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(Stroke. 1998;29:2473-2477.)
© 1998 American Heart Association, Inc.

Original Contributions

Total Homocyst(e)ine Concentration and the Likelihood of Nonfatal Stroke

Results From the Third National Health and Nutrition Examination Survey, 1988–1994

Wayne H. Giles, MD, MS; Janet B. Croft, PhD; Kurt J. Greenlund, PhD; Earl S. Ford, MD, MPH Steven J. Kittner, MD, MPH

From the Cardiovascular Health Branch, Division of Adult and Community Health (W.H.G., J.B.C., K.J.G.), and the Chronic Disease Nutrition Branch, Division of Nutrition and Physical Activity (E.S.F.), National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Ga, and the Departments of Neurology and Epidemiology and Preventive Medicine (S.J.K.), University of Maryland School of Medicine, Baltimore, Md.

Correspondence and reprint requests to Wayne H. Giles, MD, Cardiovascular Health Branch, Centers for Disease Control and Prevention, 4770 Buford Hwy, MS K-47, Atlanta, GA 30341. E-mail hwg0{at}cdc.gov

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—Elevated serum total homocyst(e)ine [H(e)] is an independent risk factor for stroke. Few studies, however, have examined this association in blacks.

Methods—Data from the Third National Health and Nutrition Examination Survey (n=4534), a nationally representative sample of US adults, were used to examine the relationship between H(e) and a physician diagnosis of stroke (n=185) in both black and white adults. Multivariate-adjusted logistic regression analyses were used to examine this relationship.

Results—Serum vitamin B₁₂ and folate concentrations were significantly lower among participants in the highest H(e) quartile (12.1 µmol/L) than among participants in the lowest quartile (7.4 µmol/L). Those in the highest quartile were older, had higher mean cholesterol and blood pressure levels, and were more likely to smoke and to have completed <12 years of education. After adjustment for age, the odds ratio (OR) for stroke was 2.9 (95% confidence interval [CI], 1.4 to 5.7; highest versus lowest quartile). Adjustment for gender, race/ethnicity, education, systolic blood pressure, cholesterol, diabetes mellitus, and smoking reduced the magnitude of the association (OR, 2.3; 95% CI, 1.2 to 4.6). The association between H(e) and stroke did not differ by race [P=0.265 for race-H(e) interaction term]. The multivariate adjusted OR for the highest quartile versus the lowest was 2.5 (1.1 to 5.5) among whites and 1.4 (0.4 to 4.7) among blacks.

Conclusions—In this nationally representative sample of US adults, H(e) concentration was independently associated with an increased likelihood of nonfatal stroke. This association was present in both black and white adults.

Key Words: epidemiology • homocyst(e)ine • race • stroke

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Elevated serum total homocyst(e)ine [H(e)] concentrations are an independent risk factor for stroke,^{1 2 3} coronary heart disease,^{4 5 6 7 8 9} and peripheral vascular disease.^{10 11} H(e) includes all molecular species that are measured and constitute the risk factor: homocysteine, homocystine, and the mixed homocysteine-cysteine disulfide. In a meta-analysis examining the association between H(e) and coronary heart disease, Boushey and colleagues¹² reported that a 5-µmol/L increase in H(e) was associated with an OR of 1.6 in men and 1.8 in women. Because of the paucity of studies, however, Boushey and colleagues were unable to comment on any possible racial differences in the association between H(e) and risk for cardiovascular disease.

H(e) concentrations can be affected by several nutritional and genetic factors. Folate consumption is a major determinant of H(e) concentration, and blacks tend to have substantially lower folate consumption rates than their white counterparts.¹³ We previously reported that the association between low serum folate concentration and risk of stroke was stronger among blacks than among their white counterparts.¹⁴ We hypothesized that this finding reflected a stronger association between H(e) and stroke among blacks.

To date, most of the studies examining the association between H(e) and stroke have been conducted in selected populations that may not reflect the age, gender, and racial or ethnic distribution of the general US population.^{1 2 3 4 5 6 7 8 9 10 11 12} In addition, few studies have included blacks or Mexican Americans. We used data from the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative sample of US adults, to examine the cross-sectional association between H(e) concentration and nonfatal stroke and to determine whether this association was stronger among black adults than among their white counterparts.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The Centers for Disease Control and Prevention's National Center for Health Statistics conducted the NHANES III between 1988 and 1994 to estimate the prevalence of common chronic conditions and associated risk factors among a nationally representative sample of the civilian, noninstitutionalized US population.¹⁵ The survey included a household interview; a medical examination at a mobile examination center; and phlebotomy to measure a number of hematologic factors, including H(e).

The study sample included 4534 persons who were over age 35 and who underwent testing for H(e). Serum H(e) concentrations were measured during phase II of the NHANES III survey (1992–1994). Blood that was drawn during the medical examination was processed with use of a standard protocol,¹⁶ and sera were stored at -70°C for 8 months to 3 years before analysis. The high-performance liquid chromatography method of Araki and Sako¹⁷ was used to obtain H(e) measurements at the US Department of Agriculture's Human Nutrition Research Center on Aging. H(e) concentrations ranged from 3.1 to 132.0 µmol/L and were grouped into the following quartiles: 7.4 µmol/L, 7.5 to 9.3 µmol/L, 9.4 to 12.0 µmol/L, and 12.1 µmol/L.

During the household interview, 185 participants (4.1%) answered in the affirmative to the question, "Has a doctor ever told you that you had a stroke?" Potential confounders in the association between H(e) and nonfatal stroke included age, gender, race/ethnicity (white, black, and Mexican American), education, systolic blood pressure, cholesterol, and cigarette smoking. Systolic blood pressure was the mean of the second and third blood pressure determinations taken during the physical examination. Although serum folate and vitamin B₁₂ concentrations were not considered potential confounders in the association between H(e) and stroke, we examined whether serum folate and vitamin B₁₂ concentrations differed by H(e) quartile and stroke status. Because folate, vitamin B₁₂, and H(e) concentrations were positively skewed, we log transformed the values and present both arithmetic and geometric means for groups defined by H(e) quartile and stroke status.

We used t tests and ² tests to compare groups defined by H(e) quartile and stroke status. Multivariate logistic regression analyses were used to determine whether the likelihood for stroke differed by H(e) quartile. The logistic regression model was adjusted for the following cardiovascular disease risk factors: age, gender, race/ethnicity, education, systolic blood pressure, cholesterol concentration, and smoking status. An ordinal variable, with values ranging from 1 to 4 to denote the 4 H(e) quartiles, was included in the multivariate logistic regression model to test for linear trend. The analysis was also stratified by race to determine whether the association between H(e) and stroke differed by race. The number of Mexican Americans who experienced a stroke (n=38) was too small to allow analysis of the association between H(e) and stroke in this population. The NHANES III data were weighted to make the results representative of the entire US population. To take into account the complex sampling design in the NHANES III survey, SUDAAN¹⁸ was used to obtain standard errors for the prevalence estimates and ORs.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Persons in the highest H(e) quartile were older and had higher mean systolic blood pressure and cholesterol values than those in the lowest quartile (Table 1). The percentage of persons in the highest quartile who were men (56.0%) was almost twice the percentage in the lowest quartile (29.2%). The percentage of blacks in each quartile did not differ; in contrast, the percentage of Mexican Americans in the highest quartile (3.3%) was approximately half that in the lowest quartile (5.9%). The prevalence of diabetes mellitus, low educational attainment (<12 years of education), and current smoking increased with H(e) concentration. Finally, as expected, an inverse relationship was observed between serum folate concentration and H(e) quartile (P<0.001) and between vitamin B₁₂ concentration and H(e) quartile (P<0.001). Persons in the lowest H(e) quartile had a mean serum folate concentration of 10.7 ng/mL, while persons in the highest quartile had a mean folate concentration of 5.5 ng/mL.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics According to Total Homocyst(e)ine Concentration, NHANES III, 1992–1994

NHANES III participants who had suffered a stroke were older and had higher systolic blood pressure values than participants who had not suffered a stroke (Table 2). In addition, stroke sufferers were more likely to have <12 years of education, to be diabetic, and to be either current or former smokers. There was no significant difference between the 2 groups in mean folate or vitamin B₁₂ concentration. For H(e) concentration, however, a significant difference was found: persons who had suffered a stroke had a mean H(e) concentration of 11.9 µmol/L whereas those who had not had a mean H(e) concentration of 10.2 µmol/L (P<0.001).

View this table: [in this window] [in a new window]   Table 2. Factors Associated With Prevalent Stroke, NHANES III, 1992–1994

The likelihood for nonfatal stroke increased with H(e) concentration (Table 3). The multivariate-adjusted ORs comparing the second, third, and fourth H(e) quartiles to the lowest quartile were 1.7 (95% CI, 0.8 to 4.0), 2.5 (95% CI, 1.2 to 5.5), and 2.3 (95% CI, 1.2 to 4.6), respectively. An interquartile increase in H(e) was associated with an OR of 1.2 (95% CI, 1.0 to 1.6). The association between H(e) and stroke was similar in both whites and blacks (P=0.265 for race-H(e) interaction; see the Figure); comparing the highest with the lowest quartile, the OR for stroke was 2.5 (95% CI, 1.1 to 5.5) among whites and 1.4 (95% CI, 0.4 to 4.7) among blacks. Because of the limited number of stroke events among blacks (n=48), the analysis was repeated, with the division of H(e) concentrations into the following tertiles: 8.0, 8.1 to 10.8, and 10.9 µmol/L. The multivariate adjusted ORs comparing the second and third tertiles with the lowest tertile were 1.6 (0.5 to 5.6) and 1.7 (0.8 to 4.5) among blacks and 1.1 (0.5 to 2.4) and 1.8 (0.8 to 4.1) among whites, respectively.

View this table: [in this window] [in a new window]   Table 3. Association Between Total Homocyst(e)ine Concentration and Likelihood for Nonfatal Stroke, NHANES III, 1992–1994

View larger version (13K): [in this window] [in a new window]   Figure 1. Association between total homocyst(e)ine concentration and the likelihood of nonfatal stroke, from the results of the Third National Health and Nutrition Examination Survey, 1988–1994. ORs are adjusted for age, gender, education, systolic blood pressure, cholesterol concentration, diabetes mellitus, smoking status, and total homocyst(e)ine quartile.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
These are the first data from a nationally representative sample of US adults to document an association between H(e) and nonfatal stroke. Persons in the highest H(e) quartile were approximately twice as likely to have suffered a stroke as those in the lowest quartile. The results from this cross-sectional study indicate that the association between H(e) and prevalent stroke was similar among black and white adults.

Although the association between H(e) and stroke did not achieve statistical significance among blacks, the results do suggest a modest association between H(e) and stroke in this population. The lack of statistical significance was largely due to the limited number of prevalent stroke events among blacks (n=48). There were <20 strokes in each of the 4 quartiles and <10 strokes in the lowest 2 H(e) quartiles. Repeating the race-stratified analysis by tertile increased the stability of the ORs, as noted by the narrower CIs.

In the present study we found that several cardiovascular disease risk factors were strongly associated with H(e) concentrations, including age, systolic blood pressure, and total cholesterol concentrations. These findings are consistent with those of the Hordaland Homocyst(e)ine Study,¹⁹ another cross-sectional study from Norway that examined the correlates of H(e) in a sample of 7591 men and 8585 women aged 40 to 67 years.

In addition, we found that completing <12 years of education was associated with higher H(e) concentrations. Such an association may be mediated through the consumption of the B vitamins B₁₂, B₆, and folate. Results from NHANES II²⁰ indicate that the percentage of persons with low red blood cell folate values was higher for both men and women with incomes below the poverty level; however, this difference did not achieve statistical significance.

Both the present study and the Hordaland Homocyst(e)ine Study¹⁹ found that cigarette smoking was positively associated with H(e) concentrations. Similarly, data from the Stroke Prevention in Young Women Study²¹ found that as the number of cigarettes smoked per day increased, so did H(e) concentrations. Additional studies should examine whether smoking cessation can reduce H(e) concentrations.

These results from NHANES III suggest that the percentage of blacks do not differ according to H(e) quartile, a finding consistent with data from the Stroke Prevention in Young Women Study,²¹ which reported similar H(e) distributions in black and white women. These results may seem surprising, given that blacks have substantially lower folate intakes than their white counterparts.¹³ However, an important genetic determinant of H(e), a polymorphism associated with the thermolabile variant to the enzyme 5,10-methylenetetrahydrofolate reductase, appears to be substantially less prevalent among blacks than among whites.^{22 23} This polymorphism has been associated with elevated H(e) concentrations, particularly when folate concentrations are low.²³

To the best of our knowledge, this is the first study to report any information on H(e) concentrations among Mexican Americans. Reasons for the low percentage of Mexican Americans among those in the highest H(e) quartile are unclear. Data from NHANES III¹³ indicate that Mexican Americans have folate intakes similar to or lower than those of their white counterparts. In contrast, vitamin B₁₂ intakes were slightly higher among Mexican Americans in NHANES III compared with their white counterparts. This finding was particularly true among Mexican American women over age 60.¹³ Whether a lower prevalence of genetic polymorphisms associated with H(e) concentration, such as the thermolabile variant to the enzyme methylenetetrahydrofolate reductase, may also explain the lower H(e) concentrations among Mexican Americans needs further exploration. In addition, whether lower H(e) levels can partially explain the lower stroke mortality rates among Hispanic adults should also be examined in future studies.²⁴ Unfortunately, the number of stroke events among Mexican Americans was insufficient to examine the association between H(e) and stroke in NHANES III.

Elevated H(e) concentration appears to be an independent risk factor for cardiovascular disease, and the increased consumption of folate, vitamin B₁₂, and vitamin B₆ may reduce H(e) values. Whether increased consumption of these B vitamins can reduce the risk of cardiovascular disease has not been determined. Currently, several primary and secondary cardiovascular disease prevention trials are attempting to answer this question.

The present study has several potential limitations. First, because the data were derived from a cross-sectional study, one cannot infer the direction of the associations. However, prospective studies^{3 25} have reported an association between H(e) and stroke, and the magnitude of the association appears to be similar to that presented in this report. Second, H(e) concentrations were not obtained from fasting adults in all cases. However, limiting the sample to those adults who were fasting did not appreciably change the risk estimates. Finally, we were able to evaluate only nonfatal stroke events. Data from patients with coronary heart disease suggest that the association between H(e) and coronary heart disease may be stronger for fatal than for nonfatal events.²⁶ If this finding is also true for stroke, it is likely that the magnitude of the association would have been even stronger if fatal stroke events had been included.

In conclusion, data from this nationally representative sample of US adults indicate that persons in the highest H(e) quartile have approximately twice the likelihood of nonfatal stroke as those in the lowest H(e) quartile. This increased likelihood was noted in both blacks and whites. There is a paucity of data on the relationship between H(e) and stroke among Mexican Americans, and there is a clear need for additional studies. Future studies, including primary and secondary prevention trials, should include an adequate number of persons from diverse racial/ethnic backgrounds to further examine the complex relationships between race/ethnicity, folate, vitamin B₆, vitamin B₁₂, H(e) and the risk for cardiovascular disease.

Received August 4, 1998; accepted September 4, 1998.

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