A genome-wide linkage scan for iron phenotype quantitative trait loci: the HEIRS Family Study.

Iron overload phenotypes in persons with and without hemochromatosis are variable. To investigate this further, probands with hemochromatosis or evidence of elevated iron stores and their family members were recruited for a genome-wide linkage scan to identify potential quantitative trait loci (QTL) that contribute to variation in transferrin saturation (TS), unsaturated iron-binding capacity (UIBC), and serum ferritin (SF). Genotyping utilized 402 microsatellite markers with average spacing of 9 cM. A total of 943 individuals, 64% Caucasian, were evaluated from 174 families. After adjusting for age, gender, and race/ethnicity, there was evidence for linkage of UIBC to chromosome 4q logarithm of the odds (LOD) = 2.08, p = 0.001) and of UIBC (LOD = 9.52), TS (LOD = 4.78), and SF (LOD = 2.75) to the chromosome 6p region containing HFE (each p < 0.0001). After adjustments for HFE genotype and other covariates, there was evidence of linkage of SF to chromosome 16p (LOD = 2.63, p = 0.0007) and of UIBC to chromosome 5q (LOD = 2.12, p = 0.002) and to chromosome 17q (LOD = 2.19, p = 0.002). We conclude that these regions should be considered for fine mapping studies to identify QTL that contribute to variation in SF and UIBC.

Familial aggregation of QT-interval variability in a general population: results from the NHLBI Family Heart Study.

QT-interval prolongation is associated with increased risk of cardiac death. Although information on genetics and molecular mechanisms of the congenital long QT syndrome is mounting, limited data are available on the genetics of QT interval in the general population. Heart rate adjusted QT intervals (Bazett's QTc, and QT index (QTI)) were assessed by electrocardiography in 2399 members aged 25-91 years of 468 randomly selected families participating in the NHLBI Family Heart Study. Familial correlation and segregation analyses were performed to evaluate the genetics of the variability of QT interval in this population. The parent-offspring (0.14+/-0.03) and sibling (0.18+/-0.03) correlations for age and sex-adjusted QTc were moderate, while the spouse correlation was close to zero (0.09+/-0.06). This suggests that there are familial/genetic influences on QT-interval variability. Segregation analysis results suggest that there is a major effect in addition to heritable multifactorial effects (h2=0.34), but the major effect did not follow Mendelian inheritance. Further adjustments of QTc for other major cardiovascular risk factors did not significantly change the results. Similar results were found for QTI. The QT-interval variation in the general population is influenced by moderate heritable multifactorial effects in addition to a major effect. A major gene effect is not directly supported.

Familial history of metabolic disorders and the multiple metabolic syndrome: the NHLBI family heart study.

UNLABELLED: A case-control study was conducted to investigate the association between family history of obesity, hypertension, and diabetes and the co-occurrence of metabolic disorders associated with the multiple metabolic syndrome (MMS). Included were 1,448 African and European American men and women aged 48-71 who participated in both the third cohort examination of the Atherosclerosis Risk in Communities study, 1992-1994, and phase I of the Family Heart Study 1993-1995. The joint occurrence of hypertension, dyslipidemia, and diabetes or impaired fasting glucose in an individual determined his/her status of "affected" (MMS: n = 97), while the absence of these three metabolic disorders determined his/her status of "unaffected" ( CONTROL: n = 527). First-degree relatives provided the information to calculate family risk scores (FRSs) for the phenotypes under study: obesity, diabetes and hypertension. Although the majority of cases were obese (76.3%), family history of obesity was associated only weakly with the MMS, while family history of diabetes, or hypertension was associated significantly with the MMS (controlling for age, race, gender, and sampling group). Obesity of cases and controls modified the strength of these associations-odds ratios were 2.5(95% CI:1.1-6.1) and 2.9(95% CI:1.2-7.0) for the diabetes and hypertension FRSs in the non-obese, while in obese individuals the respective odds ratios were 1.6(95% CI:0.9-2.8) and 1.7(95% CI:0.9-3.1). These results may imply that obesity, whether familial or environmental in nature, is associated with the development of the MMS, while in non-obese individuals a family history of diabetes, hypertension, or obesity is a marker of genetic predisposition to components of the MMS.

Insulin and hypertension in the NHLBI Family Heart Study: a sibpair approach to a controversial issue.

The association between insulin and hypertension remains equivocal. We therefore investigated insulin levels in 3037 normotensive and 1067 hypertensive subjects from the National Heart, Lung and Blood Institute (NHLBI) Family Heart Study (FHS) by two different approaches. First, we compared insulin levels between normotensive and 275 untreated hypertensive subjects. Insulin levels unadjusted as well as adjusted for age, sex, and center were significantly higher in hypertensives. After adjustment for body mass index (BMI), insulin remained significantly higher only in the diastolic hypertensive group (mean +/- SD 77.0 +/-36.7 pmol/L, P < .01) but not in the isolated systolic hypertensive group (67.0 +/- 38.2 pmol/L) when compared to normotensives (63.2 +/- 29.1 pmol/L). A sibpair analysis was then used that compared the intra-sibpair differences in insulin concentrations to the intra-sibpair differences in blood pressure (BP) levels. This approach was intended to control for the effects of genetic and residual shared environmental variance upon insulin levels. The intra-sibpair difference in insulin concentrations between concordant (diastolic and systolic deltaBP < 5 mm Hg) and discordant sibpairs (diastolic and systolic deltaBP > 15 and > 20 mm Hg, respectively) was no longer significantly different when adjusted for BMI (2.7 v 5.9 pmol/L for diastolic and -1.7 v -1.8 pmol/L for systolic BP). Even the random selection of one sibpair from each of the 326 families independently of insulin and BP levels did not result in a significant correlation between the intrasibpair differences in insulin and BP. Using an insulin resistance index instead of insulin did not change our findings. Our investigation in the FHS sample of families suggests that there is only a small, if any, influence of insulin levels on BP after adjustment for obesity-related sources of variation.

Influence of leisure time physical activity and television watching on atherosclerosis risk factors in the NHLBI Family Heart Study.

Physical activity favorably influences atherosclerosis risk factors but only a few studies in adults considered the time watching television (TV) as a measure of physical inactivity. We therefore determined in a population-based sample of 1778 subjects from the NHLBI Family Heart Study (FHS) whether leisure time physical activity and TV watching have independent or interactive associations with cardiovascular disease risk factors and carotid artery intima-media wall thickness (IMT). Subjects were free from diabetes mellitus and clinically-ascertained coronary artery disease and did not take lipid-lowering or antihypertensive drugs. Only 0.7 and 1.3% of the variance in leisure time physical activity in women and men, respectively, was explained by the amount of TV watching. Leisure time physical activity had a clearly favorable, and TV watching an unfavorable association with anthropometric measurements (BMI (body mass index), waist girth, waist-hip ratio, subscapular and triceps skinfold thickness). The odds ratio (95% CI) of being overweight was 0.41 (0.28-0.62) in women and 0.69 (0.46-1.04) in men in the highest quartile of leisure time physical activity compared to the lowest quartile. The odds ratio increased for increasing quartiles of TV watching to 2.12 (1.45-3.10) in women and 1.61 (1.07-2.43) in men. Watching TV only 1 h per day in women with a BMI of 30 kg/m2 and doing about 75 min of moderate exercise per week was associated with a BMI 1.8 kg/m2 lower than in women watching TV 3 h per day and doing the same amount of exercise. Those with twice the amount of moderate exercise and watching TV 1 h per day had a BMI 0.45 kg/m2 lower. Furthermore, leisure time physical activity was negatively associated with concentrations of triglycerides and positively with HDL cholesterol in both genders. TV watching was significantly positively associated with triglycerides and slightly negatively with HDL cholesterol in men. The observed associations of leisure time physical activity and TV watching with atherosclerosis risk factors were independent from each other. Finally, we analyzed the relation between leisure time physical activity, TV watching and the degree of IMT of the carotid arteries. Neither of these two measures was significantly associated with IMT. In summary, TV watching, in addition to leisure time physical activity, shows an independent association with obesity-related anthropometric measurements, HDL and triglycerides. Decreasing the amount of TV watching might be effective as a first step in reducing atherosclerosis risk factors, especially overweight.

Coronary heart disease. At the interface of molecular genetics and preventive medicine.

BACKGROUND: Susceptibility to common chronic diseases such as coronary heart disease (CHD) appears to be influenced by "context-dependent effects," which include interactions among genes (genetic epistasis) and among genes and environmental factors (gene-environment interactions). METHODS: A synthesis of current knowledge and research findings demonstrates the importance of integrating genetic research on cardiovascular disease with preventive medicine and public health initiatives. RESULTS: A variety of candidate genes have been implicated in risk for CHD, but only limited examples of context-dependent effects have been described. Interactions between genetic and environmental factors appear to influence lipid metabolism, plasma homocysteine levels, and pharmacologic response to many commonly prescribed medications. Quantification of genetic effects associated with increased disease risk that are modifiable by interventions such as diet, exercise, and smoking cessation is an important interface between molecular genetics and preventive medicine. CONCLUSIONS: As a primary focus of preventive medicine expands to encompass early detection and treatment of asymptomatic individuals at risk for disease, the ability to quantify the influence of context-dependent effects on disease risk will be critical for determining drug safety and effectiveness in diverse patient populations and for implementing effective prevention and treatment programs.

No linkage of the lipoprotein lipase locus to hypertension in Caucasians.

OBJECTIVE: A previous study has shown significant linkage of five markers near the lipoprotein lipase locus to systolic blood pressure, but not to diastolic blood pressure, in nondiabetic members of 48 Taiwanese families selected for noninsulin-dependent diabetes. However, lipoprotein lipase markers did not appear strongly linked to systolic blood pressure in a study of Mexican-Americans using a variety of selection schemes. The objective of the current study was to test whether markers near the lipoprotein lipase gene were linked to hypertension in Caucasians. DESIGN: To test for linkage of genetic markers in or near the lipoprotein lipase gene to hypertension in Caucasians, two sets of Caucasian hypertensive sibships were genotyped. The samples included 261 sibships (431 effective sibpairs) from four field centers of the National Heart, Lung and Blood Institute Family Heart Study and 211 sibships (282 effective sibpairs) from the Health Family Tree database in Utah. RESULTS: Two highly polymorphic markers in or near the lipoprotein lipase gene showed no evidence of excess allele sharing in either set of hypertensive sibships. Combining the two datasets resulted in 653 and 713 effective sibpairs for the two markers, sharing 0.495 +/- 0.30 and 0.486 +/- 0.28 alleles identical by descent compared to an expected sharing of 0.50. Multipoint analysis of the two loci also did not show linkage (P = 0.95). CONCLUSIONS: We conclude that the lipoprotein lipase locus and nearby regions do not appear to be linked to hypertension in Caucasians.

Cigarette smoking, environmental tobacco smoke exposure and insulin sensitivity: the Insulin Resistance Atherosclerosis Study.

PURPOSE: To investigate whether active smoking and/or exposure to environmental tobacco smoke (ETS) is associated with insulin sensitivity. METHODS: Insulin sensitivity and tobacco use history were measured in 1481 participants in the Insulin Resistance Atherosclerosis Study (IRAS). IRAS is a large mulitcenter epidemiologic study designed to explore the cross-sectional relationships among insulin resistance, cardiovascular disease risk factors and behaviors, and disease in African-American, Hispanic, and non-Hispanic white men and women, aged 40-69 years, selected to represent a broad range of glucose tolerance. Multiple linear regression models and linear contrasts were employed to describe the association between smoking history, as assessed via structured interview, and insulin sensitivity, as assessed by an insulin modified frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis. RESULTS: Active smoking was not associated with insulin sensitivity. Exposure to ETS was associated with lower insulin sensitivity. Specifically, for all participants combined, levels of SI were lower, indicating reduced insulin sensitivity, for those exposed to ETS when compared to those who were not exposed (p = 0.019). This association persisted for female participants (p = 0.013) and exhibited the same trend for males but failed to achieve statistical significance (p = 0.264). CONCLUSIONS: Our study did not reveal an association between active smoking and insulin sensitivity, as has been shown previously. The association between ETS exposure and insulin sensitivity is a puzzling finding which deserves further investigation in the longitudinal data from IRAS as well as in other populations.

Relation between dietary fiber consumption and fibrinogen and plasminogen activator inhibitor type 1: The National Heart, Lung, and Blood Institute Family Heart Study.

Considerable evidence suggests that high plasma concentrations of plasminogen activator inhibitor type 1 (PAI-1) and fibrinogen increase the risk of cardiovascular disease. Recent studies report beneficial effects of dietary fiber on coronary artery disease, although the mechanisms by which high fiber intake reduces the risk of heart disease are not well understood. This study examined the relation of dietary fiber intake to PAI-1 and fibrinogen concentrations in 883 men and 1116 women aged 50.4 +/- 13.8 and 52.1 +/- 13.7 y, respectively, in the National Heart, Lung, and Blood Institute Family Heart Study. Diet was assessed with a semiquantitative food-frequency questionnaire. The natural logarithm was used to transform PAI-1 because of a skewed distribution. In the first through fifth age- and energy-specific quintiles of fiber intake, mean (ln)PAI-1 was 6.09, 5.91, 5.88, 5.82, and 5.67 pmol/L, respectively, for men and 5.50, 5.37, 5.39, 5.23, and 5.18 pmol/L, respectively, for women. Multiple regression showed that when the lowest was compared with the second, third, fourth, and fifth age- and energy-specific quintiles of fiber intake, (ln)PAI-1 was 0.21, 0.25, 0.22, and 0.32 pmol/L lower in men (P for trend = 0.009) and 0.08, 0.06, 0.14, and 0.20 pmol/L lower in women (P for trend = 0.037), respectively, with anthropometric, lifestyle, and metabolic factors adjusted for. No significant association was found between fiber intake and fibrinogen. Waist-hip ratio did not modify the relation of fiber intake to PAI-1 (P for interaction = 0.39 for men and 0.36 for women). These data suggest that higher fiber intake is inversely associated with PAI-1, but not with fibrinogen concentration.

Validity of self-reported fat distribution in young adults: the CARDIA Study. Coronary Artery Risk Development in Young Adults.

To determine the validity of self-reported information on body fat distribution, relationships between reported location of weight gain and measured waist-to-hip ratio (WHR), high density lipoprotein cholesterol (HDL-C), and fasting insulin were analyzed in 5115 black and white men and women aged 18-30 years. In black men, WHR adjusted for age and body mass index (BMI) ranged from 0.833 among those reporting upper and central weight gain to 0.812 among those reporting lower body weight gain (trend across five reported fat distribution categories, P = 0.0004). Corresponding values were, for white men, 0.852 to 0.831; for black women, 0.777 to 0.721; and for white women, 0.772 to 0.701 (each P < 0.0001). Reported fat distribution was associated with HDL-C in women, but not in men, and with fasting insulin in all groups. While these associations were somewhat weaker than with measured WHR, self-reported fat distribution does provide valid information about body fat distribution in young adults, particularly women.

Heritability of ECG measurements in adult male twins.

To assess the genetic contribution to electrocardiographic (ECG) measurements, heritability analysis was performed on ECG data collected on 251 pairs of adult male twins during the second examination of the National Heart, Lung and Blood Institute twin study, a multicenter study of cardiovascular risk factors. Resting 12-lead ECGs were obtained on each twin, pair and, the R-R, QRS, QT, and JT intervals were measured. Both the R-R and QT intervals demonstrated significant heritable components, accounting for 77% and 36%, respectively, of the variability. No significant heritable component of the QRS complex could be identified. Although the MZ intraclass correlation was higher than the DZ intraclass correlation, the JT interval did not demonstrate significant heritability. Therefore, in adult males both heart rate and the duration of ventricular repolarization have significant heritable components. These heritable components may need to be considered when using ECG measurements to screen for patients at risk for cardiovascular disorders or sudden cardiac death.

Familial determinants of moderate and intense physical activity: a twin study.

This twin study estimates familial clustering of moderate and intense leisure-time physical activity and investigates quantitatively its genetic and environmental components. Study subjects are 3,344 male twin pairs aged 33-51 yr. Moderate activity levels were assessed with six questions about discretionary walking or stair climbing for exercise. Five questions assessed regular participation in specific, intense athletic activities (running, bicycling, swimming, racquet, and other sports). Familial aggregation is estimated by odds ratio of one twin engaging in an activity when his co-twin does. Monozygotic and dizygotic twin correlations were compared to estimate genetic and nongenetic sources of phenotypic variation. For each activity, the familial aggregation odds ratio was statistically significant with values between 2.9 to 4.6 for intense activities and between 1.4 to 1.9 for all moderate activities but one. Monozygotic twin correlations were higher than dizygotic, suggesting genes play a role in the observed phenotypic variation. For four questions, and a compromise scale of moderate activity, the difference between correlations was statistically significant (P < 0.05). In this cohort, much of the phenotypic variability for both moderate and intense activities is a result of familial effects. Genes may influence regular participation in specific intense exercises more than moderate activity, such as walking for exercise.

Correlates of sleep problems among men: the Vietnam Era Twin Registry.

The Vietnam Era Twin (VET) Registry includes 14,800 male twins born 1939-55 and in military service in 1964-75. A mailed health survey including the Jenkins Sleep Questionnaire was sent to 11,959 members and 8,870 (74.2%) provided responses on the frequency of sleep problems in the previous month. Prevalence of those experiencing conditions at least 1 day per month was 67.2% for waking often, 61.5% for waking tired/worn out, 48.1% for trouble falling asleep and 48.6% for awakening early. Ordinal logistic regression analysis was used to estimate sleep problems from demographic, behaviour and lifestyle characteristics, and morbid conditions. Black (vs. white) race, older age, church/religious group participation, social support, employment, cigarette smoking, light physical activity, and strenuous physical activity were associated with lower risk of one or more sleep problems. Eleven morbid conditions with a prevalence of 1% or more, coffee consumption, heavy alcohol consumption, and Framingham Type A behaviour pattern were associated with a higher risk of sleep problems. These analyses suggest that sleep problems may be one of the mechanisms relating reduced quality of life to many physical and behavioural characteristics. Fortunately, a number of the risk factors associated with sleep problems are lifestyle characteristics which, if modified, may reduce sleep problems.

Insulin sensitivity and abdominal obesity in African-American, Hispanic, and non-Hispanic white men and women. The Insulin Resistance and Atherosclerosis Study.

Increased abdominal obesity has been related to lower insulin sensitivity (SI), independent of overall obesity, but it has been suggested that this relationship may be weaker in non-whites. In the Insulin Resistance and Atherosclerosis Study (IRAS), SI was estimated using a minimal model analysis of the frequently sampled intravenous glucose tolerance test in 1,625 men and women aged 40-69 years. Subjects included African-Americans, Hispanics, and non-Hispanic whites from Oakland and Los Angeles, CA, San Antonio, TX, and the San Luis Valley, CO. Minimum waist circumference was significantly (P = 0.0001) associated with SI after adjusting for age, sex, height, BMI, glucose tolerance status, ethnicity, and clinic. This relationship was significantly (P = 0.0001) stronger in subjects with normal glucose tolerance (NGT) (beta = -0.030, P = 0.0001) than in those with impaired glucose tolerance (IGT) (beta = -0.010, P = 0.02; NIDDM: beta = -0.013, P = 0.0001). There were no significant ethnic differences in effect size across the spectrum of glucose tolerance. Waist circumference was also positively related to fasting insulin, an indirect measure of insulin sensitivity, in NGT (P = 0.0001), IGT (P = 0.0003), and NIDDM (P = 0.0002). The waist-fasting insulin relationship was significantly weaker in African-Americans, relative to non-Hispanic whites, in NGT and IGT (tests of statistical interaction: P = 0.04 and P = 0.02, respectively). In general, these patterns were similar in models specifying waist-to-hip ratio (WHR), rather than waist circumference, as the independent variable. While some ethnic variability exists, a negative relationship between abdominal obesity and insulin sensitivity was confirmed for all three ethnic groups across the spectrum of glucose tolerance.

Correlates and predictors of weight loss in young adults: the CARDIA study.

OBJECTIVE: To determine associations of sociodemographic characteristics, behaviors, attitudes and medical factors with weight loss in a population-based biracial cohort of young adults. DESIGN: Two-year longitudinal observation study. SUBJECTS: 4278 black and white men and women aged 18-30 years in 1985-1986. MEASUREMENTS: Weight, height, education, income, subscapular skinfold thickness, waist and hip circumferences, medical history, smoking, physical activity, dietary energy, fat and alcohol intake, physical fitness measured by treadmill testing, self-reported dieting, history of weight loss and regain, perception of body size and belief in health consequences of overweight. RESULTS: Weight loss, defined as reduction of 5% or more of baseline weight, occurred in 8.9% of the cohort, ranging from 4.9% among white men who were not overweight at baseline to 21.5% among white women who were overweight. Weight loss was more common in women than men and in overweight white women than overweight black women. Although findings differed among the four race-sex groups, weight loss was generally associated with greater baseline fatness, lower baseline physical fitness level, self-perception of being overweight, dieting and previous weight loss and regain. Greater baseline fatness, a perception of being overweight and dieting were also associated with weight gain. Among the overweight, low baseline fitness and an increase in physical activity were the factors most consistently associated with weight loss. CONCLUSION: Weight loss in young adults varies by race, sex and body weight and is associated with a variety of behaviors and attitudes, some of which are also associated with weight gain and, thus, may be associated with weight fluctuation.

Genetic influences on adult weight gain and maximum body mass index in male twins.

The National Heart, Lung, and Blood Institute Twin Study is a multicenter, longitudinal study of 514 white, male twin pairs examined during military induction at the mean age of 20 years (1943) and by the National Heart, Lung, and Blood Institute Twin Study at mean ages 48 (1971), 58 (1981), and 63 years (1986). Of these, 121 of 254 monozygotic pairs and 113 of 260 dizygotic pairs had complete data for all examinations. Using these data, genetic influences on maximum body mass index (BMI) and changes in BMI during this 43-year interval were estimated. BMI (kg/m2) was calculated for each examination and for the maximum weight as recalled by the participant at the last examination. Regression equations were fitted to each person's four-examination measurements to estimate the trend in weight change over adulthood. Twins gained an average of 0.11 kg/m2 per year from mean ages 20-63 years. Maximum BMI averaged 28.4 kg/m2 for monozygotic twins and 28.3 kg/m2 for dizygotic twins. The distribution of the ages at maximum BMI appeared to be bimodal for each zygosity, with modes around ages 20 and 60 years. Heritability (variation attributable to genetic factors) was estimated to be 0.71 (95% confidence interval 0.55-0.87) for maximum BMI and 0.70 (95% confidence interval 0.55-0.84) for trend in adult weight gain. In contrast, variability of BMI around the trend line showed no evidence of significant genetic determination.