Dorit Carmelli

Genetic influence on smoking--a study of male twins.

BACKGROUND The results of twin and family studies suggest that heredity has a small influence on smoking behavior. METHODS We conducted a genetic analysis of several aspects of smoking behavior among subjects in the National Academy of Sciences-National Research Council Twin Registry. The registry includes male twins who were born in the United States between 1917 and 1927 and who were members of the armed services during World War II. Information on smoking history was available for 4775 pairs of twins, who were first surveyed in 1967 through 1969, when they were 40 to 50 years old, and then re-surveyed in 1983 through 1985, when they were 56 to 66. Eighty percent of the subjects in this cohort had smoked at some time in their lives, 60 percent were smokers in 1967 through 1969, and 39 percent were smoking in 1983 through 1985. Similarities between twins in smoking habits at base line and at the second follow-up 16 years later were examined. The comparison of concordance for smoking between monozygotic and dizygotic twins was used to assess the relative contribution of familial and genetic factors. RESULTS In 1967-1969 survey the ratio of observed to expected concordance for smoking was higher among the monozygotic twins than among the dizygotic twins for those who had never smoked (overall rate ratio, 1.38; 95 percent confidence interval, 1.25 to 1.54), for former smokers (overall rate ratio, 1.59; 95 percent confidence interval, 1.35 to 1.85), for current cigarette smokers (overall rate ratio, 1.18; 95 percent confidence interval, 1.11 to 1.26), and for current cigar or pipe smokers (overall rate ratio, 1.60; 95 percent confidence interval, 1.22 to 2.06). The data also suggest genetic influences on quitting smoking. Monozygotic twins were more likely than dizygotic twins to be concordant for quitting smoking (overall rate ratio, 1.24; 95 percent confidence interval, 1.06 to 1.45). CONCLUSIONS In this cohort of adult male twins, there were moderate genetic influences on lifetime smoking practices.

Association of midlife blood pressure to late-life cognitive decline and brain morphology

Objective: To investigate the association between midlife systolic blood pressure (SBP) and late-life cognitive decline and brain morphology in a sample of community-dwelling elderly men 68 to 79 years of age. Methods: Subjects are surviving members from the prospective National Heart, Lung, and Blood Institute Twin Study (intake, 1969 to 1972) who, when examined for a fourth time in 1995 through 1997, underwent brain MRI and repeated assessment of neurobehavioral functioning. Quantification of the MR images determined cerebral volume and total volume of white matter hyperintensities (WMHIs) for 392 subjects. Midlife SBP levels measured in 1970, 1980, and 1985 were used to classify subjects into low, medium, and high midlife SBP categories. A 10-year change in performance on the Mini-Mental State Examination, Digit Symbol Substitution Test, Benton Visual Retention Test, and Verbal Fluency Test was also calculated for these subjects. For all reported analyses, patients were treated as genetically unrelated individuals. Results: Subjects with high midlife SBP experienced a greater decline in cognitive performance and had larger WMHI volumes at follow-up in late life than did those with low midlife SBP. Decreased brain parenchyma and increased WMHI volumes were associated with decline in neurobehavioral functioning as measured in late life independent of age, education, and baseline levels of cognition. Conclusions: Midlife SBP is a significant predictor of both decline in cognitive function and MR volumetric measures of brain atrophy in late life. Because decline in neurobehavioral functioning was associated with decreased brain volume and increased WMHI volume, we conclude that the long-term impact of elevated SBP on decline in late-life neurobehavioral functioning is likely to be mediated through its chronic, negative effect on structural characteristics of the brain.

Evidence For Genetic Variance in White Matter Hyperintensity Volume in Normal Elderly Male Twins

BACKGROUND AND PURPOSE White matter hyperintensities (WMHs), as detected by MRI, are common among the elderly and are frequently interpreted as representing a subclinical form of ischemic brain damage. We used volumetric MR techniques to investigate the contribution of genes and the environment to measures of brain morphology in a sample of community dwelling elderly male twins. METHODS Brain MR (1.5 T) scans were obtained from 74 monozygotic (MZ) and 71 dizygotic (DZ), white, male, World War II veteran twins born in the United States and age 68 to 79 when scanned. MR quantification used a previously published semiautomated segmentation algorithm to segment brain images into total brain, cerebrospinal fluid (CSF), and WMH volumes. Twin pair covariances were computed for each measure, and structural equation genetic models were fitted to these data. RESULTS Total cranial, brain parenchyma, CSF, and WMH volumes were highly correlated in MZ pairs, and correlations in MZ pairs were significantly greater than those in DZ pairs. Structural equation modeling indicated heritabilities of 91%, 92%, and 73%, respectively, for total cranial, brain parenchyma, and WMH volumes. Correction for age and head size reduced the heritability of brain parenchyma to 62% (95% confidence interval, 56% to 68%) and the heritability of WMH volume to 71% (95% confidence interval, 66% to 76%). Proband concordance rates for large amounts of WMH were 61% in MZ pairs and 38% in DZ pairs, compared with a prevalence of 15% in the entire sample. CONCLUSIONS This study is the first to quantify the relative contribution of genetic and individual environmental influences to measures of brain morphology in the elderly.

Prospective assessment after pediatric cardiac ablation: demographics, medical profiles, and initial outcomes.

Introduction: A multicenter prospective study was designed and implemented to assess the short‐ and longer‐term results and risks associated with radiofrequency (RF) ablation in children.

Predictors of Brain Morphology for the Men of the NHLBI Twin Study

BACKGROUND AND PURPOSE Cross-sectional studies show that cerebrovascular risk factors are associated with increased brain atrophy, accumulation of abnormal cerebral white matter signals, and clinically silent stroke. We extend these findings by examining the relationship between midlife cerebrovascular risk factors and later-life differences in brain atrophy, amount of abnormal white matter, and stroke on MRI. METHODS Subjects were the 414 surviving members of the prospective National Heart, Lung, and Blood Institute Twin Study, who have been examined on 4 separate occasions, spanning the 25 years between 1969-1973 and 1995-1997. Quantitative measures of brain volume, volume of abnormal white matter signal (WMHI), and volume of stroke, when present, were obtained from those participating in the fourth examination. RESULTS The mean+/-SD age of the subjects was 47.2+/-3.0 years at initial examination and 72. 5+/-2.9 years at final examination. Average blood pressure (BP) levels were normal, although 32% of the subjects had received or were currently taking antihypertensive medications. As a group, 31% had symptomatic cardiovascular disease, 11% had symptomatic cerebrovascular disease, and 8% had symptomatic peripheral vascular disease. Both systolic and diastolic BP levels at initial examination were inversely related to brain volume and positively related to WMHI volume. Multiple regression analysis identified BP-related measures and vascular risk factors as significant predictors of brain and WMHI volumes. In addition, the magnitude of orthostatic BP change was significantly associated with WMHI volume. Subjects with extensive amounts of WMHI had significantly higher systolic BP at the final examination and a higher prevalence of symptomatic cardiovascular and cerebrovascular disease, without significant differences in the prevalence of hypertension treatment. CONCLUSIONS Midlife BP measures are significantly associated with later-life brain and WMHI volumes and the prevalence of symptomatic vascular disease. Since WMHI share cerebrovascular risk factors and extensive WMHI are associated with symptomatic vascular disease, extensive WMHI may be a subclinical expression of cerebrovascular disease. Careful treatment of midlife BP elevations may diminish these later-life brain changes.

Brain structure in men remains highly heritable in the seventh and eighth decades of life.

The midsagittal cross-sectional dimensions of the corpus callosum, the coronal cross-sectional area of the lateral ventricles at the level of the pons, and a three-dimensional estimate of intracranial volume were derived from magnetic resonance brain images obtained from 45 monozygotic and 40 dizygotic male twin pairs aged 68 to 78. Univariate genetic analyses indicated strong genetic influences contributing significantly to the variability of each brain structure. The estimated proportion of genetic variance (i.e. heritability) was 81% for intracranial volume, 79% for the midline cross-sectional area of the corpus callosum, and 79% for lateral ventricle size. There was no evidence that shared environmental influences contributed significantly to twin-pair similarities. We further used bivariate genetic modeling to estimate the genetic and environmental correlation between correlated brain structures. Intracranial volume and corpus callosum area was highly correlated, and this relationship was entirely due to shared genetic effects between these two brain structures. By contrast, the relationship between the height of the corpus callosum and the size of the lateral ventricles was due to both genetic and environmental influences in common. Corresponding genetic and environmental correlations were 0.68 and 0.58, respectively, indicating that more than half of the genetic and environmental influences on these two brain structures were shared. The manner in which the brain responds to the environment with advancing age is highly genetically determined, both for the lateral ventricles, which dilate with aging and disease, and for the corpus callosum, which is deformed in shape by age-related ventricular enlargement, whereas its midline cross-sectional area remains unchanged.

The consumption of tobacco, alcohol, and coffee in Caucasian male twins: a multivariate genetic analysis.

Despite the fact that epidemiologic studies demonstrate a consistent covariation between the use of tobacco, alcohol, and coffee, most previous behavioral genetic-studies have determined the contribution of genetic and environmental influences as if the consumption of these substances occurred independently of each other. In this study, we used multivariate structural equation modeling to determine the genetic and environmental overlap in the observed correlations between tobacco smoking and alcohol and coffee drinking in 173 monozygotic and 183 dizygotic male twin pairs (M age = 59 years; range = 52-66 years) who participated in a follow-up cardiovascular examination of the National Heart, Lung, and Blood Institutes Twin Study. Consistent with hypothesized psychoneurogenetic predispositions for the joint use of these substances, the most parsimonious model fitting these data identified a common genetic latent factor underlying the observed associations between smoking, alcohol, and coffee use in this cohort. This factor, herein called polysubstance use, underscores the role of genetic influence on the clustering of these behaviors in the same individual.

Depressive symptoms and metabolic risk in adult male twins enrolled in the National Heart, Lung, and Blood Institute twin study.

Objective To determine the extent to which depressive symptoms are associated with metabolic risk factors and whether genetic or environmental factors account for this association. Method Twin structural equation modeling was employed to estimate genetic and environmental contributions to the covariation of depressive symptoms, as indexed by the Centers for Epidemiological Studies–Depression Scale, and common variance among blood pressure, body mass index, waist-to-hip ratio, and serum triglycerides and glucose among 87 monozygotic and 86 dizygotic male twin pairs who participated in the NHLBI twin study. Results Depressive symptoms were associated with individual components of the metabolic syndrome and common variance among the risk factors. Twin structural equation modeling indicated that the associations were attributable to environmental (nongenetic) factors. Conclusions These results support the hypothesis that depressive symptoms may increase risk for a pattern of physiological risk consistent with the metabolic syndrome.

Genetic regulation of regional microstructure of the corpus callosum in late life.

In order to identify brain structural phenotypes that remain under significant genetic control in late adulthood, we examined the heritability of corpus callosum macrostructure (i.e. size) using MRI and microstructure (e.g. myelin) using diffusion tensor imaging in 15 monozygotic and 18 dizygotic twin pairs of elderly men. The relative proportion of genetic to environmental influences varied considerably by region and structural type and was 5:1 for callosal macrostructure, 3:1 for splenium microstructure, and 1:1 for genu microstructure. This is the first in vivo identification of quantifiable phenotypes of brain white matter microstructure and demonstrates significant and differential genetic regulation in old age, with anterior interhemispheric connecting pathways more susceptible than posterior pathways to environmental influences.

Genetic influences and grip strength norms in the NHLBI twin study males aged 59-69

Maximal grip strength was measured in kilograms using a hand dynamometer on 344 unrelated males between the ages of 59 and 70 participating in the third examination of the NHLBI Twin Study. There was a significant linear decline in mean grip strength over this age range. Mean grip strength and grip strength per kilogram weight are presented for age 59, ages 60-64 and 65-69. Genetic analysis using 127 pairs of identical (MZ) twins and 130 pairs of fraternal (DZ) twins indicated significant genetic effects for absolute grip strength and grip strength per kilogram weight. The largest estimate of heritability (65%) was obtained for grip strength adjusted for significant effects of weight, height, age, and various anthropometric measures of fatness, muscle mass, and frame size.