognostic significance of <it>HFE </it>genotypes.</p> <p>Methods</p> <p>We studied 667 HF patients (72.7% men) with depressed systolic function, enrolled in a multicentre trial with a follow-up period of up to 5 years. All were genotyped for the known <it>HFE </it>variants C282Y, H63D and S65C.</p> <p>Results</p> <p>The genotype and allele frequencies in the HF group were similar to the frequencies determined in the general Danish population. In multivariable analysis mortality was not predicted by C282Y-carrier status (HR 1.2, 95% CI: 0.8-1.7); H63D-carrier status (HR 1.0, 95% CI: 0.7-1.3); nor S65C-carrier status (HR 1.2, 95% CI: 0.7-2.0). We identified 27 (4.1%) homozygous or compound heterozygous carriers of <it>HFE </it>variants. None of these carriers had a clinical presentation suggesting hemochromatosis, but hemoglobin and ferritin levels were higher than in the rest of the cohort. Furthermore, a trend towards reduced mortality was seen in this group in univariate analyses (HR 0.4, 95% CI: 0.2-0.9, p = 0.03), but not in multivariate (HR 0.5, 95% CI: 0.2-1.2).</p> <p>Conclusion</p> <p><it>HFE </it>genotypes do not seem to be a significant contributor to the etiology of heart failure in Denmark. <it>HFE </it>variants do not affect mortality in HF.</p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Polymorphisms in the RNASE3 Gene Are Associated with Susceptibility to Cerebral Malaria in Ghanaian Children

BACKGROUND: Cerebral malaria (CM) is the most severe outcome of Plasmodium falciparum infection and a major cause of death in children from 2 to 4 years of age. A hospital based study in Ghana showed that P. falciparum induces eosinophilia and found a significantly higher serum level of eosinophil cationic protein (ECP) in CM patients than in uncomplicated malaria (UM) and severe malaria anemia (SA) patients. Single nucleotide polymorphisms (SNPs) have been described in the ECP encoding-gene (RNASE3) of which the c.371G>C polymorphism (rs2073342) results in an arginine to threonine amino acid substitution p.R124T in the polypeptide and abolishes the cytotoxicity of ECP. The present study aimed to investigate the potential association between polymorphisms in RNASE3 and CM. METHODOLOGY/PRINCIPAL FINDINGS: The RNASE3 gene and flanking regions were sequenced in 206 Ghanaian children enrolled in a hospital based malaria study. An association study was carried out to assess the significance of five SNPs in CM (n=45) and SA (n=56) cases, respectively. The two severe case groups (CM and SA) were compared with the non-severe control group comprising children suffering from UM (n=105). The 371G allele was significantly associated with CM (p=0.00945, OR=2.29, 95% CI=1.22-4.32) but not with SA. Linkage disequilibrium analysis demonstrated significant linkage between three SNPs and the haplotype combination 371G/*16G/*94A was strongly associated with susceptibility to CM (p=0.000913, OR=4.14, 95% CI=1.79-9.56), thus, defining a risk haplotype. The RNASE3 371GG genotype was found to be under frequency-dependent selection. CONCLUSIONS/SIGNIFICANCE: The 371G allele of RNASE3 is associated with susceptibility to CM and forms part of a risk associated haplotype GGA defined by the markers: rs2073342 (G-allele), rs2233860 (G-allele) and rs8019343 (A-allele) respectively. Collectively, these results suggest a hitherto unrecognized role for eosinophils in CM pathogenesis