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,3
* Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA;
Department of Family Medicine and Community Health, Tufts University School of Medicine, Boston, MA
3To whom correspondence should be addressed. E-mail: aviva.must{at}tufts.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXLITERATURE CITED |
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10 y of age, than previously reported on the basis of smaller nonrepresentative samples. Improved understanding of the determinants of levels during growth and development may provide important clues to the etiology of adult disease.
KEY WORDS: • homocysteine • age • sex • racial-ethnic groups • nutrition surveys
In adults, elevated total circulating homocysteine concentration in a fasting state (fasting hyperhomocysteinemia) is associated with an increased risk of occlusive vascular disease (1–7) and increased mortality among individuals with previously diagnosed vascular disease (8). In youth, elevated levels of homocysteine may arise due to genetic defects, endocrine abnormalities, sickle cell disease or nutritional factors (9–11). Studies of children and adolescents indicate that even in the pediatric age group, elevated homocysteine levels are associated with elevated systolic blood pressure levels and increased weight (12). Furthermore, levels are higher in children who have a father, grandfather or uncle with early cardiovascular death (13). The importance of elevated homocysteine levels in otherwise healthy children is not known.
Certain factors have been identified in relation to fasting total homocysteine (tHcy) concentrations in adults. Age and sex are two of its stronger determinants. Concentrations are higher in men than in women and are higher at older adult ages (14–17). For women, menopausal status and estrogen replacement therapy appear to be related to fasting homocysteine concentrations (11,18,19). The influence of age and sex on fasting homocysteine concentrations during childhood has not been described systematically.
Reference data for homocysteine levels in the pediatric age group based on representative samples are lacking. Two studies based on convenience samples provide limited reference data. A study of 195 Spanish children aged 2 mo to 18 y was used to establish median and extreme percentiles of plasma homocysteine (20). Reference ranges based on the plasma homocysteine levels of 647 Belgian school children have also been published (9). Reference data on circulating serum homocysteine concentrations for U.S. children have been limited to the 13- and 14-y-old school children studied in the 1997 follow-up of the Child and Adolescent Trial for Cardiovascular Health (CATCH), a nonrepresentative population-based sample (12). Overall, there is little available information to describe circulating homocysteine concentrations in healthy children by age and by race-ethnicity. Plasma homocysteine concentrations were also reported from a subsample of children in the Bogalusa Heart Study, but given that the sample was comprised of all of the children with a family history coronary artery disease and a sample of equal numbers of African-American and Caucasian children matched by race and sex, it is not clear to what population these values generalize (21).
In 1999 we published reference data for serum tHcy concentrations for adolescents and adults (22). The present report extends these reference data to younger children. Based on assays of participants aged 4–19 y from Phase 2 (1991–1994) of the third National Health and Nutrition Examination Survey (NHANES III), we present the distribution of serum homocysteine concentrations for U.S. children and adolescents by age, sex and race-ethnicity. This study provides the first opportunity to describe tHcy concentrations in a nationally representative sample from racial and ethnic minority groups across the full range of childhood ages.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXLITERATURE CITED |
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NHANES III was designed to obtain nationally representative information on the health and nutritional status of the civilian, noninstitutionalized U.S. population through interviews and direct physical examinations. The survey began in the fall of 1988 and was completed in the fall of 1994. Approximately 40,000 persons were selected from 81 counties located in 26 states; >36,000 persons were interviewed and > 30,000 completed a standardized detailed physical examination in especially equipped mobile examination centers.
The sampling scheme, which included persons aged 
2 mo old, was a stratified, multistage probability design. Young children (<5 y), older persons (>60 y), African-Americans and Mexican Americans were oversampled to allow more precise estimates of health and nutritional characteristics for these specific population subgroups. Other racial and ethnic groups such as non-Mexican American Hispanics, Native Americans, and Asian and Pacific Islanders were included but were not oversampled. The survey was conducted in two 3-y phases, and each phase was designed to provide nationally representative samples.
For the present analyses, tHcy concentrations were measured as an NHANES III surplus sera project on serum samples from individuals aged 4–19 y seen during Phase 2 of this survey (1991–1994). The surplus serum samples were derived from a Phase 2 total population sample of 5186 children aged 4–19 y, of whom 4921 (94.9%) were examined. Of these subjects, 2894 did not provide tHcy data, due either to a lack of surplus sera or failure to obtain serum samples at the survey examination; the final sample comprised 2027 (41.2% of those examined) with tHcy for analysis. Younger children (ages 4–11) were much less likely to have tHcy data than older children, and information was comparable across racial/ethnic groups. The measurement of serum tHcy concentrations for this study was approved by Tufts New England Medical Center Institutional Review Board.
Determination of serum homocysteine concentration.
Blood was drawn and processed in the mobile examination center under controlled, constant environmental conditions using a standard protocol (23). Although only children > 12 y old were asked to fast, fasting times were recorded for all participants. At the time of venipuncture, 48% participants had fasted for >8 h, 15% for >6–8 h, 8% for 4–6 h and 29% for <4 h. However, within sex, we found no differences in tHcy concentrations with fasting time, after adjusting for age and race-ethnicity (data not shown). Whole blood, which was not treated with an anticoagulant, was collected in serum separator tubes and was held at room temperature for 30–60 min before centrifugation at 115 x g for 15 min. Although tHcy in whole blood is artificially increased when held at room temperature because of its continued production by red cells, the increase is minimal if the sample is centrifuged within 1 h of collection (24). Sera were separated, frozen at -20°C and transferred on dry ice to the Centers for Disease Control and Prevention central laboratory for priority analyses. Samples went through 1–4 freeze-thaw cycles. It was demonstrated previously that repeated freezing and thawing does not affect serum homocysteine concentration (24). After priority analyses were completed, additional analyses, subject to approval by the Surplus Sera Bank Steering Committee, were carried out. The surplus sera were stored at -70°C for 8 mo to 3 y before being analyzed for tHcy concentration. Homocysteine measurements were carried out at the USDA Human Nutrition Research Center on Aging by the HPLC method of Araki and Sako (25). A single measure of homocysteine has been shown to reliably characterize a person’s average, long-term homocysteine concentration, with reliability coefficients of 0.66–0.82 over 30 mo (26).
Statistical analysis.
We used sample weights in all analyses to account for unequal probability of selection and nonresponse, and to produce estimates of means and percentiles that were representative of the noninstitutionalized civilian U.S. population. SUDAAN statistical software (27), which incorporates the sample weights, was used to account for the complex survey design in the variance estimates. Because tHcy concentrations were extremely skewed, a logarithmic transformation was applied to these data to obtain the age-specific and age-adjusted geometric mean serum tHcy concentrations for males and females and for each racial-ethnic group. We used SAS to create and manipulate the data files (28). Means were adjusted using SUDAAN PROC DESCRIPT standardization statements and the 1980 population, proportions as recommended in the NHANES III analytic guidelines (29). We tested the geometric means for interactions between age, sex, and race-ethnicity using SUDAAN PROC REG (27). We also obtained smoothed curves of the age-specific geometric means by using the SYSTAT LOWESS smoothing procedure (30,31), which reduces the difference between adjacent age categories associated with sampling variability.
The mean design effect, which is the ratio of the complex sampling design variance derived from SUDAAN (27) to the simple random sample variance calculated by SAS (28) averaged over the age categories, was used to determine the recommended minimum stratum sample size, in accordance with the National Center for Health Statistics analytic guidelines and recommendations to achieve stable estimates of means and percentiles (32). Based on a mean effect of 1.5 for our sample, we identified as unstable the means for those strata in which there were <45 individuals. Individuals from other racial or ethnic groups were not considered separately in these analyses because of their small numbers (n = 105).
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXLITERATURE CITED |
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The age-specific tHcy concentrations were lower in girls than in boys in every age group, except for age 6–11 for which non-Hispanic Caucasian and African-American girls were slightly higher than boys (Table 1). The age-adjusted geometric mean homocysteine concentration was significantly greater in boys than in girls for non-Hispanic African-Americans and Mexican Americans (P < 0.01), but not for non-Hispanic Caucasians (Fig. 1).
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Because the age-related changes in tHcy concentrations did not differ across racial/ethnic groups, we examined the entire population stratified by sex in single-year age groups (Fig. 2). The tHcy concentrations of boys and girls began to diverge at age 10 y, and increased during adolescence.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONAPPENDIXLITERATURE CITED |
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Data from population-based samples with which to characterize changes in homocysteine levels over childhood are very limited. Gender differences were not observed in a large sample (n = 1137) of 5- to 17-y-old Caucasian and African-American children studied in the Bogalusa Heart Study. Using four childhood age groups, only the oldest children (ages 15 y) had plasma homocysteine levels that were significantly higher than at younger ages (21). In contrast, among 3524 13- and 14-y-old school children studied in the 1997 follow-up of CATCH, boys had significantly higher values than girls. Levels did not differ by Tanner developmental stage, however (12). Among 647 Belgian school children aged 5–17 y, plasma tHcy concentrations increased with increasing age (9). Using three age groups, gender differences did not become apparent until after age 15 y. Gender differences in homocysteine levels were not observed in a German study that included 257 school children aged 6–17 y (33). Age-specific data were not presented, likely due to inadequate sample size. Our data suggest that sexual dimorphism in homocysteine concentrations occurs earlier than noted in the Belgian study, with divergence at about age 10 y, during the pubertal period for girls. The observation that tHcy concentrations are higher postmenopausally and during pregnancy (34,35) is consistent with a role for endogenous estrogen in homocysteine metabolism, as has been suggested by others (18,19,22). An examination of the figures, however, suggests that in females, tHcy concentrations continue on their childhood trajectories, whereas in males, the rise accelerates during adolescence, consistent with a role for androgens such as testosterone. In adult male-to-females transsexuals, plasma tHcy concentrations decreased after estrogen and antiandrogen administration, and in female-to-male transsexuals, tHcy levels increased with androgen administration (36). Because tHcy levels responded to both estrogen and androgen administration, this result does not help clarify whether estrogens or androgens account for the dimorphism in tHcy concentrations observed in our cross-sectional data at age 10 y. Longitudinal studies are best suited to establish the hormonal determinants of tHcy levels during adolescence.
Overall, there is little available information concerning circulating homocysteine concentrations in healthy children by age and by race-ethnicity. Looking across all childhood ages, we identified sex x race-ethnicity and age x sex interactions in mean tHcy concentrations. Consistent with the adolescent and adult data from NHANES III previously reported (22), Mexican American girls had significantly lower concentrations than non-Hispanic African-American girls. However, the concentrations of Mexican American girls were not significantly lower than those for non-Hispanic Caucasians; this may reflect limited power, i.e., the concentrations appeared to be lower in Mexican Americans compared with non-Hispanic Caucasians at each childhood age group. In CATCH, African-American children aged 13–14 y had higher serum tHcy concentrations than Caucasian and Hispanic children; the authors did not report whether race-ethnic/sex interactions were evaluated (12). In the biracial Bogalusa Heart Study, no race or sex differences in plasma homocysteine levels were observed (21). The explanation for racial-ethnic differences observed in our analyses is not readily apparent. Previous studies of race-ethnic differences in tHcy concentration have focused on African-American/Caucasian differences, where there is some suggestion that metabolic differences may be responsible (37–39).
The lower levels of homocysteine we observed among Mexican Americans adolescent girls are consistent with race-ethnicity patterns observed in adults (22). Like the adult patterns, the childhood patterns are not readily explained by levels of folate or by patterns of fruit and vegetable intake, however. Among subjects 17 y old studied as part of NHANES III, serum folate for Mexican American females was higher than for African Americans, but lower for Mexican American than Caucasian females. For red cell folate, values were lower for Mexican American females than Caucasians, but Mexican American and African American females did not differ (40,41). In a comparison of intakes based on NHANES III, Mexican Americans adults consumed more vegetable protein than African-American adults of all ages, and of Caucasian adults aged 20–39 y (42). Data were not reported stratified by sex. In contrast, data from the Continuing Survey of Food Intakes by Individuals for children aged 2–18 y, suggest that intakes of green/yellow vegetables were lowest among Hispanics, intermediate among Caucasians, and highest among African-Americans (43). Intakes were similar among boys and girls, but were not reported as gender x race-ethnicity subgroups.
Our understanding of factors that influence circulating homocysteine concentrations is still largely incomplete. As a strong risk factor for vascular disease (1–8,44), an improved understanding of the basis for the age-, gender- and race-ethnicity related differences we observe is fundamental. Given that tHcy levels during childhood predict parental risk of cardiovascular disease (13,21,45,46), a focus on determinants of levels during growth and development may provide important clues to the etiology of adult disease.
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APPENDIX |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
4 Abbreviations used: CATCH, Child and Adolescent Trial for Cardiovascular Health; NHANES III, third National Health and Nutrition Examination Survey; tHcy, total homocysteine.
Manuscript received 10 January 2003. Initial review completed 11 February 2003. Revision accepted 15 May 2003.
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LITERATURE CITED |
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