Jean W. MacCluer

Influence of the Genotype on the Clinical Course of the Long-QT Syndrome

BACKGROUND The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease. METHODS We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus. We determined the cumulative probability and lethality of cardiac events (syncope, aborted cardiac arrest, or sudden death) occurring from birth through the age of 40 years according to genotype in the 246 gene carriers and in all 1378 members of the families studied. RESULTS The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (P<0.001 for the comparison of all three groups). In a multivariate Cox analysis, the genotype and the QT interval corrected for heart rate were significant independent predictors of a first cardiac event. The cumulative mortality through the age of 40 among members of the three groups of families studied was similar; however, the likelihood of dying during a cardiac event was significantly higher (P<0.001) among families with mutations at the LQT3 locus (20 percent) than among those with mutations at the LQT1 locus (4 percent) or the LQT2 locus (4 percent). CONCLUSIONS The genotype of the long-QT syndrome influences the clinical course. The risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although cumulative mortality is similar regardless of the genotype, the percentage of cardiac events that are lethal is significantly higher in families with mutations at the LQT3 locus.

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.

Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans: The San Antonio Family Heart Study

BACKGROUND The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes. METHODS AND RESULTS Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for < 15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure. CONCLUSIONS These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.

Genetic variation in selenoprotein S influences inflammatory response

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1β and TNF-α. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, −105G → A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-α. To investigate further the significance of the observed associations, we genotyped −105G → A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-α (P = 0.0049) and IL-1β (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.

Chemerin Is Associated with Metabolic Syndrome Phenotypes in a Mexican-American Population

CONTEXT Chemerin is a novel adipokine previously associated with metabolic syndrome phenotypes in a small sample of subjects from Mauritius. OBJECTIVE The aim of the study was to determine whether plasma chemerin levels were associated with metabolic syndrome phenotypes in a larger sample from a second, unrelated human population. DESIGN, SETTING, PATIENTS, AND INTERVENTION Plasma samples were obtained from the San Antonio Family Heart Study (SAFHS), a large family-based genetic epidemiological study including 1431 Mexican-American individuals. Individuals were randomly sampled without regard to phenotype or disease status. This sample is well-characterized for a variety of phenotypes related to the metabolic syndrome. MAIN OUTCOMES Plasma chemerin levels were measured by sandwich ELISA. Linear regression and correlation analyses were used to determine associations between plasma chemerin levels and metabolic syndrome phenotypes. RESULTS Circulating chemerin levels were significantly higher in nondiabetic subjects with body mass index (BMI) greater than 30 kg/m(2) compared with those with a BMI below 25 kg/m(2) (P < 0.0001). Plasma chemerin levels were significantly associated with metabolic syndrome-related parameters, including BMI (P < 0.0001), fasting serum insulin (P < 0.0001), triglycerides (P < 0.0001), and high-density lipoprotein cholesterol (P = 0.00014), independent of age and sex in nondiabetic subjects. CONCLUSION Circulating chemerin levels were associated with metabolic syndrome phenotypes in a second, unrelated human population. This replicated result using a large human sample suggests that chemerin may be involved in the development of the metabolic syndrome.

Sudden Cardiac Death, Genes, and Arrhythmogenesis Consideration of New Population and Mechanistic Approaches From a National Heart, Lung, and Blood Institute Workshop, Part II*

This is Part II of a 2-part article dealing with malignant ventricular arrhythmias, which are the leading mechanism of death in common cardiac diseases. Genetic population studies directed at discovering common proximal sources of inherited molecular risk most directly linked to arrhythmia initiation and propagation would appear to have considerable potential in helping reduce cardiovascular mortality.

Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

Heritability of Carotid Artery Structure and Function: The Strong Heart Family Study

Objective—Alterations in carotid artery structure and function may represent phenotypic measures of vascular disease that contain information beyond that which can be inferred from conventional cardiovascular disease risk assessment. However, apart from their associations with cardiovascular disease risk factors and outcome, the genetic basis of variations in carotid artery structure and function is largely unknown. The purpose of this study was to examine the genetic and environmental contributions to carotid artery structure and function in 3 large groups of American Indians. Methods and Results—Approximately 950 men and women, aged ≥18 years, in 32 extended families were examined between 1997 and 1999. By use of a variance component approach and the program Sequential Oligogenic Linkage Analysis Routines, heritabilities for carotid artery structure and function phenotypes were estimated. After accounting for the effects of covariates (sex, age, diabetes, impaired glucose tolerance, smoking, cholesterol, body surface area, and hypertension), we detected significant heritabilities (given as h2 values) for common carotid artery diastolic diameter (h2<0.44), intimal-medial wall thickness (h2<0.21), vascular mass (h2<0.27), arterial stiffness (h2<0.23), and the augmentation index (h2<0.18). Conclusions—These results suggest that the additive effects of genes explain a moderate proportion of the variability of carotid artery structure and function.

Plasma HDL Cholesterol, Triglycerides, and Adiposity A Quantitative Genetic Test of the Conjoint Trait Hypothesis in the San Antonio Family Heart Study

BACKGROUND The conjoint trait hypothesis proposes that combined low HDL cholesterol (HDL-C) and high triglyceride (TG) levels represent a single, inherited phenotype that adiposity may influence in an unspecified manner. We conducted formal statistical genetic tests of the conjoint trait hypothesis and the relation of the conjoint trait to adiposity using data for 569 subjects in 25 pedigrees from the San Antonio Family Heart Study. METHODS AND RESULTS We conducted multivariate genetic analyses to detect the effects of genes and environmental factors on variation in plasma concentrations of HDL-C and TG, fat mass (as percent body weight [FM%], determined by bioelectric impedance), and body mass index (BMI). We used maximum-likelihood methods to simultaneously estimate the phenotypic means and SDs, heritabilities (h2), effects of sex, age-by-sex, eight dietary and medical covariates, and genetic and environmental correlations. Likelihood ratio tests disclosed significant heritabilities (P < .001) for all traits (h2HDL-C = 0.55, h2TG = 0.53, h2FM% = 0.37, h2BMI = 0.44) but significant genetic correlations (P < .001), indicating pleiotropy, between two trait pairs only: HDL-C and TG (PG = -0.52) and fat mass and BMI (PG = 0.86). We obtained significant environmental correlations between all trait pairs except HDL-C and BMI (P > .05). CONCLUSIONS Both shared genes (pleiotropy) and shared environmental factors contribute to the commonly observed inverse phenotypic association between plasma levels of HDL-C and TG. Rather than low HDL-C and high TG being a single, genetically transmissible entity, it is the inverse relation between these two phenotypes throughout their normal ranges of variation as well as at the extremes that is influenced by shared genes and shared environments. However, common environmental factors, not shared genes, account for reported associations of plasma HDL-C and TG levels with measures of adiposity.

Human Pedigree-Based Quantitative-Trait–Locus Mapping: Localization of Two Genes Influencing HDL-Cholesterol Metabolism

Common disorders with genetic susceptibilities involve the action of multiple genes interacting with each other and with environmental factors, making it difficult to localize the specific genetic loci responsible. An important route to the disentangling of this complex inheritance is through the study of normal physiological variation in quantitative risk factors that may underlie liability to disease. We present an analysis of HDL-cholesterol (HDL-C), which is inversely correlated with risk of heart disease. A variety of HDL subphenotypes were analyzed, including HDL particle-size classes and the concentrations and proportions of esterified and unesterified HDL-C. Results of a complete genomic screen in large, randomly ascertained pedigrees implicated two loci, one on chromosome 8 and the other on chromosome 15, that influence a component of HDL-C-namely, unesterified HDL2a-C. Multivariate analyses of multiple HDL phenotypes and simultaneous multilocus analysis of the quantitative-trait loci identified permit further characterization of the genetic effects on HDL-C. These analyses suggest that the action of the chromosome 8 locus is specific to unesterified cholesterol levels, whereas the chromosome 15 locus appears to influence both HDL-C concentration and distribution of cholesterol among HDL particle sizes.