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© 2003 The American Society for Nutritional Sciences J. Nutr. 133:3630-3635, November 2003

Nutritional Epidemiology

Geographical, Seasonal and Gender Differences in Folate Status among Chinese Adults1

Ling Hao*, Jing Ma{dagger},2, Meir J. Stampfer{dagger},**, Aiguo Ren*, Yihua Tian*, Yi Tang*, Walter C. Willett{dagger},** and Zhu Li*

* Institute of Reproductive and Child Health, Peking University, Beijing, China; {dagger} Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and ** Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA 02115

2To whom correspondence should be addressed. E-mail: jing.ma{at}channing.harvard.edu.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Low blood folate concentrations have been associated with cardiovascular disease, neural tube defects and selected cancers, but little is known about folate status in Chinese adults. In a cross-sectional study we measured the plasma and red blood cell folate concentrations in 2422 Chinese men and women aged 35 to 64 y, living in the North and South of China, who provided blood samples either in March or September of 2001. The geometric mean concentrations of plasma and red blood cell folate were lower among Northerners than Southerners (adjusted geometric means, 8.4 and 502, and 16.7 and 811 nmol/L, respectively) controlling for age, gender, season (spring and fall), area (urban and rural), BMI, multivitamin use, alcohol intake and current smoking status. We estimated that ~40% of the Northerners and ~6% of the Southerners had plasma folate concentrations lower than the 6.8 nmol/L (3 µg/L), and ~30% of the Northerners and ~4% of the Southerners had red blood cell folate comcentrations lower than the 363 nmol/L (160 µg/L), levels used to define folate deficiency. Within each region, men had lower plasma folate concentrations than women (6.9 versus 9.8 nmol/L in the North, and 14.5 versus 19.6 nmol/L in the South). In men, current smokers had a higher risk of folate deficiency compared with nonsmokers [adjusted odds ratios, 1.9 (95% CI, 1.4–2.6) for plasma folate deficiency and 2.5 (95% CI, 1.7–3.6) for red blood cell folate deficiency (P < 0.001)]. Our findings suggest that a large proportion of Chinese adults have a low folate status, especially those living in northern China where 60% of the men are plasma folate deficient in the spring. Further studies are needed to elucidate the factors that influence folate concentrations among middle-aged Chinese and to evaluate possible intervention strategies.

KEY WORDS: • folate • Chinese adults • gender • season • geographic difference • smoking

Overt folate deficiency causes megaloblastic anemia, but this is relatively uncommon in most of the world. However, recent studies in both developed and developing countries have shown that folic acid supplementation can reduce the incidence of neural tube defects (NTD) even in the absence of overt deficiency (1–3). Also, low concentrations of folate cause elevations in homocysteine concentrations (4,5), and low folate and high homocysteine concentrations are associated with the risk of cardiovascular disease (CVD), which is emerging as a major chronic disease in China and other developing countries (6–9). Folic acid supplementation has been shown to reduce homocysteine concentrations (10,11), which provides indirect but biologically plausible support for the hypothesis that folate supplementation may prevent CVD. In addition, low folate concentrations may increase the risk of several cancers and perhaps Alzheimer’s disease (12,13). Because of the likely role of folate in these chronic diseases, knowledge about plasma and red blood cell folate concentrations in different populations is important.

Folate status and its determinants have been studied extensively in North America and in Europe (4,14–17), but seldom in Asian countries. We previously found geographical variations in folate status among Chinese women of childbearing age, with lower serum folate concentrations in northern China where the incidence of NTD is high (5–6/1000 births), compared with southern China where incidence of NTD is low (~1/1000 births), suggesting that folate deficiency is one of the main causes of NTD in China (3,18). We subsequently demonstrated in a large-scale community intervention study that the periconceptional intake of 400 µg of folic acid daily reduces the NTD rate by 85% in northern areas and by 40% in southern areas (3). Our previous study indicated that low folate status might be a general health problem in the Chinese population. We therefore conducted the present study to assess geographic, seasonal and gender variations in folate status (in both plasma and red blood cells) among Chinese men and women aged 35 to 64 y. We also evaluated the possible influences of cigarette smoking, alcohol intake and BMI on folate status.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
Study population.

This study was conducted in March (spring) and September (fall), 2001, in two rural counties (1 northern, Xianghe County, Hebei province, and 1 southern, Wuxi-xinqu, Jiangsu province) and two cities (1 northern, Taiyuan city, Shanxi province, and 1 southern, Wuxi city, Jiangsu province) that are currently part of the U.S.-China Collaborative Project on Neural Tube Defects Prevention in China (19). The subjects from the North lived near Beijing, and those from the South lived near Shanghai. The subjects were selected using multistage, stratified cluster sampling by region (North and South), area (urban and rural), village or residential quarter, gender (male and female), and age (35–44, 45–54 and 55–64 y) using a village or residential registration database. Researchers informed and invited 3840 age-eligible people; among these 2545 agreed to participate and were recruited to attain enrollment of 50 men and 50 women in each of the three age groups, in each of the two areas, in each of the two seasons and in each of the two regions. Subjects who were pregnant or had a severe illness (renal, heart, liver disease or cancer) were excluded.

Information on birth date, personal history, use of vitamin supplements, current smoking habits and alcohol consumption were collected by face-to-face interview. Current smoking status was recorded in four categories: nonsmoker, smoking 1–10, 11–20 or >=21 cigarettes/d. Alcohol consumption (including liquor, beer, and wine) was classified in four categories according to the average number of drinks per day: 0 (never), <1, 1–1.9 or >=2 drinks/d. Multivitamin use in the past three months was categorized as frequently (defined as multivitamin users), occasionally or never. Dietary data were collected as part of this study using a semiquantitative food frequency questionnaire which had been validated (20). Weight and height were measured and BMI was calculated as weight (kg)/height (m)2. This study was approved by the Institutional Review Boards of the Ministry of Public Health of People’s Republic of China. All invited participants provided oral informed consent.

Blood sample collection and biochemical analyses.

Venous blood samples were collected after the subjects had fasted overnight. Blood samples were drawn into k3EDTA-containing Vacutainer tubes (Becton Dickinson, Franklin, NJ), held at 4°C and centrifuged at 800 x g for 15 min. The plasma and red blood cells were separated and frozen at -20°C within 1 h of collection. All specimens were transported on dry ice to the central laboratory of the Institute of Reproductive and Child Health, Peking University and stored at -70°C until assay. Red blood cell samples were hydrolyzed with chicken pancreas conjugase prior to analyses according to a previously described method (21). The red blood cell folate extract was stored at -70°C until assay. The plasma and red blood cell folate concentrations were determined by a microbial assay using a 96-well plate as described by O’Broin et al. (22). The intra- and interassay CV were <9% across the full range of folate concentrations. Red blood cell folate data were corrected using the hemoglobin concentrations to calculate the folate/hemoglobin ratio (ng of folate/g of hemoglobin) and the data were then converted to red blood cell folate concentrations (nmol/L) for statistical analyses using the mean cell hemoglobin concentration (23).

Statistical methods.

Because the distributions of plasma and red blood cell folate concentrations were positively skewed, natural logarithmic transformations were used to normalize their distributions, and the geometric means as well as the 95% CI were determined. Student t tests and one-way ANOVA were used to compare means. The analysis of covariance was conducted to compare means controlling for differences in region, age, gender, season, BMI, area (urban and rural), multivitamin use, alcohol intake and current smoking status. In addition, polynomial contrasts were used to test for folate concentration trends across age. The significance of categorical variables was assessed by the chi-square test. Folate deficiency was defined as <6.8 nmol/L (3 µg/L) for plasma folate (24) and 363 nmol/L (160 µg/L) for red blood cell folate (21). The prevalence of folate deficiency in the population was estimated adjusting for age and gender with weighting according to the local demographic data. The association between BMI and folate status was also assessed. Multivariate logistic models were used to examine the odds ratio of blood folate deficiency in association with alcohol drinking, BMI and cigarette-smoking status. The data were analyzed with SPSS 10.0 (SPSS, Beijing). All P values were two-sided at the alpha level 0.05.


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
Of the 2545 participants, 2422 (~95%) provided complete data for analyses; among these 1226 were recruited in March and 1196 in September. The demographic characteristics were similar among the subjects in the analysis compared with those eligible participants who were excluded because of missing data, and similar among participants who had their blood samples collected in the two seasons. Overall, plasma folate concentrations were positively correlated with red blood cell folate (r = 0.63, P < 0.001). Overall, Northerners had higher BMI than Southerners. The prevalence of multivitamin supplement use was lower in all Northerners and in southern men compared with southern women. Northerners smoked more than Southerners, and men smoked and drank more than women (Table 1).


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  		TABLE 1 Selected characteristics of the Chinese adult folate status study participants

 
Those living in the North had lower plasma and red blood cell folate concentrations than those living in the South, controlling for season, gender, area, age, BMI, multivitain use, alcohol intake and current smoking status (Table 2). Northerners also had a higher prevalence of folate concentration deficiency defined as plasma folate < 6.8 nmol/L (3 µg/L) or red blood cell folate < 363 nmol/L (160 µg/L).


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  		TABLE 2 Distribution of plasma and red blood cell folate concentrations in Chinese adults by region, gender and season1

 
Within each season, Northerners had lower folate concentrations than those of Southerners, although the North-South difference in folate concentrations was larger in spring than in fall (Table 2). In spring, 60% of men and 35% of women in the North had plasma folate deficiency and 32–35% of the men and women had red blood cell folate deficiency. In the North, folate concentrations were lower in spring than in fall, whereas in the South, both plasma and red blood cell folate concentrations were lower in fall than in spring, probably reflecting the difference in the availability of fresh fruits and vegetables between the two regions.

Within each region and each season, plasma and red blood cell folate concentrations were lower in men than in women, except for red blood cell folate between northern men and women in spring (P = 0.31; Table 2). We found no differences in folate concentrations between urban and rural areas in each region and in each season, except that in the North, plasma folate concentrations in fall and the red blood cell folate concentrations in spring were lower in the rural area (adjusted geometric mean of plasma and red blood cell folate concentration, 9.0 and 401 nmol/L, respectively) compared with the urban area (10.4 and 507 nmol/L, respectively, P < 0.001).

In general, older individuals had higher folate concentrations, especially for plasma folate in southern men (Table 3). The gender differences in plasma and red blood cell folate concentrations were persistent in all three age groups and remained unchanged after adjusting for area, season, age, BMI, multivitamin use, current smoking status and alcohol intake in either region (Table 3).


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  		TABLE 3 Comparisons of plasma and RBC folate in Chinese adults by gender and age1

 
In the univariate analyses, alcohol consumption was positively associated with the risk of plasma folate deficiency (Table 4). However, in the multivariate analyses controlling for region, gender, season, area, age, BMI, multivitamin use and smoking status, the positive direction was reversed to an inverse relationship. In the univariate analysis, a BMI >= 27 kg/m2 was positively associated with the risk of both plasma and red blood cell folate deficiency (Table 4). However, after controlling for region, gender, area, season, age, multivitamin use, alcohol consumption and current cigarette-smoking status, there was a J-shape relationship between BMI and risk of red blood folate deficiency, but no apparent relation between BMI and plasma folate status. Individuals with a BMI < 21 had a twofold increased risk of red cell folate deficiency compared with those with a BMI of 23–24.9 kg/m2. After additional control for fruit and vegetable intake, all of the results in the multivariate analyses above changed only slightly.


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  		TABLE 4 Odd ratios of blood folate deficiency by cigarette smoking, alcohol consumption or BMI1

 
Among the male participants, 61% of the Northerners and 55% of the Southerners were current smokers, whereas only 9% of the women in the North and 0.7% of the women in the South were current smokers. Because very few women smoked in this population, we evaluated the association between cigarette-smoking and folate status among men (Table 4). The male smokers had lower plasma and red blood cell folate concentrations compared with nonsmokers (adjusted geometric means of plasma folate for smokers versus nonsmokers, 8.9 versus 10.9 nmol/L, and red blood cell folate, 547 versus 657 nmol/L, P < 0.001). The male smokers had a higher risk of blood folate deficiency relative to the nonsmokers [adjusted odd ratio,1.9 (95% CI, 1.4–2.6) for plasma folate deficiency, and 2.5 (95% CI, 1.7–3.6) for red blood cell folate deficiency, P < 0.001]. The positive dose-responsive association between current smoking status and risk of folate deficiency was persistent in both the univariate and the multivariate analyses (Table 4).


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
To our knowledge, this is the first study to report data on folate concentrations, including plasma and red blood cell folate in a large sample of Chinese adults. The geometric mean concentrations of blood folate for those living in the North were lower than those living in the South among men and women, both in spring and fall. Our results also suggest that in spring (probably also in winter), folate status is low among those living in the North, especially in the rural areas. These findings on the regional and seasonal differences of blood folate status in Chinese adults are consistent with the greater availability of fresh vegetables throughout the year in the South than in the North, whereas in the North, especially in the rural areas, the variety and supply of fresh vegetables are limited in winter and spring and relatively ample in summer and fall. From our preliminary dietary intake data collected from these participants, the Northerners, especially in winter and spring and in the rural areas, tended to eat green vegetables less frequently than the Southerners. This might explain the difference by urbanicity in folate concentrations in the North but not in the South.

Plasma folate concentration is sensitive to recent intake, whereas red blood cell folate concentration provides the best indicator of long-term folate stores (25). This is consistent with our finding that, although both plasma and red blood cell folate concentrations showed similar directions in terms of regional, seasonal and gender differences, the magnitude of the differences were larger for plasma folate than for red blood cell folate concentrations. The prevalence of folate deficiency was also generally higher when assessed by plasma folate than by red blood cell folate concentrations. In addition, in the fall, Northerners living in the rural areas had lower plasma folate concentrations than those living in the urban areas, whereas there was a similar pattern for red blood cell folate concentrations in spring rather than in fall. This may reflect a longer time lag between low folate intake in the fall and low red blood cell folate status in spring among northern rural Chinese. The association between dietary intakes and folate status among these participants will be further evaluated.

Men had lower folate concentrations than women, which is consistent with the results of Ford et al. among Americans (14). However, Selhub et al. found similar folate concentrations in American men and women, despite higher folate intake in women (4). In previous studies of Caucasian populations, cigarette smoking and alcohol consumption were both inversely associated with plasma folate concentrations (17,26). In our study, Chinese men had a much higher prevalence of cigarette smoking and drinking compared with women, and among these Chinese men, the Northerners smoked more than the Southerners. Therefore, cigarette smoking might partially explain the gender and regional differences observed in this study. Consistent with previous studies (17,29), current cigarette smoking was a risk factor for folate deficiency among the male participants even after controlling for region, season, area, age, BMI, multivitamin use and alcohol intake. Because smokers tend to have lower intakes of fruits and vegetables and higher intake of alcohol (27,28), we also evaluated the associations with additional control for fruit and vegetable intake and found similar results. However, residual confounding due to smoking, fruit and vegetable intake and other dietary and lifestyle factors may contribute to the regional, seasonal and gender differences in folate status.

The unexpected inverse association between alcohol consumption and the risk of folate deficiency in the multivariate analysis controlling for region, gender, season, area, age, BMI, multivitamin use and smoking status was most pronounced in northern men. Our preliminary data from the semiquantitative food frequency questionnaire suggest that regular alcohol drinkers tended to have a higher intake of protein and vitamin B-rich foods, such as peanuts and fermented soy paste compared with alcohol abstainers and infrequent drinkers. The association between BMI and folate status was evaluated because BMI is not only related to cigarette smoking but also could be considered an indicator of nutritional status especially in the developing countries. Our findings suggest a poor folate status among those Chinese adults with either a low (<21 kg/m2) or a high (>=27 kg/m2) BMI even after controlling for regional and seasonal factors, gender, alcohol intake and smoking status. This observation needs to be confirmed in other studies.

The geographic differences for folate concentrations are similar to those for CVD incidence in China, which is higher in the North than in the South, and higher in men than in women (30,31). Also the incidence of stroke in the North is higher in rural areas than in urban areas (32). Our results suggest a potential ecological link between low folate status and the risk of CVD in Chinese adults. However, further study is needed to directly associate folate status with the risk of CVD in China, and proof of a cause-and-effect relation between folate status and CVD awaits the results of controlled intervention trials.

A limitation of our study was the cross-sectional design with blood samples collected only in spring and fall. We plan to further evaluate dietary and other lifestyle factors that may influence folate metabolism and might explain the regional and gender differences. Furthermore, although our study subjects were not a random sample of all the Chinese, they have typical lifestyles representative of the population in the North around Beijing and in the South around Shanghai, sites that include a population of 21 million. These data provide strong evidence for a high prevalence of folate insufficiency, suggesting the need for intervention studies.


   ACKNOWLEDGMENTS
 
We thank Jecob Selhub, Marie Nadeau, the Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, and Sean O Broin, Department of Hematology, St. James’s Hospital in Dublin, for their valuable help in setting up the folate assay.


   FOOTNOTES
 
1 Supported by research Grants CA 42182, CA 78293, CA 70817, CA 58684 and CA 90598 from the NIH. Back

Manuscript received 29 May 2003. Initial review completed 11 June 2003. Revision accepted 12 August 2003.


   LITERATURE CITED
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

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J. Nutr., May 1, 2007; 137(5): 1278 - 1285.
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 J. Nutr.Home page
L. Hao, J. Ma, J. Zhu, M. J. Stampfer, Y. Tian, W. C. Willett, and Z. Li
High Prevalence of Hyperhomocysteinemia in Chinese Adults Is Associated with Low Folate, Vitamin B-12, and Vitamin B-6 Status
J. Nutr., February 1, 2007; 137(2): 407 - 413.
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 JNCI J Natl Cancer InstHome page
S. J. Lewis, R. M. Harbord, R. Harris, and G. D. Smith
Meta-analyses of Observational and Genetic Association Studies of Folate Intakes or Levels and Breast Cancer Risk.
J Natl Cancer Inst, November 15, 2006; 98(22): 1607 - 1622.
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 CarcinogenesisHome page
W. Tan, X. Miao, L. Wang, C. Yu, P. Xiong, G. Liang, T. Sun, Y. Zhou, X. Zhang, H. Li, et al.
Significant increase in risk of gastroesophageal cancer is associated with interaction between promoter polymorphisms in thymidylate synthase and serum folate status
Carcinogenesis, August 1, 2005; 26(8): 1430 - 1435.
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 StrokeHome page
S. Cronin, K. L. Furie, and P. J. Kelly
Dose-Related Association of MTHFR 677T Allele With Risk of Ischemic Stroke: Evidence From a Cumulative Meta-Analysis
Stroke, July 1, 2005; 36(7): 1581 - 1587.
[Abstract] [Full Text] [PDF]

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