Heidi Fodstad

association between HERG K897T polymorphism and QT interval in middle-aged finnish women

OBJECTIVES The aim of this study was to test whether a recently reported polymorphism in the HERG gene coding for the rapidly activating delayed rectifier K+ channel has influence on myocardial repolarization. BACKGROUND The length of myocardial repolarization, measured as the QT interval, has a hereditary component, but no genes that would explain the variability of repolarization have been identified in healthy subjects. METHODS QT intervals were measured from the 12-lead electrocardiogram in a random middle-aged population (226 men/187 women). The longest QT interval at any of the 12 leads (QTmax), QTV(2), and the Tpeak-Tend interval were used as measures of repolarization. Deoxyribonucleic acid samples were genotyped for the nucleotide 2690A>C variation of the HERG gene, corresponding to the HERG K(lysine)897T(threonine) amino acid polymorphism. RESULTS The allele frequencies were 0.84 (A) and 0.16 (C). Females with the genotype AC or CC had longer QTcmax (477 +/- 99 ms) and Tpeak-Tend intervals (143 +/- 95 ms) than females with the genotype AA (441 +/- 69 ms and 116 +/- 65 ms, p = 0.005 and p = 0.025, respectively). In males, the QTcmax and the Tpeak-Tend intervals did not differ between the genotypes. After adjustment for echocardiographic and various laboratory variables, the HERG K897T polymorphism remained as an independent predictor of QTcmax (p = 0.009) and the Tpeak-Tend intervals (p = 0.026) in females. CONCLUSIONS; The common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females.

Four potassium channel mutations account for 73% of the genetic spectrum underlying long-QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland.

BACKGROUND. Mutations in five cardiac voltage‐gated ion channel genes, including KCNQ1, HERG, SCN5A, KCNE1 and KCNE2, constitute the principal cause of inherited long‐QT syndrome (LQTS). Typically, each family carries its own private mutation, and the disease manifests with varying phenotype and incomplete penetrance, even within particular families. We had previously identified 14 different LQTS‐causing mutations in 92 Finnish families. AIM. In order to complete the characterization of Finnish spectrum of LQTS genes, we conducted a systematic search for mutations in the five LQTS genes among 188 additional unrelated probands. METHODS. The screening was performed by denaturing high‐performance liquid chromatography (dHPLC) and DNA sequencing. RESULTS. Nineteen novel and 12 previously described mutations were identified. Collectively, these data extend the number of molecularly defined affected Finnish LQTS families and patients at present to 150 and 939, respectively. Four presumable founder mutations (KCNQ1 G589D and IVS7‐2A > G, HERG R176W and L552S) together account for as much as 73% of all established Finnish LQTS cases. CONCLUSIONS. The extent of genetic homogeneity underlying LQTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LQTS, and constituting an excellent basis to study the role of genetic and non‐genetic factors influencing phenotypic variability in this disease.

Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects

Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N‐terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20‐30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals. Hum Mutat 15:580–581, 2000.

Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG)

OBJECTIVE To determine whether the amino acid 897 threonine (T) to lysine (K) polymorphism of the KCNH2 (HERG) potassium channel influences channel performance or patient phenotype. METHODS The phenotypic effects of this polymorphism were investigated in vitro by electrophysiological experiments in HEK-293 cells and in vivo by exercise electrocardiography in a group of LQTS patients carrying the same genetically proven KCNQ1 mutation. RESULTS When expressed in HEK-293 cells, the 897T isoform of the KCNH2 channel exhibited changes in inactivation and deactivation properties, and a smaller current density than the more common 897K isoform. Western blot experiments indicated that the decreased current density associated with 897T was caused by reduced channel expression. During a maximal exercise test in 39 LQT1 patients carrying an identical KCNQ1 mutation (G589D) and showing a prolonged QT interval (>440 ms), QT intervals were longer in patients carrying the 897T allele than in those homozygous for the 897K allele. CONCLUSIONS The K897T variation has an effect on channel function and clinical phenotype. Our data warrant further investigations into the significance of this polymorphism in drug-induced and inherited LQTS.

Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension

BackgroundRare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddles syndrome. We decided to screen for common variants in the ENaC βand γ subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system.MethodsInitially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests.ResultsTwo commonly occurring βENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel γENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly higher than that in normotensive males (2.9%, p = 0.007) and blood donors (3.0%, p = 0.001). βENaC i12-17CT was significantly more prevalent in the hypertension group than in the two control groups combined (4.6% vs. 1.1%, p = 0.001). When expressed in Xenopus oocytes, neither of the two ENaC amino acid-changing variants showed a significant difference in activity compared with ENaC wild-type. No direct evidence for a mRNA splicing defect could be obtained for the βENaC intronic variant. The ratio of daily urinary potassium excretion to upright and mean (of supine and upright values) plasma renin activity was higher in variant allele carriers than in non-carriers (p = 0.034 and p = 0.048).ConclusionsAt least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of β and γENaC, a three times higher prevalence than in the normotensive individuals or in random healthy controls. Patients with the variant alleles showed an increased urinary potassium excretion rate in relation to their renin levels.

Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients

Background. Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death. Aim. The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study. Methods. To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS‐7 or HEK293 cells. Results. The KCNQ1 IVS7‐2A>G (KCNQ1‐FinB) mutation associated with a mean QTc interval of 464 ms and a complete loss‐of‐channel function. The HERG R176W (HERG‐FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448 ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7‐2A>G). When present simultaneously with an apparent LQTS‐causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect. Conclusions. The HERG R176W mutation represents a population‐prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.

Molecular screening of selected long QT syndrome (LQTS) mutations in 165 consecutive bodies found in water.

Abstract. The association of the long QT-syndrome (LQTS) with single accidental drowning or near-drowning cases has been recently emphasised, but no data on the prevalence of LQTS among drowning victims are currently available. In this study, we have retrospectively screened specific founder mutations in KCNQ1 (KVLQT1) and KCNH2 (HERG) genes in 165 consecutive bodies found in water in Finland. We found a KCNH2-Fin mutation in a 44-year-old woman whose death was classified as suicidal drowning, whereas no other carriers of the two LQTS founder mutations were identified among the remaining 164 victims. This study provides the first estimate of the minimum prevalence of LQTS (0.61%, CI95: 0.02–3.33) in such a setting and demonstrates the value of genetic analysis of LQTS in putative drownings. The detection of a LQTS founder mutation in a body found in water is a relatively rare event based on our study sample. This finding is, however, of utmost medico-legal importance, since it broadens the spectrum of potential causes and manners of death.

Common genetic variation of β1- and β2-adrenergic receptor and response to four classes of antihypertensive treatment

Varying results have been reported on the association of β-adrenergic receptor polymorphisms with blood pressure (BP) response to β-blockers. We investigated the influence of ADRB1 Ser49Gly and Arg389Gly, and ADRB2 Gly16Arg and Glu27Gln polymorphisms on ambulatory BP response to bisoprolol and three other antihypertensive drug monotherapies in a placebo-controlled, double-blind, cross-over study with 233 moderately hypertensive men. ADRB1 Ser49Ser homozygotes tended to have a better ambulatory BP response to bisoprolol but the difference was statistically nonsignificant. ADRB1 Arg389Arg homozygotes did not show better BP response to bisoprolol than the other genotypes. There were no significant associations of ADRB2 polymorphisms with BP responses to any of the study drugs. The results from this controlled study in hypertensive men do not support clinical use of common polymorphisms in ADRB1 and ADRB2 in predicting BP responses to β-blockers or to three other antihypertensive drugs.

Renin–Angiotensin System and α-Adducin Gene Polymorphisms and Their Relation to Responses to Antihypertensive Drugs: Results From the GENRES Study

BACKGROUND Polymorphisms in genes coding for components of the renin-angiotensin system (RAS) and alpha-adducin (ADD1) have been reported to be associated with blood pressure (BP) responses to antihypertensive agents. The results, however, have not been consistent and most of the earlier studies have been small and lacked placebo-control. Therefore, the association of common polymorphisms in these genes with BP responses to four different antihypertensive drugs was analyzed in a controlled study. METHODS The study included 208 hypertensive Finnish men from the GENRES study. All of them used amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide (HCT) 25 mg, and losartan 50 mg daily, each for 4 weeks as a monotherapy in a double-blind, randomized, study. The treatment periods were separated by 4-week placebo periods. Both 24-h ambulatory (ABP) and office BP (OBP) measurements were carried out. The polymorphisms analyzed were ADD1 Gly460Trp, angiotensinogen (AGT) Met235Thr, angiotensin converting enzyme (ACE) insertion/deletion (I/D), and angiotensin II type 1 receptor (AGTR1) 1166A/C. RESULTS The presence of 460Trp allele of ADD1, previously suggested to be a marker of thiazide responsiveness, did not predict a better response to HCT. There was no significant association of AGT Met235Thr, ACE I/D, and AGTR1 1166A/C polymorphisms with BP responses to the study drugs. ADD1 460Trp and AGT 235Thr alleles were associated with higher systolic white coat effect (WCE) during the placebo periods (P values 0.03 and 0.01, respectively). CONCLUSIONS Common polymorphisms of ADD1, AGT, ACE, and AGTR1 do not markedly predict BP responses to amlodipine, bisoprolol, HCT, and losartan, at least in white hypertensive men.