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G M Vincent

Publications and source records attributed to G M Vincent.

At least 37 records · Page 2Linked to original sources
PubMed1998

The molecular genetics of the long QT syndrome: genes causing fainting and sudden death.

The congenital long QT syndrome is an autosomal-dominant genetic disorder of cardiac electrical repolarization. It is caused by mutations of at least six genes, of which four, all encoding for cardiac ion channels, have been identified: KVLQT1, HERG, and Min K encode for cardiac potassium ion channels, and SCN5A encodes for the cardiac sodium ion channel. In each case the altered ion channel function produces prolongation of the action potential and propensity to torsade de pointes ventricular tachycardia. A fifth gene locus is known to be on chromosome 4, but the gene has not been isolated. At least one other gene must exist, and there may be several more. Long QT syndrome is a frequent but often overlooked cause of unexpected syncope and sudden death in children and young adults. Characteristic findings are prolongation of the QT interval and T wave abnormalities on the electrocardiogram. However, the QT interval at presentation is normal about 10% of the time and just borderline prolonged another 30%, so diagnosis may be difficult. Symptoms are syncope and sudden death, typically occurring during exercise or emotional upset. The manifestations vary, depending on the genotype present. The phenotype also probably varies, depending on the specific mutation involved. Phenotypic heterogeneity is also caused by variable penetrance and expressivity.

Action Potentials↗
PubMed1997

Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome.

OBJECTIVES: We sought to analyze age-gender differences in the rate-corrected QT (QTc) interval in the presence of a QT-prolonging gene. BACKGROUND: Compared with men, women exhibit a longer QTc interval and an increased propensity toward torsade de pointes. In normal subjects, the QTc gender difference reflects QTc interval shortening in men during adolescence. METHODS: QTc intervals were analyzed according to age (< 16 or > or = 16 years) and gender in 460 genotyped blood relatives from families with long QT syndrome linked to chromosome 11p (KVLQT1; n = 199), 7q (HERG; n = 208) or 3p (SCN5A; n = 53). RESULTS: The mean QTc interval in genotype-negative blood relatives (n = 240) was shortest in men, but similar among women, boys and girls. For genotype-positive blood relatives, men exhibited the shortest mean QTc interval in chromosome 7q- and 11p-linked blood relatives (n = 194), but not in the smaller 3p-linked group (n = 26). Among pooled 7q- and 11p-linked blood relatives, multiple regression analysis identified both genotype (p < 0.001) and age-gender group (men vs. women/children; p < 0.001) as significant predictors of the QTc interval; and heart rate (p < 0.001), genotype (p < 0.001) and age-gender group (p = 0.01) as significant predictors of the absolute QT interval. A shorter mean QT interval in men was most evident for heart rates < 60 beats/min. CONCLUSIONS: In familial long QT syndrome linked to either chromosome 7q or 11p, men exhibit shorter mean QTc values than both women and children, for both genotype-positive and -negative blood relatives. Thus, adult gender differences in propensity toward torsade de pointes may reflect the relatively greater presence in men of a factor that blunts QT prolongation responses, especially at slow heart rates.

Adolescent↗
PubMed1997

Lipoprotein(a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease.

An interaction between high plasma lipoprotein(a) [Lp(a)], unfavorable plasma lipids, and other risk factors may lead to very high risk for premature CAD. Plasma Lp(a), lipids, and other coronary risk factors were examined in 170 cases with early familial CAD and 165 control subjects to test this hypothesis. In univariate analysis, relative odds for CAD were 2.95 (P < .001) for plasma Lp(a) above 40 mg/dL. Nearly all the risk associated with elevated Lp(a) was found to be restricted to persons with historically elevated plasma total cholesterol (6.72 mmol/L [260 mg/dL] or higher) or with a total/HDL cholesterol ratio > 5.8. Nonlipid risk factors were also found to at least multiply the risk associated with Lp(a). When Lp(a) was over 40 mg/dL and plasma total/HDL cholesterol > 5.8, relative odds for CAD were 25 (P = .0001) in multiple logistic regression. If two or more nonlipid risk factors were also present (including hypertension, diabetes, cigarette smoking, high total homocysteine, or low serum bilirubin), relative odds were 122 (P < 1 x 10(-12)). The ability of nonlipid risk factors to increase risk associated with Lp(a) was dependent on at least a mildly elevated total/HDL cholesterol ratio. In conclusion, high Lp(a) was found to greatly increase risk only if the total/HDL cholesterol ratio was at least mildly elevated, an effect exaggerated by other risk factors. Aggressive lipid lowering in those with elevated Lp(a) therefore appears indicated.

Age of Onset↗
PubMed1997

George M. Cober Lecturer: Mark T. Keating. Molecular basis of the long-QT syndrome associated with deafness.

Jervell and Lange-Nielsen syndrome is an autosomal recessive form of long-QT syndrome. In addition to QT interval prolongation, this disorder is associated with congenital deafness. Jervell and Lange-Nielsen syndrome is rare, but affected individuals are susceptible to cardiac arrhythmias with a high incidence of sudden death and short life expectancy. A proband with Jervell and Lange-Nielsen syndrome and family members were ascertained and phenotypically characterized. Linkage, mutational, and DNA sequence analyses were used to define the genetic basis of this disorder. We found that the proband had long-QT syndrome and sensory deafness. Some family members also had QTc prolongation with an autosomal dominant pattern of inheritance, but these patients had normal hearing. The gene responsible for QTc prolongation in this family was mapped to chromosome 11p15.5 using linkage analyses. The maximum LOD score at D11S1318 was 5.46, indicating odds greater than 100,000:1 favoring linkage. Mutation analyses revealed a single base pair insertion in KVLQT11, the potassium channel gene responsible for chromosome 11-linked long-QT syndrome. This mutation caused a premature stop codon. All family members with QTc prolongation, except the proband, were heterozygous for the mutation. The proband with Jervell and Lange-Nielsen syndrome resulted from a consanguineous marriage and was homozygous for the KVLQT1 mutation. Homozygous mutation of KVLQT1 causes Jervell and Lange-Nielsen syndrome. Members of Jervell and Lange-Nielsen syndrome families should be examined for long-QT syndrome, even if they have normal hearing.

Adolescent↗
PubMed1996

Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS.

The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease, Mutations in the human ether-à-go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KVLQT1, a newly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HERG mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings.

Cardiology↗
PubMed1996

Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.

Genetic factors contribute to the risk of sudden death from cardiac arrhythmias. Here, positional cloning methods establish KVLQT1 as the chromosome 11-linked LQT1 gene responsible for the most common inherited cardiac arrhythmia. KVLQT1 is strongly expressed in the heart and encodes a protein with structural features of a voltage-gated potassium channel. KVLQT1 mutations are present in affected members of 16 arrhythmia families, including one intragenic deletion and ten different missense mutations. These data define KVLQT1 as a novel cardiac potassium channel gene and show that mutations in this gene cause susceptibility to ventricular tachyarrhythmias and sudden death.

Amino Acid Sequence↗
PubMed1996

Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease.

Mildly increased serum bilirubin has recently been suggested as a protective factor, possibly reducing the risk of coronary artery disease (CAD) by acting as an antioxidant. We tested this hypothesis by examining serum bilirubin concentrations and other coronary risk factors in 120 men and 41 women with early familial CAD and 155 control subjects. At screening, both cases and control subjects were 38 to 68 years old. Early familial CAD patients had experienced myocardial infarction, coronary artery bypass grafting, or coronary angioplasty by age 55 years for men and 65 for women and had another sibling similarly affected. The average total serum bilirubin concentration was 8.9 +/- 6.1 mumol/L in cases and 12.4 +/- 8.1 mumol/L in control subjects (P = .0001 for difference). In univariate analysis stratified by sex, serum bilirubin was strongly and inversely related to CAD risk, with relative odds of 0.4 to 0.1 (relative to the lowest quintile, P = .04 to .00001) in both men and women as bilirubin increased into the upper two quintiles. Multiple logistic regression analysis was performed including age, sex, smoking, body mass index, diabetes, hypertension, plasma measured LDL cholesterol, HDL cholesterol, triglycerides, and serum bilirubin as potential risk factors. Bilirubin entered as an independent protective factor with an odds ratio of 0.25 (P = .0015) for an increase of 17 mumol/L (1 mg/dL). The standardized logistic regression coefficient for bilirubin was -.33 compared with -.34 for HDL, suggesting that the protective effect of bilirubin on CAD risk in the population is comparable to that of HDL cholesterol. A history of cigarette smoking was associated with significantly lower serum bilirubin concentration and appeared to attenuate the protective effect of bilirubin.

Aged↗
PubMed1995

ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome.

BACKGROUND: The long QT syndrome is an inherited disorder with prolonged ventricular repolarization and a propensity to ventricular tachyarrhythmias and sudden arrhythmic death. Recent linkage studies have demonstrated three separate loci for this disorder on chromosomes 3, 7, and 11, and specific mutated genes for long QT syndrome have been identified on two of these chromosomes. We investigated ECG T-wave patterns (phenotypes) in members of families linked to three genetically distinct forms of the long QT syndrome. METHODS AND RESULTS: Five quantitative ECG repolarization parameters, ie, four Bazett-corrected time intervals (QTonset-c, QTpeak-c, QTc, and Tduration-c, in milliseconds) and the absolute height of the T wave (Tamplitude, in millivolts), were measured in 153 members of six families with long QT syndrome linked to markers on chromosomes 3 (n = 47), 7 (n = 30), and 11 (n = 76). Genotypic data were used to define each family member as being affected or unaffected with long QT syndrome. Affected members of all six families had longer QT intervals (QTonset-c, QTpeak-c, or QTc) than unaffected family members (P < .01). Each of the three long QT syndrome genotypes was associated with somewhat distinctive ECG repolarization features. Among affected individuals, the QTonset-c was unusually prolonged in those individuals with mutations involving the cardiac sodium channel gene SCN5A on chromosome 3 (lead II QTonset-c [mean +/- SD]: chromosome 3, 341 +/- 42 ms; chromosome 7, 290 +/- 56 ms; chromosome 11, 243 +/- 73 ms; P < .001); Tamplitude was generally quite small in the chromosome 7 genotype (lead II Tamplitude, mV: chromosome 3, 0.36 +/- 0.14; chromosome 7, 0.13 +/- 0.07; chromosome 11, 0.37 +/- 0.17; P < .001); and Tduration was particularly long in the chromosome 11 genotype (lead II Tduration-c: chromosome 3, 187 +/- 33 ms; chromosome 7, 191 +/- 51 ms; chromosome 11, 262 +/- 65 ms; P < .001). Similar ECG findings were observed in leads aVF and V5. A considerable variability exists in the quantitative repolarization parameters associated with each genotype, with overlap in the T-wave patterns among the three genotypes. CONCLUSIONS: Three separate genetic loci for the long QT syndrome including mutations in two cardiac ionic channel genes were associated with different phenotypic T-wave patterns on the ECG. This study provides insight into the influence of genetic factors on ECG manifestations of ventricular repolarization.

Adult↗
PubMed1995

A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.

To identify genes involved in cardiac arrhythmia, we investigated patients with long QT syndrome (LQT), an inherited disorder causing sudden death from a ventricular tachyarrythmia, torsade de pointes. We previously mapped LQT loci on chromosomes 11 (LQT1), 7 (LQT2), and 3 (LQT3). Here, linkage and physical mapping place LQT2 and a putative potassium channel gene, HERG, on chromosome 7q35-36. Single strand conformation polymorphism and DNA sequence analyses reveal HERG mutations in six LQT families, including two intragenic deletions, one splice-donor mutation, and three missense mutations. In one kindred, the mutation arose de novo. Northern blot analyses show that HERG is strongly expressed in the heart. These data indicate that HERG is LQT2 and suggest a likely cellular mechanism for torsade de pointes.

Amino Acid Sequence↗
PubMed1995

Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia.

Long QT syndrome (LQT) is an inherited cardiac disorder that causes syncope, seizures and sudden death from ventricular tachyarrhythmias. We used single-strand conformation polymorphism (SSCP) and DNA sequence analyses to identify mutations in the cardiac sodium channel gene, SCN5A, in affected members of four LQT families. These mutations include two identical intragenic deletions and two missense mutations. These data suggest that SCN5A mutations cause LQT. The location and character of these mutations suggest that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation.

Amino Acid Sequence↗
PubMed1995

Heterogeneity in the inherited long QT syndrome.

Heterogeneity is present in the inherited long QT syndrome and affects the diagnosis of patients. The evidence of genetic heterogeneity is clear, with at least five genetic loci responsible for the syndrome. Phenotypic heterogeneity is less well defined, but differences in QT prolongation, T wave morphology, and the risk and frequency of syncope and sudden death are very likely. Of particular importance, it is likely that there are differences in the molecular pathophysiology of the syndrome, which are dependent on the genetic substrate present. Elucidation of the specific molecular physiology of each of the genetic subtypes of long QT syndrome will not only allow precise diagnosis and, potentially, treatment of patients with the syndrome, but will enhance our understanding of the pathophysiology of arrhythmias in general, which will extend the benefit of more precise therapy to many patients in addition to those with the long QT syndrome.

Death, Sudden↗
PubMed1995

Higher plasma homocyst(e)ine and increased susceptibility to adverse effects of low folate in early familial coronary artery disease.

To examine the graded risks for coronary artery disease (CAD) associated with plasma homocyst(e)ine [H(e)] and to evaluate the extent to which this risk is mediated by altered vitamin status, we measured plasma concentrations of H(e), vitamins B6 and B12, and folate as well as other coronary risk factors in subjects with early familial CAD and in control subjects. We studied 120 male and 42 female patients with early CAD who were unrelated to each other but were from families in which at least one other sibling had early CAD. Control subjects were 85 men and 70 women with the same age range (38 to 68) as the subjects with CAD at screening. Increasing H(e) was associated with graded increased risks of CAD that appeared consistent with a multiplicative model. Relative odds for CAD were approximately 12.8 in women when those with H(e) levels of 9 mumol/L and above were compared with those with H(e) levels of 9 mumol/L or less (P = .007). For men, the same comparison yielded relative odds of 13.8 (P = .0002). Plasma H(e) remained a strong, independent risk factor after adjustment for standard risk factors and plasma vitamin levels in multiple logistic regression (relative odds, 8.1 for a 10-mumol/L increase in H(e); 95% confidence interval, 3.2 to 20.4; P < .0001). In multivariate ANCOVA the slope of H(e) versus folate was much steeper in subjects with CAD than in control subjects (P = .0035). These data suggest that high plasma H(e) is an important, independent contributor to risk for early familial CAD.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity.

Cardiac arrhythmias cause sudden death in 300,000 United States citizens every year. In this study, we describe two new loci for an inherited cardiac arrhythmia, long QT syndrome (LQT). In 1991 we reported linkage of LQT to chromosome 11p15.5. In this study we demonstrate further linkage to D7S483 in nine families with a combined lod score of 19.41 and to D3S1100 in three families with a combined score of 6.72. These findings localize major LQT genes to chromosomes 7q35-36 and 3p21-24, respectively. Linkage to any known locus was excluded in three families indicating that additional heterogeneity exists. Proteins encoded by different LQT genes may interact to modulate cardiac repolarization and arrhythmia risk.

Base Sequence↗
PubMed1994

Genetics and molecular biology of the inherited long QT syndrome.

Two forms of the inherited long QT syndrome have been known for many years: the autosomal recessive Jervell and Lange-Nielsen form and the autosomal dominant Romano-Ward form. A gene marker at the 11p 15.5 locus has been identified for some, but not all, families with the autosomal dominant form, but as yet the gene has not been identified. It is apparent that mutations of at least four genes, and possibly more, can cause the syndrome. The molecular biology of the syndrome is not yet clarified, but abnormalities of ion channel function are likely, particularly the potassium delayed rectifier current. Proposals for the pathophysiology include an abnormality of a G protein which controls ion channel and adrenergic pathway function, as well as a disturbance of the sympathetic nervous system. The identification of the abnormal gene(s) and the gene products will provide precise information on the molecular physiology of the syndrome.

Animals↗
PubMed1994

Analysis of HLA and disease susceptibility: chromosome 6 genes and sex influence long-QT phenotype.

The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.

Chromosomes, Human, Pair 6↗
PubMed1994

Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease.

We measured plasma homocyst(e)ine [H(e)] and other coronary risk factors in 266 patients with early coronary artery disease from 170 families in which two or more siblings were affected and in 168 unmatched controls. The mean H(e) concentration adjusted for significant correlates (serum creatinine, uric acid, and low-density lipoprotein cholesterol) was 12.0 mumol/L in proband cases compared with 10.1 mumol/L in controls (P = 0.0001). Many (17.6%) of the proband cases had H(e) concentrations exceeding the 95th percentile for the controls (relative odds = 4.9, P < 0.001). H(e) among cases was bimodally distributed even after adjustment for concentrations of plasma vitamins. Concordant high H(e) was seen in at least 10 (12%) of 85 families with two or more affected siblings. We conclude that a substantial proportion of early familial coronary artery disease is probably related to production of high concentrations of H(e) by one or more major genes.

Adult↗