Biomedical subjects

D Carmelli

Publications and source records attributed to D Carmelli.

At least 37 records · Page 2Linked to original sources

PubMed1999

Differential genetic influence for components of memory in aging adult twins.

OBJECTIVE: To investigate the relative proportion of genetic and environmental contributions to verbal memory in community-dwelling World War II veteran twins. DESIGN: The California Verbal Learning Test (CVLT) was administered to 94 monozygotic (MZ) and 89 dizygotic (DZ) elderly male twin pair participants in the fourth examination of the National Heart, Lung, and Blood Institute Twin Study. SETTING: Subjects voluntarily participated on an outpatient basis at a research or medical center facility in 1 of 4 sites in the United States. PARTICIPANTS: Subjects had a mean age of 71.8 years (SD, 2.9 years), a mean educational level of 13.6 years (SD, 2.8 years), and no history of stroke and/or a Mini-Mental State Examination score of 23 or greater. MAIN OUTCOME MEASURES: Twin pair similarity in performance on 4 factor analytically derived components of the CVLT measuring verbal learning and memory, response discrimination, learning strategy, and recognition memory. RESULTS: The MZ intraclass correlation was significantly larger than the DZ correlation for verbal learning and memory (I<.001) but not for the other 3 components of memory. Using maximum likelihood methods, the best-fitting genetic model indicated that verbal learning and memory has a substantial genetic component (56% of total variance), whereas response discrimination has a much smaller, although still detectable, genetic component (24% of total variance). There is no evidence of genetic influence on learning strategy or recognition memory. CONCLUSION: Differential contribution of genetic and environmental influences to specific components of memory suggest that, in this group of elderly male twin pairs, some components may be more amenable to intervention than others.

Aged↗

PubMed1999

The effect of apolipoprotein E epsilon4 in the relationships of smoking and drinking to cognitive function.

OBJECTIVES: To investigate the joint effect of the apolipoprotein E epsilon4 (APOE epsilon4), smoking and drinking on cognitive performance in a population-based longitudinal study of elderly men. DESIGN AND SETTING: The NHLBI Twin Study, a longitudinal cardiovascular study of World War II, white, male veterans. PARTICIPANTS: A total of 589 male participants in the third cardiovascular examination of this panel and aged 59-69 when assessed for cognitive function. OUTCOME MEASURES: Cognitive function assessed by the Mini-Mental State Examination, the Digit Symbol Substitution Test, the Benton Visual Retention Test, APOE epsilon4 allele frequency and cardiovascular disease (CVD) health status. RESULTS: For the sample as a whole, after adjustment for age, education and CVD, smoking was significantly associated with poor cognitive function (odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.2-3.2, in current smokers compared with never smokers), whereas light drinking (one or fewer drinks per day) showed a protective effect (OR = 0.6, 95% CI 0.4-0.9 compared with abstainers). Stratification by APOE epsilon4 indicated that the protective effect of light drinking was stronger and the harmful effect of smoking was weaker among APOE epsilon4 carriers than among noncarriers. CONCLUSIONS: These data suggest a possible mediating effect of the APOE epsilon4 allele in the relation of smoking and drinking to cognitive function in the elderly.

Aged↗

PubMed1999

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.

Age Factors↗

PubMed1999

Impact of apolipoprotein E epsilon4 and vascular disease on brain morphology in men from the NHLBI twin study.

BACKGROUND AND PURPOSE: Apolipoprotein E epsilon4 genotype (ApoE4) has been associated with increased risk for cardiovascular disease morbidity or mortality. This appears to be mediated by an ApoE4-related increase in cardiovascular atherosclerosis. Given the similarities between risk factors for heart disease and risk factors for stroke, a positive association between ApoE4 and stroke would be expected. Since age-related brain atrophy and the extent of white matter hyperintensities (WMH) share similar risk factors, we examined the combined effect of ApoE4 and history of vascular disease on brain volume, WMH, and MRI evidence of stroke. METHODS: Subjects were the surviving members of the National Heart, Lung, and Blood Institute Twin Study. This is a longitudinal study of the effects of cardiovascular disease risk factors in community-dwelling male veterans. The fourth and final examination of this cohort included cerebral MRI and was completed in 1997. Apolipoprotein E (ApoE) genotype, quantitative measures of brain volume, WMH, and the presence of stroke on MRI were obtained from the 396 participants in the final examination. The presence or absence of a history of coronary heart disease, cerebrovascular disease, peripheral arterial disease, and ApoE genotype were determined for each subject. RESULTS: Of the 396 men, 88 (22%) had at least 1 ApoE4 allele. ApoE4 was not associated with differences in age or education. While the prevalence of vascular disease was generally greater in the ApoE4 group, this was only significant for coronary heart disease (29.8% in subjects without ApoE4 versus 40.7% in subject with ApoE4; P=0.03). ApoE4 subjects had significantly smaller brain volumes (942.4+/-34.5 versus 952.2+/-40.1 cm(3); P=0. 02). MRI evidence of stroke was detected in 88 (22%) of the subjects. The distribution of ApoE genotype was marginally different between subjects with MRI-detected stroke compared with those without. Further analysis revealed that the co-occurrence of cerebrovascular disease and ApoE4 was associated with significantly greater brain atrophy and WMH than either ApoE4 or cerebrovascular disease alone. Similar relations were seen for coronary heart disease and peripheral arterial disease. CONCLUSIONS: We conclude that ApoE4 enhances the extent of brain abnormalities in the presence of various vascular diseases. We speculate that this effect may be mediated by an increased susceptibility to brain injury or impaired repair mechanisms associated with ApoE4.

Adult↗

PubMed1999

Correlates of the "don't know" response to questions about snoring.

Many persons say that they "don't know" whether they snore. The purpose of this study was to investigate the prevalence and correlates of such responses in an elderly population. Subjects were 1715 members (1,155 men, 560 women) of a previously defined cohort (Western Group Collaborative Study) followed prospectively since 1960-1961 with a current mean age of 75.9 (SD = 4.3) for the men and 71.4 (SD = 5.3) for the women. We collected survey questionnaires and reviewed medical records. Results indicated that risk factors for the "don't know" response in this population were similar to those for frequent snoring and included: male sex, higher Body Mass Index, smoking, and use of sinus medication. Between 28 and 44% of the cohort answered questions about snoring with a "don't know" response. These data are compatible with the interpretation that subjects may disavow knowledge of their own snoring and suggest that future studies consider the "don't know" response to questions about snoring as a response of potential interest.

Aged↗

PubMed1998

Systolic blood pressure tracking over 25 to 30 years and cognitive performance in older adults.

OBJECTIVE: To determine the extent to which individual changes in systolic blood pressure (SBP) over a 30-year interval are associated with differential neuropsychological outcomes in old age. METHODS: Seven hundred seventeen survivors from the Western Collaborative Group Study, a longitudinal study of cardiovascular risk factors now in its 38th year of follow-up, with blood pressures measured in middle age (mean=45 years) and in old age (mean=75 years) and neuropsychological tests administered at follow-up were included in this analysis. Participants were grouped according to 30-year change in SBP (increased, decreased, or "normal"). Analyses focused on comparisons of neuropsychological performance of "high SBP trackers" (ie, those with persistent SBP>/=140 mm Hg throughout adult life) and of SBP "decreasers" with the performance of those whose SBP was either stable or changed in an expected way over time. RESULTS: Only 7.5% of participants had elevated SBP in middle age, but 43.8% of participants had elevated SBP in old age. After adjustment for age, education, depression, clinically defined stroke, and use of antihypertensive medications and after exclusion of individuals with impaired cognitive performance at follow-up, high SBP trackers, 5.0% (n=36), performed consistently less well than the "normal" SBP subgroups on a composite measure of verbal learning and memory (P=0.04). When compared with the "normal" SBP subgroup, the SBP decreasers, 5.3% (n=38), performed less well on speeded performance (P=0.03). CONCLUSIONS: There is a relatively small group of people who maintain elevated SBP throughout their adult lives. These persons are at increased risk for reduced verbal learning and memory function. There is also a group of individuals who experience a decrease in SBP and who are at risk for decreased psychomotor speed. Delineation of these 2 SBP subgroups may lead to further clarification of the effects of SBP on neurobehavioral function in older adults.

Adult↗

PubMed1998

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.

Aged↗

PubMed1998

Midlife cardiovascular risk factors, ApoE, and cognitive decline in elderly male twins.

OBJECTIVE: To investigate the combined effect of the apolipoprotein E epsilon4 (ApoE*4) allele and midlife cardiovascular risk factors on cognitive decline. METHODS: Data are from the National Heart, Lung, and Blood Institute Twin Study-a longitudinal cardiovascular epidemiologic study of World War II male veteran twins currently in its 27th year of follow-up. Subjects were assessed for cardiovascular risk factors, including BP and glucose levels, at mean ages 48, 58, and 63 years. Participants in the current study are 410 individual twin subjects for whom cognitive function was measured twice, at ages 63 and 73 years. Ten-year change scores in performance on neuropsychological test examinations were adjusted for age, education, baseline score, and incident cardiovascular disease. RESULTS: For the sample as a whole, we observed a significant decline (p < 0.01) in cognitive performance over the 10 years of follow-up. ApoE*4 carriers with midlife hyperglycemia experienced the greatest decline in performance, which was also greater than expected from the separate effects combined. Midlife hypertension and ApoE*4, were each associated with excess decline in performance on tests of psychomotor speed. Their joint effect, however, was not greater than expected from the separate effects combined. CONCLUSIONS: ApoE*4 and midlife cardiovascular risk factors may have a synergistic effect on decline in cognitive function. This effect may be due to greater vascular or degenerative damage among subjects with ApoE*4.

Aged↗

PubMed1998

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.

Adult↗

PubMed1998

Segregation analysis reveals a major gene effect controlling systolic blood pressure and BMI in an Israeli population.

It has been suggested that genetic factors control blood pressure level at all ages. However, the evidence is limited because of the composite nature of blood pressure and the heterogeneity of the studied samples. The purpose of the present study is to test for genetic influences on systolic blood pressure (SBP) level in a community-based Israeli family study. Segregation analysis was performed on 622 adults from 208 pedigrees. Age, sex, and body mass index (BMI) were significant covariates of SBP. Segregation analysis rejected the environmental transmission model but not the mixed Mendelian transmission model. The best-fitting genetic model was the mixed codominant model, with a heritability of 0.32 and an allele frequency of 0.18 for high SBP level. We further tested whether SBP and BMI shared a common major gene effect. Using bivariate segregation analysis involving two traits and a single locus, we found evidence for a single-locus pleiotropic effect on SBP and BMI. The allele frequency of this major locus was 0.24. The residual genetic correlation resulting from additive polygenes and the environmental correlation between these two traits were not different from zero after taking into account the shared major gene effect. The proportion of phenotypic variation attributable to this major gene effect increased with age for SBP but decreased with age for BMI.

Adult↗

PubMed1997

Segregation analysis of cardiovascular reactivity to laboratory stressors.

To better understand the contribution of major gene influences to individual differences in cardiovascular reactivity, we performed a segregation analysis on blood pressure responses to two laboratory tasks, mental arithmetic and bicycle exercise. The study population consisted of 1,451 adults (age > or = 18 years) who were members of 81 Utah pedigrees. Only 864 members performed the bicycle task because persons age 60 years or older or with heart disease were excluded. Blood pressure reactivity to mental arithmetic was defined as change from resting values, and reactivity to the bicycle task was defined as the difference between maximum blood pressure during exercise and resting values adjusted for the individual's workload. Complex segregation analysis and likelihood procedures were used to test for a major gene effect controlling blood pressure reactivity to each task. Two modifiers of the penetrance, age and sex, were considered parameters in these models. We found that diastolic blood pressure (DBP) but not systolic blood pressure reactivities to the mental arithmetic and bicycle exercise tasks were controlled by major gene effects. The best-fitting model, however, differed for the two tasks. For DBP reactivity to mental arithmetic, a major codominant model with gene frequency 0.10 was the best-fitting model; for the bicycle task, the best-fitting model was a mixed recessive model with gene frequency 0.21. Sex differences in DBP reactivity were significant in both tasks: the effect of age was significant only for the mental arithmetic task. These results suggest a significant genetic component for DBP reactivity to laboratory stressors.

Adult↗

PubMed1997

Obesity and 33-year follow-up for coronary heart disease and cancer mortality.

We used tree-structured survival analysis (TSSA), a computer-intensive method of classification, to determine prospectively the relation of the body mass index and the waist-to-calf circumference ratio to coronary heart disease and cancer mortality in 3,155 middle-aged men initially free of these diseases. Applied to coronary heart disease mortality, TSSA identified seven subgroups that differed in profile of risk factors and associated survival. Among the seven subgroups, a small subgroup of older, obese, normotensive men (N = 71) experienced an exceptionally high risk of coronary heart disease deaths over the 33 years of follow-up (34%), similar to the risk of 36% experienced by a larger subgroup (N = 387) of men of similar ages who were less obese and had higher blood pressure levels. We also observed a higher overall risk of coronary heart disease deaths during follow-up (10.3% vs 5.3%) in younger centrally obese men who had low blood pressure levels compared with their counterparts of similar age who were less obese. When applied to mortality from cancer of all sites, TSSA identified five subgroups that differed in survival distributions and profile of risk factors. A subgroup of younger, centrally obese, and ever-smoker men experienced a higher risk of cancer deaths than their counterparts who were less obese (14% vs 8%). Results from these analyses demonstrate the usefulness of a tree-structured analysis for classification of subjects into high- and low-risk survival subgroups.

Adult↗

PubMed1997

Correlates of change in cognitive function in survivors from the Western Collaborative Group Study.

Changes in cognitive function were investigated in 566 subjects 65-86 years old at baseline, who are a subsample of the Western Collaborative Group Study, a cardiovascular epidemiologic study of middle-aged men that began in the 1960s. Cognitive function was assessed in 1986-1988 (baseline) and again in 1992-1994 by three standardized measures: the Benton Visual Retention Test, the Controlled Oral Word Association Test, and the Digit Symbol Substitution (DSS) Test. Longitudinal change in performance was defined as the shift over time in a subject's quartile rank ordering, using the baseline distribution of test scores as a standard. 'Decliners' and 'improvers' in cognitive function were subjects who lost or gained, respectively, two or more quartile ranks on all three tests combined. By this definition, 20% (n = 113) of subjects declined, compared with 17% (n = 95) who improved in cognitive performance from 1986-1988 to 1992-1994. After adjustment for age, education, and physical health, decline in cognitive performance was significantly associated with poor self-perceived health ratings, depression scale scores, and self-reports of physical activity. Rank score change in the DSS Test was the single best predictor of cognitive function at follow-up on a diverse battery of neuropsychological tests.

Aged↗

PubMed1997

Heavy consumption of cigarettes, alcohol and coffee in male twins.

OBJECTIVE: To determine the relative contribution of environmental and genetic influences on the joint distribution of heavy smoking, heavy alcohol use and heavy coffee drinking. METHOD: Multivariate structural equation modeling in a large cohort of male twins (N = 2,220 monozygotic and 2,373 dizygotic twin pairs; mean age = 62.1 years) from the National Academy of Sciences-National Research Council's World War II Twin Registry. RESULTS: The best-fitting model identified two independent (i.e., uncorrelated) sets of genetic and environmental latent factors, with one set underlying joint heavy smoking and heavy alcohol use and the other set underlying joint heavy smoking and heavy coffee drinking (chi 2 = 14,13,22 df, p > .80). Heavy alcohol use and heavy coffee drinking were uncorrelated in this sample. While common genetic factors accounted for 35% to 78% of the total genetic variance in heavy substance use, a substantial amount of genetic variance remained specific to each of the three substances. CONCLUSIONS: Several hypotheses involving genetic and environmental factors are presented to account for the independent clustering of heavy smoking and heavy alcohol use and of heavy smoking and heavy coffee drinking.

Alcohol Drinking↗

PubMed1996

The relationship of Type A behavior and its components to all-cause mortality in an elderly subgroup of men from the Western Collaborative Group Study.

This study examined prospectively the relationship of Type A behavior and its components to all-cause mortality in 1,118 men (age 60 to 86) who participated in a 27-year follow-up examination of the Western Collaborative Group Study. Global Type A/B behavior was assessed in these subjects using a modified version of the Structured Interview. Additional psychological data that related to this construct were obtained from self-report questionnaires. The relationship of these data, controlling for other biological risk factors, to 6-year all-cause mortality was investigated by means of a tree-structured survival analysis (TSSA). Using age, Type A behavior, Cook-Medley hostility, ever smoking, and cancer status at follow-up, TSSA identified 6 subgroups that differed in survival rates and associated risk factor profiles. The most favorable survival was experienced by 2 subgroups, one composed of older Type A subjects who scored the lowest on anger-hostility and depression, the other consisting entirely of Type B subjects who had never smoked. The worst survival was experienced by subjects with diagnosed cancer at the 27-year follow-up, and intermediate survival rates were experienced by 3 subgroups that differed markedly on age, smoking, Type A/B behavior, and Cook-Medley hostility. The present study is the first to characterize Type A's with favorable and unfavorable survival rates among the elderly.

Aged↗

PubMed1996

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 Institute's 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.

Aged↗

PubMed1996

Curiosity and mortality in aging adults: a 5-year follow-up of the Western Collaborative Group Study.

Research suggests that curiosity in older people is associated with maintaining the health of the aging central nervous system. We examined prospectively the relationship of curiosity in 1,118 community-dwelling older men to subsequent survival over a 5-year period. Curiosity was measured when the participants were a mean age of 70.6 years. Initial levels of trait and state curiosity were higher in survivors than in those who subsequently died. After adjustment for other risk factors, the state curiosity-mortality association remained significant in the Cox regression model. Ancillary analyses in 1,035 older women (M age at initial examination = 68.6 years) confirmed the pattern found in the men. State curiosity in these women was significantly associated with survival after adjustment for other risk factors. This is the first study to identify a predictive role for curiosity in the longevity of older adults.

Adult↗

PubMed1996

Twenty-four year mortality in World War II US male veteran twins discordant for cigarette smoking.

BACKGROUND: This study was undertaken to test the constitutional hypothesis which attributes the association of tobacco smoking with morbidity and mortality to genetic predispositions to smoking and/or disease. METHODS: Subjects were World War II veterans, born in the US between 1917 and 1927, and surveyed at mean age 47 for present and past smoking habits. Twenty-four year mortality follow-up data were available for 1515 male twin pairs discordant for lifelong cigarette smoking. Using the first or only death of a smoking-discordant pair, 24-year relative risks of mortality were calculated by zygosity, cause of death, amount smoked, and age at death. RESULTS: We found that active smokers at baseline, regardless of zygosity, had a higher risk of death than their co-twins who had never smoked or quit smoking (monozygotic pairs: relative risk [RR] = 2.5; 95% confidence interval [CI] : 1.3-6.1 and RR = 1.7; 95% CI : 1.2-2.5; dizygotic pairs: RR = 2.4; 95% CI : 1.4-3.8 and RR = 2.0; 95% CI : 1.7-3.3). The elevated risk of death among smokers was due to deaths from lung cancer (monozygotic pairs: RR = 5.0; 95% CI: 2. 6-15.0; dizygotic pairs: RR = 11.0; 95% CI : 4.3-45.0) or deaths from cardiovascular diseases (monozygotic pairs: RR = 3.9; 95% CI : 1.9-115; dizygotic pairs: RR = 2.8; 95% CI : 1.7-4.9). Apart from these findings the relationship of smoking with all-cause mortality was stronger for earlier/younger deaths and for heavy to moderate smoking. CONCLUSIONS: The present results, from the largest and longest-studied series of smoking-discordant twins negate the constitutional hypothesis that genetic or early shared familial influences underlie the significant association between tobacco smoking and premature mortality.

Cardiovascular Diseases↗