Linkage and segregation analyses of apolipoproteins A1 and B, and lipoprotein cholesterol levels in a large pedigree with excess coronary heart disease: the Bogalusa Heart Study

Robust methods were employed, using data from a single large pedigree, to screen serum apolipoprotein A1 and B levels, serum lipoprotein cholesterol levels, and ratios of serum lipoprotein cholesterol fractions to apolipoprotein A1 and B levels for genetic linkage to 31 polymorphic markers. Segregation analyses were performed for each of the apolipoprotein and lipoprotein cholesterol fractions to obtain estimates for use in applying likelihood methods of linkage analysis. Trait-marker combinations for which linkages were suggested from the robust methods were then reexamined for linkage using the likelihood (lod score) method. Results from the segregation analyses were consistent with major gene determination of apo B and HDL-C levels, the HDL-C to apo A1 ratio, the LDL-C to apo B ratio, and a measure of relative content of cholesterol in HDL-C and LDL-C. Linkage between haptoglobin and the HDL-C/apo A1 ratio was suggested, with a lod score of 1.72 at theta = 0.05.     

An approach to the multivariate analysis of high-density-lipoprotein cholesterol in a large kindred: the Bogalusa Heart Study

The genetic determination of high-density-lipoprotein cholesterol (HDL-C) levels was evaluated using segregation analysis techniques in a large multigenerational kindred with a high prevalence of coronary heart disease and myocardial infarction. Univariate segregation analysis of HDL-C levels with the effects of age and sex removed by regression provided evidence of a Mendelian mode of inheritance for a portion of the variability in HDL-C levels. Subsequent analyses included low-density-lipoprotein cholesterol (LDL-C) levels and several behavioral and anthropometric variables that affect HDL-C levels. Pedigree discriminant analysis was used to find the linear functions of the variables that maximized the likelihood given the pedigree structure and assuming monogenic segregation. The best linear function was found to be approximately equivalent to the log of the HDL-C to LDL-C ratio, with concomitant and environmental effects removed by regression. Genetic hypotheses were tested by cross-validation; linear functions derived from data on each side of the kindred were used to test hypotheses on the other side of the kindred. On one side of the kindred, all hypotheses were accepted. On the other side of the kindred, only Mendelian inheritance of the linear function was indicated. Segregation of the age- and sex-adjusted HDL-C values, and of the linear function, was evaluated using a regressive model that allows for intrafamilial correlations in addition to a monogenic effect. All analyses provide evidence for levels of HDL-C being controlled by a major locus with neither dominant nor recessive expression.     

Linkage between the APOB gene and serum apoB levels in a large pedigree from the Bogalusa heart study

Maximum likelihood linkage analyses were performed to test for linkage between serum apoB levels and several candidate gene markers including apolipoprotein B, lipoprotein lipase, hepatic lipase, cholesterol ester transfer protein, and apolipoprotein AI in a large pedigree. Parameters of general Mendelian inheritance derived from maximum likelihood segregation analysis of the serum apoB levels were used in the linkage analysis. The highest two-point lod score between the quantitative trait and a marker defined by a single restriction digest was 1.86 at recombination fraction (θ) = 0. This was observed for linkage between serum apoB levels and the presence or absence of a PvuII digestion site in the apoB gene. Linkage between serum apoB levels and polymorphisms of the apoB gene defined by the two restriction digests EcoR1 and PvuII was supported by a lod score of 3.30, while inclusion of VNTR typings led to a lod score of 2.33. None of the other candidate genes gave positive evidence of linkage. © 1994 Wiley-Liss, Inc.

1 This article is a US government work and, as such, is in the public domain in the United States of America.

     

Race and gender differences in serum lipoproteins of children, adolescents, and young adults--emergence of an adverse lipoprotein pattern in white males: the Bogalusa Heart Study.

METHODS. Serum lipoprotein profiles in 4,231 individuals, ages 5-26 years, were studied cross-sectionally in a biracial community to describe the race- and gender-specific changes from adolescence into young adulthood. RESULTS. White children and adolescents of both genders showed significantly higher covariates--adjusted triglycerides (9-11 mg/dl) and very-low-density lipoprotein cholesterol (1-2 mg/dl)--and lower total cholesterol (3-14 mg/dl) and high-density lipoprotein cholesterol (6-10 mg/dl) levels than their black counterparts. These black-white differences persisted among young adults of both genders with the exception of total cholesterol levels (higher triglycerides: 23-32 mg/dl; higher very-low-density lipoprotein cholesterol: 5-7 mg/dl; lower high-density lipoprotein cholesterol: 9-11 mg/dl); in addition, white young adult males began to show higher levels of low-density lipoprotein cholesterol (14 mg/dl) than black young adult males. A consistent gender-related pattern emerged only among white young adults with males showing higher triglyceride levels (22 mg/dl), very-low-density lipoprotein cholesterol (5 mg/dl), and low-density lipoprotein cholesterol (10 mg/dl) and lower high-density lipoprotein cholesterol (10 mg/dl) than females. Lipoprotein changes from adolescence into young adulthood were more pronounced among white males than other race-gender groups, resulting in higher triglyceride, very-low-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, a higher total cholesterol/high-density lipoprotein cholesterol ratio, and a lower high-density lipoprotein cholesterol in their young adulthood. According to the National Cholesterol Education Program criteria, a relatively higher proportion of young adult white males was classified as borderline-high (22.6%) or high (9.1%) for low-density lipoprotein cholesterol. Adiposity was the major contributor to the adverse lipoprotein pattern, especially among white males. Sexual maturation and age influenced the lipoprotein levels to a greater extent among white males. Cigarette smoking, alcohol intake, and oral contraceptive use began to emerge as minor but significant factors contributing to the lipoprotein levels in adolescents and young adults. CONCLUSION. These results underscore the desirability of early targeting for primary prevention.     

Investigating Effects of Plasma Apolipoprotein E on Ischemic Heart Disease Using Mendelian Randomization Study

Background: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). Methods: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. Results: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. Conclusions: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.     

Relation of serum lipoprotein lipids and apolipoproteins to obesity in children: the Bogalusa Heart Study.

BACKGROUND. The relationship of serum lipoprotein lipids and apolipoproteins to obesity was studied in a biracial sample of 2,816 children of ages 5-17 in Bogalusa, Louisiana. METHODS. Two measures of obesity were used: fatness (subscapular skinfold thickness) and fat centrality (the ratio of subscapular to triceps skinfold thickness). Plasma insulin and glucose were included as metabolic markers related to obesity. RESULTS. The obesity associations were relatively strong with insulin (rs = 0.29, P less than 0.001, skinfold; rs = 0.15, P less than 0.001, skinfold ratio) and triglycerides (rs = 0.25, P less than 0.001, skinfold; rs = 0.19, P less than 0.001, skinfold ratio). The relationships of serum low-density lipoprotein cholesterol (LDL-C) (rs = 0.17, P less than 0.001, skinfold; rs = 0.13, P less than 0.001, skinfold ratio) and apolipoprotein (apo) B (rs = 0.16, P less than 0.001, skinfold; rs = 0.13, P less than 0.001, skinfold ratio) with the obesity measures were of lesser magnitude, but persisted after adjustment for insulin and triglycerides. The inverse association of obesity to serum high-density lipoprotein cholesterol (HDL-C) (rs = -0.13, P less than 0.001, both skinfold and skinfold ratio) and apo A-I (rs = -0.04, P = 0.03, skinfold; rs = -0.05, P = 0.004, skinfold ratio) was significant only before adjustment for insulin and serum triglycerides. Multiple linear regression of obesity measures showed that, like insulin, serum triglycerides had consistently higher standardized coefficients than LDL-C, HDL-C, apo B, and apo A-I. Apo A-I and apo B added only a small amount (less than 2%) of information to the relationship of serum lipoproteins with obesity measures. CONCLUSION. These results indicate that serum very-low-density lipoprotein (VLDL) levels are directly and independently related to obesity. The well-known inverse association between obesity and serum HDL-C is not independent, but secondary to the elevated VLDL or triglyceride levels associated with obesity. While associations of obesity and lipoprotein cholesterol are found, far fewer occur with apolipoproteins, especially Apo A-I. Interesting race and sex differences in the relationship of obesity to serum lipoproteins and apoproteins are noted, being greater among white children and more consistent in white males.     

Caffeine intakes of children from a biracial population: the Bogalusa Heart Study

To investigate caffeine intake patterns in children, dietary intakes were examined for a biracial sample of 1,284 infants and children. Twenty-four-hour dietary recalls were completed by parents of children aged 6 months and repeated at ages 1, 2, 3, and 4 years; children 10 years old served as their own respondents and were surveyed at ages 13, 15, and 17 years. The sample was 60% white and 40% black. Additional cohorts of 10-year-olds (no. = 686) were studied for temporal trend. Whites consumed significantly more caffeine than blacks as early as 1 year and persisted at a higher intake level from 2 to 17 years. This trend continued whether intake was measured in total milligrams, milligrams per 1,000 kcal, or milligrams per kilogram body weight. Significant sex differences in caffeine intakes per 1,000 kcal occurred among 15- and 17-year-olds (girls greater than boys). Peak periods of consumption occurred at ages 2, 3, 13, and 17. Snacks contributed large quantities of caffeine, particularly for 10-year-olds. Most frequent sources of caffeine were regular carbonated beverages, chocolate-containing foods, and tea. Mean intakes of caffeine for 10-year-olds were consistent from 1973 to 1982. Those observations document caffeine intakes beginning early in life.     

Relation of body fat patterning to lipid and lipoprotein concentrations in children and adolescents: the Bogalusa Heart Study

Although a truncal distribution of adipose tissue in adults is associated with several metabolic complications, its importance in early life has received little attention. The relation of several anthropometric measures to serum concentrations of lipids, lipoproteins, and apolipoproteins was therefore examined in 361 children who were between ages 6 and 18 y. (Children had been selected previously because of extreme levels of very-low-density- and low-density-lipoprotein cholesterol.) Analyses revealed two groups of anthropometric variables: truncal measures (waist circumference and subscapular, subcostal, and suprailiac skinfold thicknesses) and thickness of peripheral skinfolds (femoral, triceps, calf, and biceps). After generalized obesity was adjusted for children with high concentrations of both cholesterol fractions had more truncal fat but less peripheral fat than did children with low lipoprotein cholesterol concentrations. A truncal fat pattern was also associated with decreased concentrations of high-density-lipoprotein cholesterol and apolipoprotein A-1. Knowledge of fat patterning may help identify persons prone to hyperlipidemia.     

Race and gender differences in serum lipoproteins of children, adolescents, and young adults—Emergence of an adverse lipoprotein pattern in white males: The Bogalusa Heart Study

Methods. Serum lipoprotein profiles in 4,231 individuals, ages 5–26 years, were studied cross-sectionally in a biracial community to describe the race- and gender-specific changes from adolescence into young adulthood.Results. White children and adolescents of both genders showed significantly higher covariates—adjusted triglycerides (9–11 mg/dl) and very-low-density lipoprotein cholesterol (1–2 mg/dl)—and lower total cholesterol (3–14 mg/dl) and high-density lipoprotein cholesterol (6–10 mg/dl) levels than their black counterparts. These black-white differences persisted among young adults of both genders with the exception of total cholesterol levels (higher triglycerides: 23–32 mg/dl; higher very-low-density lipoprotein cholesterol: 5–7 mg/dl; lower high-density lipoprotein cholesterol: 9–11 mg/dl); in addition, white young adult males began to show higher levels of low-density lipoprotein cholesterol (14 mg/dl) than black young adult males. A consistent gender-related pattern emerged only among white young adults with males showing higher triglyceride levels (22 mg/dl), very-low-density lipoprotein cholesterol (5 mg/dl), and low-density lipoprotein cholesterol (10 mg/dl) and lower high-density lipoprotein cholesterol (10 mg/dl) than females. Lipoprotein changes from adolescence into young adulthood were more pronounced among white males than other race-gender groups, resulting in higher triglyceride, very-low-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, a higher total cholesterol/high-density lipoprotein cholesterol ratio, and a lower high-density lipoprotein cholesterol in their young adulthood. According to the National Cholesterol Education Program criteria, a relatively higher proportion of young adult white males was classified as borderline-high (22.6%) or high (9.1%) for low-density lipoprotein cholesterol. Adiposity was the major contributor to the adverse lipoprotein pattern, especially among white males. Sexual maturation and age influenced the lipoprotein levels to a greater extent among white males. Cigarette smoking, alcohol intake, and oral contraceptive use began to emerge as minor but significant factors contributing to the lipoprotein levels in adolescents and young adults.Conclusion. These results underscore the desirability of early targeting for primary prevention.     

High density lipoprotein cholesterol: an evolving target of therapy in the management of cardiovascular disease

Since the pioneering work of John Gofman in the 1950s, our understanding of high density lipoprotein cholesterol (HDL-C) and its relationship to coronary heart disease (CHD) has grown substantially. Numerous clinical trials since the Framingham Study in 1977 have demonstrated an inverse relationship between HDL-C and one's risk of developing CHD. Over the past two decades, preclinical research has gained further insight into the nature of HDL-C metabolism, specifically regarding the ability of HDL-C to promote reverse cholesterol transport (RCT). Recent attempts to harness HDL's ability to enhance RCT have revealed the complexity of HDL-C metabolism. This review provides a detailed update on HDL-C as an evolving therapeutic target in the management of cardiovascular disease.     

Secular trends of obesity in early life: the Bogalusa Heart Study

Secular changes in height and weight measurements were examined in five- to 14-year-olds from 1973 to 1984. The age-sex specific 85th percentile was used to classify persons as overweight (based on ponderal index; kg/m3). Secular increases in weight (2.5 kg), and ponderosity (0.5-0.7 kg/m3) were found. Gains in ponderosity over the 11-year period were greater at the 75th percentile than at the 25th percentile, and the prevalence of overweight increased from 15 per cent to 24 per cent.     

Persistence of juvenile-onset obesity over eight years: the Bogalusa Heart Study

The persistence of obesity and overweight over eight years was assessed in a biracial (Black-White) cohort of 1,490 two-to 14-year-olds. Initial levels of triceps skinfold thickness (TRSF) and Rohrer index (weight/height3) were moderately predictive of subsequent levels: r = 0.54 and 0.67, respectively. However, TRSF and Rohrer index tended to track most strongly in Black females (r = 0.64 and 0.72) and less well in both White females (r = 0.45 and 0.57) and preschool children (r = 0.45 and 0.54). Based on elevated levels of TRSF or Rohrer index, children were classified as obese or overweight, respectively. Of the 222 children who were initially above the 85th percentile for TRSF, 43 per cent remained obese after eight years. Persistence of overweight was slightly greater at follow-up, with 50 per cent of initially overweight children staying above the 85th percentile for Rohrer index. Severe, initial obesity/overweight (greater than 95th percentile) and consecutively elevated levels increased the probability of remaining obese/overweight. Results indicate that moderate, juvenile-onset obesity is malleable, but that the child who is extremely obese over consecutive examinations is likely to become an obese adult.     

Linkage analysis of low-density lipoprotein subclass phenotypes and the apolipoprotein B gene.

A common heritable phenotype has recently been identified which is characterized by a relative abundance of small, dense low-density lipoproteins (LDL), and mild elevations of plasma triglycerides and reductions in plasma high-density lipoproteins (HDL) cholesterol. This phenotype, designated LDL subclass phenotype B, has been associated with up to a three-fold increase in coronary disease risk. Complex segregation analysis in two large family studies has demonstrated that LDL subclass phenotype B is influenced by an allele at a single genetic locus with a population frequency of 0.25-0.3, and autosomal dominant inheritance, but with full penetrance only in males age 20 and over and in postmenopausal women. Since apolipoprotein B (apoB) is the principal protein component of LDL, linkage analysis was used to investigate possible linkage between the phenotype B phenotype and the apoB gene, using a variable number of tandem repeats site located 0.5 kb from the 3' end of the apoB gene. In 6 informative families including only family members in the penetrant classes, a total LOD score of -7.49 was found at a recombination fraction of 0.001. Thus, under the assumptions of the single gene model, it is unlikely that the apoB locus controls LDL subclass phenotype B.     

Relationship between change in height and changes in serum lipid and lipoprotein levels in adolescent males: the Bogalusa Heart Study

The relationship between increase in height and changes in levels of serum lipids and lipoproteins in adolescent males were examined through a biracial sample of 397 individuals, ages 8-12 years, who were reexamined 5 years after the initial screening. Significant negative correlations were observed between height change and changes in levels of serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) after controlling for age, initial cholesterol level, height, weight, Tanner stage, and changes in Tanner stage and weight. There was significant inverse association between height change and change in the level of HDL-C in black males, while there was significant inverse association between height change and change in the level of LDL-C in white males. These associations were independent of age, sexual maturation, and weight. Thus, changes in levels of serum lipids and lipoproteins in males during adolescence are partly associated with the growth spurt in height.     

Lack of evidence for linkage between low-density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia.

Low-density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small, dense LDL particles, appears to be a genetically influenced risk factor for coronary heart disease. Phenotype B, as determined by gradient gel electrophoresis, appears to be inherited in a manner consistent with the presence of a single major genetic locus, based on complex segregation analysis. Familial combined hyperlipidemia (FCHL) is a disorder characterized by elevations in total plasma cholesterol and/or triglyceride levels in probands and family members, variable lipoprotein phenotypes over time, and elevations in apolipoprotein B levels. Because apo B is the primary protein component of LDL particles, the present study was undertaken to determine whether LDL subclass phenotypes are controlled by the APOB locus in FCHL families. The evidence against linkage was very strong based on lod score analyses (total lod = -13.3), under assumptions that LDL subclass phenotypes are influenced by a major genetic locus and that the mode of inheritance and penetrance functions are known. Other methods requiring fewer assumptions also provided evidence against linkage, although the strength of this evidence was weaker. Thus the results demonstrate that the proposed gene responsible for LDL subclass phenotypes is unlikely to be the APOB gene in families with FCHL.     

不同放射线检查方法诊断冠心病临床研究分析

目的:关于不同放射线检验方法对于冠状动脉粥样硬化性心脏病(简称,冠心病)进行诊断的临床价值分析.方法:将本院在2018年3月~2019年3月收治的100例冠心病患者作为观察对象进行调查研究,对所有患者在进行确诊以前分别为患者应用常规冠状动脉造影方法和放射线检验方法进行检验,同时对两种不同检验方法检验的正确率和患者的满意率等情况进行比较.结果:对患者选择采用常规的冠状动脉造影诊断确诊患者76例,诊断准确率为76.00%,而选择采用放射线检验方法进行诊断患者正确诊断96例,诊断准确率为96.00%,后者的诊断准确率明显高于前者,P<0.05,存在统计学差异性;选择常规冠状动脉造影进行诊断患者的满意人数为75例,满意度为75.00%,而选择放射线检验方法进行诊断的患者满意97例,满意度为97.00%,后者明显高于前者,P<0.05,存在统计学差异.结论:对冠心病患者在进行诊断的过程中,通过放射线检验方法进行诊断的价值要明显的高于常规冠状动脉造影的诊断方法.     

Persistent hypercholesterolemia is associated with the development of obesity among girls: the Bogalusa Heart Study

BACKGROUND: Obesity is associated with cardiovascular disease (CVD) risk factors. Cross-sectional data suggest that hypercholesterolemia is associated with the development of childhood obesity. OBJECTIVE: The objective was to assess age-related changes in relative weight and the association between relative weight and CVD risk factors in hypercholesterolemic and nonhypercholesterolemic children who were nonobese at baseline. DESIGN: Data on relative weight and CVD risk factors were extracted from the Bogalusa Heart Study for nonobese 5-6-y-old black and white hypercholesterolemic (LDL cholesterol > 75th percentile; n = 58) and nonhypercholesterolemic (LDL cholesterol < 60th percentile; n = 215) children (41% black, 52% girls) who were also assessed 3 and 6 y later. Changes in body mass index (BMI) and CVD risk factors were assessed as a function of age, sex, race, and cholesterol concentration. RESULTS: BMI increased more in the hypercholesterolemic (n = 31) than in the nonhypercholesterolemic (n = 111) girls during the 6 y of follow-up but was not significantly different between hypercholesterolemic (n = 27) and nonhypercholesterolemic (n = 104) boys aged 5-12 y. Associations between BMI and the risk factors blood pressure, insulin, and blood lipids were observed to be stronger with increasing age and, in some cases, stronger in hypercholesterolemic children and girls. CONCLUSIONS: Hypercholesterolemia is associated with increased relative weight in girls. The increased relative weight, even at an early age, is associated with a deleterious effect on blood lipids and other CVD risk factors in hypercholesterolemic children, although the strength of these associations is sex dependent.     

Tracking of serum lipids and lipoproteins in children over an 8-year period: the Bogalusa Heart Study

Although children initially identified as having elevated levels of coronary heart disease risk factors tend to have elevated follow-up levels (track), a substantial proportion show regression to the mean. Relationships of both genetic and environmental factors to tracking of serum lipids and lipoproteins over an 8-year period were examined in children from a biracial community. Associations between initial and follow-up levels were similar at 3, 5, and 8 years of follow-up; however, differences between the race-sex groups were observed. Two initial measurements reduced the number of nontrackers (children with high initial and decreased follow-up levels). Fathers of children showing persistently elevated levels of either serum total cholesterol or triglycerides were more likely to have diabetes mellitus or to have had heart attacks than were fathers of nontrackers. Children tracking for elevated low-density lipoprotein cholesterol levels had larger increases in triceps skinfold thickness than did the nontrackers. Children consuming alcohol tended to have elevated levels of high-density and decreased levels of low-density lipoprotein cholesterol at follow-up. These observations indicate that the use of repeated serum lipid and lipoprotein determinations, along with measurements of obesity and information concerning family history of heart attack and diabetes mellitus, can aid in the prediction of future elevated serum lipid and lipoprotein levels.