NHLBI Family Heart Study Research Articles

Segregation analysis of HDL cholesterol in the NHLBI Family Heart Study and in Utah pedigrees.

We investigated the genetic determination of high-density-lipoprotein cholesterol (HDL-C) levels in the NHLBI Family Heart Study by segregation analysis. Included was a total of 3755 subjects from 560 randomly selected nuclear families and 522 families selected due to a high family risk of coronary heart disease (CHD). In the whole dataset, there was no evidence for an allele at a major gene locus responsible for HDL-C levels lower than the population mean or even for significant bimodality for low levels of HDL-C. However, we observed evidence for a recessive allele that was associated with higher HDL-C levels than average. This evidence for a recessive major gene was independent of triglyceride concentrations and was most strongly observed in families recruited for CHD. The environmental model was rejected (P=0.0027) while the codominant and recessive models were not rejected (P=0.085 and P=0.133, respectively). The dominant model was also rejected (P<0.0001). In the recessive segregation model, the means of those inferred to be homozygous for the high HDL-C allele and those without the high HDL-C allele were separated by about 25 mg/dl HDL-C (73.9+/-1.99 vs 48.2+/-0.36 mg/dl). Because these results were unexpected, segregation was tested in a separate sample of 2013 individuals in 85 large pedigrees ascertained for early heart disease deaths, early stroke deaths, and early hypertension in Utah. Similar evidence for an allele at a major gene locus for high HDL-C was found. In summary, we did not find evidence for an allele at a major gene locus associated with low HDL-C levels segregating in pedigrees recruited for the NHLBI Family Heart Study, or in pedigrees ascertained in Utah for early CHD or related phenotypes. Instead we found some evidence for the segregation of an allele associated with high HDL-C. d

Genome Scan for Quantitative Trait Loci Linked to High-Density Lipoprotein Cholesterol

We conducted a genome-wide linkage scan for quantitative trait loci influencing total HDL-cholesterol (HDL-C) concentration in a sample of 1027 whites from 101 families participating in the NHLBI Family Heart Study. To maximize the relative contribution of genetic components of variance to the total variance of HDL-C, the HDL-C phenotype was adjusted for age, age(2), body mass index, and Family Heart Study field center, and standardized HDL-C residuals were created separately for men and women. All analyses were completed by the variance components method, as implemented in the program GENEHUNTER using 383 anonymous markers typed at the NHLBI Mammalian Genotyping Service in Marshfield, Wis. Evidence for linkage of residual HDL-C was detected near marker D5S1470 at location 39.9 cM from the p-terminal of chromosome 5 (LOD=3.64). Suggestive linkage was detected near marker D13S1493 at location 27.5 cM on chromosome 13 (LOD=2.36). We conclude that at least 1 genomic region is likely to harbor a gene that influences interindividual variation in HDL cholesterol.

The 1298A→C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine

A common mutation in methylenetetrahydrofolate reductase (MTHFR), 677C→T, is associated with reduced enzyme activity, a thermolabile enzyme and mild hyperhomocysteinemia, a risk factor for vascular disease. Recently, a second common mutation (1298A→C; glutamate to alanine) was reported, but this mutation was suggested to increase homocysteine only in individuals who carried the bp677 variant. To evaluate the functional consequences of this mutation, we performed site-directed mutagenesis and in vitro expression. For in vivo assessment of clinical impact, we examined the 1298A→C genotypes and plasma homocysteine in 198 individuals from the NHLBI Family Heart Study that had previously been assessed for the 677 substitution. Site-directed mutagenesis of the human cDNA was performed to generate enzymes containing each of the two mutations, as well as an enzyme containing both substitutions. Enzyme activity and thermolability were assessed in bacterial extracts. The activity of the wild-type cDNA was designated as 100%; mutant enzymes containing the 1298 and 677 mutations separately had 68% (±5.0) and 45% (±10.8), respectively, of control activity while the enzyme containing both mutations had 41% (±12.8) of control activity. The 1298 mutation was not associated with a thermolabile enzyme. In the Family Heart Study, fasting homocysteine was significantly higher ( P<0.05) in individuals heterozygous for both substitutions, compared to individuals who carried only the 677C→T variant. This study suggests that two variants in MTHFR should be assessed as genetic risk factors for hyperhomocysteinemia.

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.

Relation between Dietary Linolenic Fatty Acid and Coronary Heart Disease in the NHLBI Family Heart Study

0014 Epidemiologic studies suggest that higher consumption of alpha linolenic acid, eicosapentaenoic acid, and docosahexanoic acid is associated with lower risk of coronary heart disease (CHD). Little is known about the influence of the linoleic-to-linolenic ratio on the relation of linolenic acid to CHD. We used data collected on 4,406 participants of the NHLBI Family Heart Study (mean age of 52 years)to examine the relation between dietary linolenic acid and prevalent coronary heart disease and to determine if such a relation was influenced by fish consumption and linoleic-to-linolenic ratio. Dietary linolenic acid was assessed by semiquantitative food frequency questionnaire. We used generalized estimating equations to estimate the odds ratios of coronary heart disease across age- and energy-adjusted quintiles of linolenic acid. From the lowest to the highest quintile of linolenic acid, the prevalence odds ratios (95 % CI) of coronary heart disease were 1.00 (referent), 0.77 (0.49-1.21), 0.51 (0.32-0.81), 0.52 (0.33-0.84), and 0.48 (0.30-0.76), respectively, for men (p for trend 0.0009) and 1.00, 0.55 (0.29-1.04), 0.75 (0.41-1.38), 0.43 (0.21-0.88), and 0.40 (0.20-0.82), respectively, for women (p for trend 0.015), controlling for age, energy intake, anthropometric, lifestyle, and metabolic factors. This association was observed across all categories of fish consumption frequency. When stratified by tertiles of linoleic-to-linolenic ratio (ranges of 2.3-8.4, 8.5-11.1, and 11.2-64.0), a statistically significant inverse relation between linolenic acid and CHD was observed only in the lowest tertile of linoleic-to-linolenic ratio (p for trend 0.0001, 0.39, and 0.13, respectively, for the first, second, and third tertile of linoleic-to-linolenic ratio). In conclusion, these data suggest an inverse relation between dietary linolenic acid intake and prevalent coronary heart disease in both sexes, independent of fish consumption. A lower ratio of linoleic-to-linolenic fatty acid might be necessary to observe the benefits of linolenic acid on coronary heart disease.

Birth weight and cardiovascular disease: The NHLBI Family Heart Study

P66 Epidemiologic studies have been inconsistent on the association between low birth weight and increased risk of cardiovascular disease (CVD). Little is known about potential mechanisms by which determinants of low birth weight affect CVD. We used data collected on 2,540 participants of the NHLBI Family Heart Study to assess the relation of birth weight to CVD, hypertension, and diabetes mellitus. Birth weight was obtained by self report. CVD was defined as positive history of myocardial infarction, coronary angioplasty, coronary bypass surgery, congestive heart failure, or stroke. Hypertension was defined as systolic blood pressure of at least 140 mm Hg, or diastolic pressure of at least 90 mm Hg, or use of antihypertensive medication. Diabetes mellitus was ascertained by medical history and pathologic blood sugar levels. We used generalized estimating equations to assess the prevalence odds ratios, adjusting for age, risk group, anthropometric, metabolic, and lifestyle factors. Prevalence odds ratios (95% CI) are presented below. Low birth weight was associated with increased prevalence odds of CVD compared with normal and large babies (p=0.0012). The trend was suggestive of increased prevalence odds of hypertension (p=0.05) and diabetes mellitus (p=0.0012) from the highest to the lowest category of birth weight. In conclusion, low birth weight was associated with increased prevalence odds ratio of CVD, diabetes mellitus, and hypertension. Low birth weight may add to other traditional risk factors in identifying subjects at low and high risk of CVD. Table 1.

Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study

Inflammation is thought to play a central role in the etiology and outcome of atherosclerosis. Animal studies as well as in vitro and in vivo human studies suggest that host factors modulate the magnitude and extent of inflammatory responses. We investigated familial aggregation of three systemic markers of inflammation (C-reactive protein (CRP), white blood cell count (WBC), and albumin) in a large, cross-sectional study conducted in four US communities. We found evidence of substantial heritability (35–40%) for CRP levels as well as for WBC and albumin levels. Negligible spouse correlations suggested little influence of shared household environment on these traits. The combination of sociodemographic factors (age, center, education), behavioral and lifestyle factors (cigarette smoking, alcohol intake, hormone replacement therapy), obesity and fat patterning, and prevalent diabetes explained 13–30% the interindividual variability of these traits. There was no evidence that these inflammation phenotypes were linked to a microsatellite marker in the interleukin-1 gene cluster on chromosome 2q, a region that includes several candidate genes for chronic inflammatory diseases. Our findings suggest that CRP levels, albumin levels, and WBC are determined at least partially by genetic factors. Further efforts to identify gene loci affecting these traits are warranted.

Association of plasma bilirubin with coronary heart disease and segregation of bilirubin as a major gene trait: the NHLBI family heart study

Decreased serum bilirubin levels have been associated with coronary heart disease (CHD). It is believed that bilirubin acts as an antioxidant, preventing formation of oxidized LDL and subsequent atherosclerosis. Serum bilirubin also segregates as a major gene, with the rarer genotype associated with elevated bilirubin levels and occurring in about 12% of the population. Using a large population-based study of random and CHD high risk families, this analysis was designed to replicate the association of lower serum bilirubin levels with early CHD (onset by age 55 for males and 65 for females) using 328 case/control samples and the major gene segregation of bilirubin levels in 555 families. There were significant differences in plasma bilirubin levels between 188 males (12.5 μmol/l) and 140 females (9.3 μmol/l, P<0.0001). Higher serum albumin and lower HDL-C significantly correlated with higher plasma bilirubin levels in females but not males. In sex-specific logistic regression models of early CHD (148 cases and 180 controls), lower plasma bilirubin was associated with increased prevalence of CHD in males with borderline significance (odds ratio=0.93 for a 1 μmol/l increase in bilirubin, P=0.056) but not in females. Bilirubin was found to segregate as a major gene using all 555 families consisting of 1292 individuals, with estimates replicating those in the previously published study. The most parsimonious model was a recessive model for high bilirubin levels that occurred in about 23% of the population. The means were separated by 1.7 standard deviations and there was a significant polygenic effect ( h 2=0.33, P=0.0009). We conclude that decreased bilirubin is mildly related to CHD in males but not in females. Because of an inverse correlation between HDL-C and bilirubin, the protective high HDL-C levels may have counteracted the CHD risk associated with lower bilirubin levels in females. The inferred major gene for bilirubin may protect against CHD, since elevated levels, rather than lower levels, were associated with this inferred gene.

Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (The Health Family Tree Study and the NHLBI Family Heart Study)

Detailed medical family history data have been proposed to be effective in identifying high-risk families for targeted intervention. With use of a validated and standardized quantitative family risk score (FRS), the degree of familial aggregation of coronary heart disease (CHD), stroke, hypertension, and diabetes was obtained from 122,155 Utah families and 6,578 Texas families in the large, population-based Health Family Tree Study, and 1,442 families in the NHLBI Family Heart Study in Massachusetts, Minnesota, North Carolina, and Utah. Utah families with a positive family history of CHD (FRS ≥0.5) represented only 14% of the general population but accounted for 72% of persons with early CHD (men before age 55 years, women before age 65 years) and 48% of CHD at all ages. For strokes, 11% of families with FRS ≥0.5 accounted for 86% of early strokes (<75 years) and 68% of all strokes. Analyses of >5,000 families sampled each year in Utah for 14 years demonstrated a gradual decrease in the frequency of a strong positive family history of CHD (−26%/decade) and stroke (−15%/decade) that paralleled a decrease in incidence rates (r = 0.86, p <0.001 for CHD; r = 0.66, p <0.01 for stroke). Because of the collaboration of schools, health departments, and medical schools, the Health Family Tree Study proved to be a highly cost-efficient method for identifying 17,064 CHD-prone families and 13,106 stroke-prone families (at a cost of about $27 per high-risk family) in whom well-established preventive measures can be encouraged. We conclude that most early cardiovascular events in a population occur in families with a positive family history of cardiovascular disease. Family history collection is a validated and relatively inexpensive tool for family-based preventive medicine and medical research.

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/m 2 and doing about 75 min of moderate exercise per week was associated with a BMI 1.8 kg/m 2 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/m 2 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.

Familial history of metabolic disorders and the Multiple Metabolic syndrome: The NHLBI family heart study

Familial history of metabolic disorders and the Multiple Metabolic syndrome: The NHLBI family heart study

Plasma homocysteine and its association with carotid intimal-medial wall thickness and prevalent coronary heart disease: NHLBI Family Heart Study

Mildly elevated plasma total homocysteine (tHcy) levels have been associated with increased risk of coronary heart disease (CHD). Carotid artery intimal-medial wall thickening is a predictor of cardiovascular disease and has been previously shown to be positively associated with plasma tHcy in studies of asymptomatic subjects. In the current study we examined 1467 subjects with regard to their fasting plasma tHcy levels and intimal-medial wall thickness as measured by B-mode ultrasound and early onset CHD. The results showed that there is a significant positive association between plasma tHcy levels and carotid-artery wall thickness in participants 55 years or older even after the tHcy levels are adjusted for age, smoking and anti-hypertensive medication. The direction and magnitude of the relationship is similar although the result was not statistically significant in younger participants (<55 years). Early onset CHD at any age was not significantly different across the tHcy quintiles. The lack of an association of tHcy and CHD in the presence of a positive association with intimal-medial wall thickening may be a reflection of increased statistical power of quantitative versus qualitative traits. We conclude that the present finding of a positive association between tHcy and intimal-medial wall thickness strengthens the in vitro finding of the stimulating effect of homocysteine on vascular smooth muscle cell growth. Vascular smooth muscle cell proliferation may be an important mechanism through which mildly elevated plasma tHcy promotes atherosclerosis.

Genetic background of Lewis negative blood group phenotype and its association with atherosclerotic disease in the NHLBI Family Heart Study

To examine the prevalence of four mutations, T59G, T1067A, T202C and C314T, of the human alpha(1,3/1,4) fucosyltransferase 3 (FUT 3) gene amongst persons with Lewis negative and those with Lewis positive blood group phenotype. An additional objective was to explore the hypothesis that these mutations are associated with coronary heart disease and inflammatory reaction. A population-based cross-sectional study. Analysis of samples and data from the National Heart Lung and Blood Institute Family Heart Study. All Lewis (a-b-) participants (n = 136) and a sample of Lewis positive participants (n = 136) of the Family Heart Study; all were of Caucasian ethnicity. The prevalence of examined mutations by Lewis phenotype. The examined mutations were common and strongly associated with the Lewis (a-b-) phenotype. Accordingly, 90-95% of Lewis (a-b-) individuals amongst Caucasians can be identified by screening for these four mutations. Exploratory analyses suggested that with the exception of T59G, all examined mutations were positively associated with prevalent coronary heart disease, although not statistically significantly, perhaps due to the small number of prevalent coronary heart disease cases. C-reactive protein tended to be higher amongst persons with a TC or CC genotype at position 202 (3.07 +/- 0.41 vs. 2.08 +/- 0.32 mg L-1, P = 0.06). Four specific mutations of fucosyltransferase 3 gene are responsible for the vast majority of Lewis (a-b-) phenotypes in Caucasians. These mutations are common in the population at large and may be associated with increased risk of coronary heart disease. Further studies using larger samples are warranted.

Segregation analysis of serum uric acid in the NHLBI Family Heart Study

Segregation analysis of serum uric acid in the NHLBI Family Heart Study

Segregation analysis of serum uric acid in the NHLBI Family Heart Study.

Segregation analysis was performed on the serum uric acid measurements from 523 randomly ascertained Caucasian families from the NHLBI Family Heart Study. Gender-specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analysis. Uric acid residuals were adjusted for age, age2, age3, body mass index (kg/m2), creatinine level, aspirin use (yes/no), total drinks (per week), HOMA insulin resistance index [(glucose * insulin)/22.5], diuretic use (yes/no), and triglyceride level. Sibling correlations (r=0.193) and parent-offspring correlations (r=0.217) were significantly different from zero, but these two familial correlations were not significantly different from one another. After adjustment for covariates, the heritability estimate for serum uric acid was 0.399. Segregation analysis rejected the "no major gene" model but was unable to discriminate between an "environmental" and a "Mendelian major gene" model. These results support the hypothesis that uric acid is a multifactorial trait possibly influenced by more than one major gene, modifying genes, and environmental factors.

Family risk score of coronary heart disease (CHD) as a predictor of CHD: the Atherosclerosis Risk in Communities (ARIC) study and the NHLBI family heart study.

Family history of coronary heart disease (CHD) has been found to be a risk factor for CHD in numerous studies. Few studies have addressed whether a quantitative measure of family history of CHD (family risk score, FRS) predicts CHD in African Americans. This study assessed the association between FRS and incident CHD of participants, and the variation of the association by gender and race. Participants in the study were a biracial population-based cohort with 3,958 African Americans and 10,580 Whites aged 45-64 years old in the ARIC baseline survey (1987-1989). They were randomly selected from four U. S. communities. During follow-up (1987-1993), 352 participants experienced the onset of CHD. Incidence density of CHD (per 1,000 person-years) was 7.8 and 3.6 among African-American men (AAM) and women (AAW), and 7.2 and 2.2 among White men (WM) and women (WW). The hazard rate ratio (HRR) of CHD associated with one standard deviation increase of FRS was 1.52 in AAW, 1.46 in AAM, 1.41 in WW, and 1.68 in WM. The HRRs decreased 4.6% in AAW, 1.4% in WW, 5.7% in AAM, and 3.0% in WM, but increased 2.1% in AAM after adjustment for selected covariates. FRS predicts incident CHD in African Americans and Whites, men and women. The relation of FRS to incident CHD can be only partially explained by the selected risk factors in the biological causal pathways: IMT, T-G, LDL, HDL, Lp(a), fibrinogen and hypertension. No significant difference by race has been found in this study.

Familial resemblance for hostility: the National Heart, Lung, and Blood Institute Family Heart Study.

The purpose of this study was to examine whether several aspects of hostility as measured by the Cook-Medley Hostility Scale (ie, aggressive responding, hostile affect, cynicism, and overall hostility score) were determined in part by family factors (ie, genes and/or familial environments). Analyses were based on 680 European-American families (2525 individuals) from the NHLBI Family Heart Study (FHS), a population-based study of genetic and nongenetic determinants of CHD, atherosclerosis, and cardiovascular risk factors. The influence of family relationships, age, and education on the variation in each of the four hostility scores were estimated. Significant familial resemblance in all hostility scores was found, accounting for 42% of the variance in total hostility, 30% in cynicism, 38% in aggressive responding, and 18% in hostile affect. Very little of this resemblance could be explained by similarities in education. Familial resemblance for cynicism was solely due to significant parent-offspring and sibling correlations (ie, no spouse resemblance), suggesting the possibility of genetic influences. Gender and generation differences were also evident in the familial correlations. Hostility aggregates in families. Both family environmental and genetic sources of resemblance are suggested for hostility.

Evidence for major genes influencing pulmonary function in the NHLBI family heart study.

Segregation analysis was performed on the pulmonary measures forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of FEV1/FVC in 455 randomly ascertained families from the NHLBI Family Heart Study (FHS). Gender specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analyses. These residuals represented adjustments for the effects of age, age(2), age(3), Body Mass Index (BMI, kg/m(2)), height, the ratio of waist to hip measurements (WHR), the presence of coronary heart disease, smoking history, and pack years for current smokers. Sibling correlations were not different from parent-offspring correlations for all three traits, and heritability estimates for FEV1, FVC, and the FEV1/FVC ratio were 0. 515, 0.540, and 0.449, respectively. Segregation analysis of FEV1, a trait that measures airflow, indicated that a dominant major gene best fits the data, although a residual familial correlation supports the presence of an additional polygenic or common environmental component. For FVC, a trait that measures lung volume, alternative models could not be statistically differentiated, but the transmission probabilities do not support a Mendelian major gene. The best model for FEV1/FVC ratio is a non-Mendelian codominant model, perhaps due to the mixing of the individual underlying distributions influencing airflow and lung volume. These results support the hypothesis that complex relationships exist for lung function traits and that multiple genes and environmental factors influence lung function.

Familial history of metabolic disorders and the Multiple Metabolic syndrome: The NHLBI family heart study

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" ( 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.

Effects of similarities in lifestyle habits on familial aggregation of high density lipoprotein and low density lipoprotein cholesterol: the NHLBI Family Heart Study.

It is generally assumed that familial aggregation of lipids relates to both genetic and shared environmental factors. To determine the degree to which familial similarities in lifestyle habits explain familial aggregation of high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, the authors analyzed 1994-1996 data from 2,284 US adult participants in the National Heart, Lung, and Blood Institute Family Heart Study. For men and women, respectively, HDL cholesterol correlated with alcohol consumption (r = 0.27, p < 0.001; r = 0.21, p < 0.001), exercise (r = 0.06, p = 0.05; r = 0.10, p = 0.002), and smoking (r = -0.09, p = 0.005; r = -0.13, p < 0.001). There was strong familial aggregation of HDL cholesterol (parent-child, r = 0.32; sibling-sibling, r = 0.29), but less than 10% was explained by lifestyle habits. For LDL cholesterol, weak correlations were found for intake of total fat (r = 0.06, p = 0.07) and fruits/vegetables (r = -0.09, p = 0.005) among men and for smoking (r = 0.10, p = 0.002) among women. LDL cholesterol correlated strongly among family members (parent-child, r = 0.24; sibling-sibling, r = 0.31), but essentially none of this aggregation related to the lifestyle factors studied. This study suggests that lifestyle factors have little effect on the familial aggregation of HDL and LDL cholesterol.