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(Circulation. 1999;99:2144-2149.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Plasma Homocysteine Distribution and Its Association With Parental History of Coronary Artery Disease in Black and White Children

The Bogalusa Heart Study

Kurt J. Greenlund, PhD; Sathanur R. Srinivasan, PhD; Ji-Hua Xu, MD; Edward Dalferes, Jr, BS; Leann Myers, PhD; Arthur Pickoff, MD; Gerald S. Berenson, MD

From the Tulane Center for Cardiovascular Health (K.J.G., S.R.S., J.-H.X., E.D., G.S.B.) and the Department of Biostatistics and Epidemiology (L.M.), Tulane University School of Public Health and Tropical Medicine; and Department of Pediatrics (A.P.), Tulane University Medical School, New Orleans, La.

Correspondence to Gerald S. Berenson, MD, Tulane Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine, 1501 Canal St, 14th Floor, New Orleans, LA 70112.

	Abstract

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Background—Elevated homocysteine is associated with increased risk for coronary artery disease (CAD) in adults, but its distribution in children is not well documented. We examined the distribution of homocysteine in children and its relation to parental history of CAD.

Methods and Results—A subsample of 1137 children (53% white, 47% black) aged 5 to 17 years in 1992 to 1994 examined in the Bogalusa Heart Study (n=3135), including all with a positive parental history of CAD (n=154), had plasma homocysteine levels measured. Homocysteine correlated positively with age (r=0.16, P=0.001). No race or sex differences in homocysteine levels were observed; geometric mean (GM) levels were 5.8 µmol/L (95% CI, 5.6 to 6.1) among white males, 5.8 µmol/L (95% CI, 5.5 to 6.0) among white females, 5.6 µmol/L (95% CI, 5.4 to 5.8) among black males, and 5.6 µmol/L (95% CI, 5.4 to 5.9) among black females. Children with a positive parental history of CAD had a significantly greater age-adjusted GM homocysteine level (GM, 6.7 µmol/L; 95% CI, 6.4 to 7.1) than those without a positive history (GM, 5.6 µmol/L; 95% CI, 5.4 to 5.7); this relation was observed in each race-sex group.

Conclusions—Higher homocysteine levels were observed among children with a positive family history of CAD. Additional studies should elucidate the contribution of genetic, dietary, and other factors to homocysteine levels in children.

Key Words: homocysteine • coronary disease • pediatrics • risk factors

	Introduction

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Elevated total homocysteine is a potentially important risk factor for coronary artery disease (CAD) among adults.^{1 2 3 4 5 6} Among several prospective epidemiological studies,^{7 8 9 10 11} only 1 Finnish study¹⁰ observed no association of homocysteine with cardiovascular disease mortality. Not all of these studies observed a statistically significant association, however. Furthermore, in a nested case-control study, no association of homocysteine with nonfatal myocardial infarction or coronary heart disease deaths among men was observed.¹² Homocysteine is formed during methionine metabolism; elevated levels may be due to (1) genetic factors, such as a mutation in the methylenetetrahydrofolate reductase gene; (2) deficiencies in folic acid or vitamins B₆ and B_12, coenzymes that convert homocysteine back to either methionine or to cystathionine; or (3) some drugs and renal and liver diseases.² In the Framingham elderly population, 67% of elevated homocysteine levels were due to low folate and inadequate plasma B-vitamin concentrations.¹³

The distribution of homocysteine in children of different race/ethnic groups is not well documented. Examination of homocysteine levels in children may be important, because CAD risk factor development begins early in life.^{14 15} Furthermore, homocysteine levels in asymptomatic young offspring may be related to parental CAD, given a familial association of many CAD risk factors.^{16 17 18} We examined plasma homocysteine levels and the association with parental history of CAD among a sample of black and white children in southeastern Louisiana.

	Methods

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Study Sample
The Bogalusa Heart Study is a long-term investigation of the development of CAD beginning in childhood in a biracial community (65% white, 35% black). Data collection methods have been described.¹⁵ During the 1992 to 1994 school years, a cross-sectional survey of 3135 children aged 5 to 17 years was conducted, with an overall participation rate of 80%. For the present study, a subsample of participants, including 50% of black children of both sexes and an equal number of white children matched by age and sex, was randomly selected to have plasma homocysteine levels measured. Additionally, all children with a reported parental history of CAD from the remaining sample were included in the study. The final sample includes 1137 subjects (47% black, 53% white) after exclusion of 161 subjects with missing data for study variables and those with nonfasting status.

General Examination
Standardized protocols were used in all examinations, and data were collected by trained staff.¹⁵ Procedures were approved by the university institutional review board, and consent was obtained from a parent and the children. Subjects were instructed to fast for 12 hours before examination; compliance was ascertained by interview.

We took 2 measurements each of height (in cm), using a stationary height board, and weight (in kg), using a balance-beam metric scale (Detecto scales), while subjects were dressed in light clothing but without shoes. Body mass index (kg/m²) was calculated from averages of the 2 readings. Subscapular and triceps skinfolds were measured with Lange skinfold calipers. Physicians ascertained Tanner stage of pubertal maturation¹⁹ during a physical examination.

Blood pressure was measured by 2 trained technicians, 3 times each, using standard mercury sphygmomanometers. Readings were taken at 1-minute intervals after an initial 5-minute rest. The 6 readings were averaged. The fourth Korotkoff sound was used as the measure of diastolic blood pressure in analyses.

Children aged 8 years and older were administered questionnaires regarding tobacco use. Children who reported smoking 1 cigarette per week were considered current smokers.

Parental history of CAD was based on a health history questionnaire given to the parents of children scheduled for examination. Parents recorded whether the child's biological mother or father ever had a heart attack, stroke, diabetes, bypass surgery, balloon angioplasty, angina, hypertension, or hypercholesterolemia. For each condition, the year of onset and the parent's age at diagnosis were obtained. If a parent was deceased, the cause, year of death, and age at death were ascertained. A positive parental history of CAD was defined as either biological parent having had a myocardial infarction, bypass surgery, balloon angioplasty, or angina. Among the 3135 children aged 5 to 17 years, 204 had a positive parental history; 154 had complete data and were included in analyses.

Laboratory Analyses
Serum cholesterol and triglyceride levels were determined by enzymatic assay with an Abbott VP instrument (Abbott Laboratories). Serum VLDL, LDL, and HDL cholesterol levels were measured by a combination of heparin-calcium precipitation and agar–agarose gel electrophoresis.²⁰ The laboratory is monitored by the Lipid Standardization Program of the Centers for Disease Control and Prevention in Atlanta, Ga, and procedures met the accuracy and precision requirements of that agency. Plasma immunoreactive insulin levels were measured with a Phadebas radioimmunoassay kit (Pharmacia Diagnostics). Plasma glucose was determined as part of a multiple chemistry profile. Measurement errors (coefficients of variation) were as follows: total cholesterol, 2.0%; triglycerides, 3.2%; VLDL cholesterol, 10.0%; LDL cholesterol, 4.3%; HDL cholesterol, 3.5%; glucose, 2.9%; and insulin, 18.2%.

Plasma homocysteine was determined by a modification of the method of Malinow and colleagues.²¹ Homocystine, other mixed disulfides, and protein-bound homocysteine were first reduced by 10% sodium borohydride in 0.1N sodium hydroxide. The proteins were then precipitated with perchloric acid, and the supernatant was subjected to high-pressure liquid chromatography (Dionex DX-300 PED System) without derivitization of thiols. The thiols were separated with a Spherisorb ODS reverse-phase column (5 mm, 4.6x250 mm) with 0.1 mol/L perchloric acid–0.15 mol/L sodium perchlorate–5% acetonitrile as mobile phase and detected by a single gold-silver electrode at a potential of 1.6 V. We calculated the concentration of total homocysteine in samples by comparing peak areas of samples with peak areas obtained from L-homocystine (homocystine=2xhomocysteine) standards added to aliquots of pooled plasma. The interassay coefficient of variation was 7.6%.

Statistical Analyses
To examine potential selection biases, we compared CAD risk factor levels among those who did and did not have homocysteine levels measured by t tests and ² tests. Only serum triglyceride levels were different between the 2 groups, being lower among those who had plasma homocysteine measured (mean, 79 mg/dL; SE, 1.1) than those who did not have homocysteine measured (mean, 84 mg/dL; SE, 1.0; P for difference, 0.001). No differences between the 2 groups were observed in age, body mass index, blood pressure, other serum lipids and lipoproteins, or plasma insulin or glucose.

Race and sex differences in plasma homocysteine levels were examined by age-adjusted ANCOVA. Associations of plasma homocysteine with risk factors were assessed with Spearman correlations. Homocysteine levels were divided into approximate quintiles within each of 4 age groups (5 to 8, 9 to 11, 12 to 14, and 15 to 17 years) to examine whether there was a threshold effect of homocysteine with other risk factors. We then conducted age-adjusted ANCOVAs to assess differences in homocysteine and other CAD risk factor levels by parental history of CAD.

Distributions of plasma homocysteine, serum triglycerides, serum VLDL cholesterol, plasma insulin, body mass index, and subscapular skinfolds were skewed to the right. Values for these variables were logarithmically transformed and are presented as geometric means and 95% CIs. A P value 0.05 was considered statistically significant.

	Results

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The overall plasma homocysteine mean level in the sample was 6.1 µmol/L (geometric mean, 5.7 µmol/L); values ranged from 1.2 to 21.4 µmol/L (Table 1). The median was 5.8 µmol/L. Mean levels were similar among boys and girls and among blacks and whites. Furthermore, no sex or race differences in plasma homocysteine levels were observed by age group. The overall (geometric) mean levels for ages 5 to 8, 9 to 11, 12 to 14, and 15 to 17 years, respectively, were 5.7, 5.4, 5.8, and 6.4 µmol/L among white children and 5.5, 5.3, 5.5, and 6.2 µmol/L among black children. The oldest age groups had significantly higher homocysteine levels than the other age groups (P=0.003 among white children and P=0.01 among black children). No race or sex differences were observed by Tanner stage (data not shown).

View this table: [in this window] [in a new window]   Table 1. Distributions of Plasma Homocysteine Among Children Aged 5 to 17 Years, by Race, Sex, and Age Group: the Bogalusa Heart Study

The correlations between plasma homocysteine and CAD risk factors were generally low in magnitude (Table 2). Significant positive correlations were observed with age, Tanner stage, systolic and diastolic blood pressures, body mass index, and subscapular skinfold thickness. Significant negative correlations were observed with serum total and HDL cholesterols. After controlling for age, significant correlations disappeared except for those with serum total cholesterol and diastolic blood pressure. Plasma homocysteine levels were not related to current smoking status nor to parental education (data not shown).

View this table: [in this window] [in a new window]   Table 2. Spearman Correlation Coefficients of Plasma Homocysteine With CAD Risk Factor Variables in Children Aged 5 to 17 Years: the Bogalusa Heart Study

Plasma homocysteine was positively associated with parental history of CAD (Table 3). The age-adjusted geometric mean level was 6.7 µmol/L (95% CI, 6.4 to 7.1) among those with a positive parental history versus 5.6 µmol/L (95% CI, 5.4 to 5.7) among those without a positive history (P=0.0001). The greater plasma homocysteine level among those with a positive parental history was observed among all race-sex groups. Adjustment for Tanner stage did not significantly alter these associations. Those in the top age-specific quintile of plasma homocysteine had a significantly greater percentage (P=0.001 among white children and P=0.002 among black children) with a positive parental history than those in the lower quintiles, in which there appeared to be no statistically significant differences in the percentage of children with a positive parental history (Figure).

View this table: [in this window] [in a new window]   Table 3. Age-Adjusted CAD Risk Factor Levels (Mean and 95% CI) in Children Aged 5 to 17 Years by Parental History of CAD, Race, and Sex: the Bogalusa Heart Study

View larger version (18K): [in this window] [in a new window]   Figure 1. Percent of children with a positive parental history of CAD, by age-specific quintile of plasma homocysteine: the Bogalusa Heart Study.

Other risk factors were less consistently associated with parental history (Table 3). Among the total sample, parental history was positively related with serum triglycerides, systolic blood pressure, plasma insulin, and body mass index. Parental history was positively related with serum triglycerides, serum VLDL cholesterol, diastolic blood pressure, plasma insulin, and plasma glucose among white males and with body mass index among black females. Parental history was not related with CAD risk factors among white females or black males.

	Discussion

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Normative values for plasma homocysteine among a large sample of healthy black and white children from a community cohort have been provided. Values were similar to those observed by Tonstad et al^{16 22 23} and lower than those provided by Reddy.²⁴ As in previous studies,^{16 22 23 24} plasma homocysteine levels were similar among boys and girls. Studies of adults suggest that homocysteine levels are higher in males than in females.^{25 26 27} Puberty may influence homocysteine levels through increased muscle mass and/or hormonal effects. However, no sex differences were observed when homocysteine levels were compared either by age group or by Tanner stage, although 40% of the sample were prepubertal (Tanner stage 1), whereas only 8% had reached Tanner stage 5. Tonstad et al²³ observed a positive correlation of homocysteine with Tanner stage but no sex differences. Additional studies are required to examine the development of sex differences in homocysteine levels.

No previous studies comparing homocysteine levels among black and white children were found in the literature. In a study of premenopausal women,²⁸ black women had higher homocysteine levels and lower folate levels than white women. In that study, plasma folate explained 26% of the variability in homocysteine levels.²⁸ In the present study, homocysteine levels were similar among black and white children. We did not assess either dietary or blood levels of folate or vitamins B₆ and B₁₂; thus, it is not known how these factors may influence homocysteine levels in our study population.

Parental history of CAD is correlated with CAD risk factors^{29 30} and is considered a useful indicator for risk factor screening (for example, lipid screening³¹ ). A study among nonfasting children in Oslo, Norway also reported a modest increase in homocysteine (0.7 µmol/L) with a positive history of cardiovascular disease in first-degree male relatives.¹⁶ We observed an association of parental history with homocysteine levels among all 4 race-sex groups, with differences ranging from 0.9 to 1.3 µmol/L. In all but 4 cases, reported age of the parent experiencing a CAD event was <50 years; thus, these were largely cases of early CAD.

Associations of parental history with other risk factor levels (lipids, blood pressure, adiposity, glucose, and insulin) were not consistent. Several previous studies also observed that overall lipid and lipoprotein levels were not related with parental history of CAD among children^{29 32 33 34} but did show an association by young adulthood.^{29 34} Dyslipidemia in childhood (LDL cholesterol above the 95th percentile or HDL cholesterol below the 5th percentile), however, is related to a greater history of parental CAD.^{35 36}

Sampling procedures for the present study included all those children with a reported positive parental history of CAD; thus, the prevalence of family history should not be estimated from the subsample examined here. Furthermore, reported parental history was not verified in the present study. However, data were based on parental report. Previous studies observed a concordance of 78%³⁷ to 83%³⁸ between reported and verified cases. Nonsystematic misclassification of self-reported histories (both false-positive and false-negative histories), furthermore, would tend to underestimate the true differences between the groups.

The tendency for CAD to cluster in families^{17 39} may be attributed to both genetic and shared environmental factors. The association of homocysteine with CAD risk also reflects genetic and environmental contributions.⁴⁰ A defect in the methylenetetrahydrofolate reductase gene has been associated with elevated homocysteine levels, especially among those with low folate intake or blood levels,^{41 42} although the association of the mutation with CAD itself is less clear.^{43 44} Homocysteine levels are also influenced by folate and vitamins B₆ and B₁₂. Among children with familial hypercholesterolemia, Tonstad et al²³ observed a trend toward increased homozygosity for the C677T mutation in methylenetetrahydrofolate reductase among children with a positive history of cardiovascular disease compared with those without a parental history. However, homocysteine levels were also related to lower parental education and lower intake of fruits and vegetables,²³ which indicates that both genetic and environmental factors contribute to homocysteine levels in children.

In conclusion, future studies should elucidate the contributions of genetic, dietary, and other factors to plasma homocysteine levels in children and the relation of plasma homocysteine levels in children to parental history of CAD. Longitudinal studies are required to assess the potential impact of homocysteine levels in childhood and adulthood on CAD risk later in life.

	Acknowledgments

 
This research was supported by grants HL-38844 of the National Heart, Lung, and Blood Institute and HD-32194 of the National Institute of Child Health and Human Development of the United States Public Health Service. The Bogalusa Heart Study is a joint effort of many investigators and staff members whose cooperation is gratefully acknowledged. We especially thank the Bogalusa, La, children, parents, teachers, and schools that participated in this study.

	Footnotes

 
Dr Greenlund is currently with the Cardiovascular Health Branch, Division of Adult and Community Health, Centers for Disease Control and Prevention, Atlanta, Ga.

Received August 4, 1998; revision received December 30, 1998; accepted January 26, 1999.

	References

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