The Journal of Allergy and Clinical Immunology
Volume 123, Issue 6 , Pages 1253-1259.e2, June 2009

Higher serum folate levels are associated with a lower risk of atopy and wheeze

  • Elizabeth C. Matsui, MD, MHS

      Affiliations

    • Division of Pediatric Allergy and Immunology, Johns Hopkins School of Medicine, Baltimore, Md
    • Corresponding Author InformationReprint requests: Elizabeth C. Matsui, MD, MHS, The Johns Hopkins Hospital, CMSC 1102, 600 N Wolfe St, Baltimore, MD 21287.
    • ,
  • William Matsui, MD

      Affiliations

    • Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Md

Received 9 November 2008; received in revised form 27 February 2009; accepted 3 March 2009. published online 01 May 2009.

Article Outline

Background

Folic acid is known to be associated with inflammatory diseases, but the relationship between folic acid and allergic diseases is unclear.

Objectives

The purpose of the study was to examine the relationship between serum folate levels and markers of atopy, wheeze, and asthma.

Methods

Data were obtained from the 2005-2006 National Health and Nutrition Examination Survey in which serum folate and total IgE levels were measured in 8083 subjects 2 years of age and older. A high total IgE level was defined as greater than 100 kU/L. Allergen-specific IgE levels were measured for a panel of 5 common aeroallergens. Atopy was defined as at least 1 positive allergen-specific IgE level. Doctor-diagnosed asthma and wheeze in the previous 12 months were assessed by means of questionnaire.

Results

Serum folate levels were inversely associated with total IgE levels (P < .001). The odds of a high total IgE level, atopy, and wheeze decreased across quintiles of serum folate levels, indicating a dose-response relationship between serum folate levels and these outcomes. Each of these associations remained statistically significant after adjusting for age, sex, race/ethnicity, and poverty index ratio. Adjusted odds ratios associated with the fifth quintile of folate relative to the first quintile were as follows: high IgE level, 0.70 (95% CI, 0.53-0.92); atopy, 0.69 (95% CI, 0.57-0.85); and wheeze, 0.60 (95% CI, 0.44-0.82). Higher folate levels were also associated with a lower risk of doctor-diagnosed asthma, but this finding was not statistically significant (odds ratio for fifth quintile vs first quintile, 0.84 [95% CI, 0.70-1.02]).

Conclusions

Serum folate levels are inversely associated with high total IgE levels, atopy, and wheeze.

Key words: Asthma, allergy, atopy, folate, National Health and Nutrition Examination Survey, Centers for Disease Control

Abbreviations used: MTHFR, Methylenetetrahydrofolate reductase, NHANES, National Health and Nutrition Examination Survey

 

The prevalence of asthma and allergy has increased dramatically over the past 20 to 30 years in developed countries, and the reasons behind this striking trend remain unclear. This increase in prevalence cannot be attributed to changes in the genetic makeup of the population because this trend has occurred over a relatively short period of time. As such, there has been active investigation into changes in environmental exposures as a potential cause of the recent increase in allergic diseases.

Allergen exposure,1, 2, 3, 4, 5, 6, 7 pollutant exposure,8, 9, 10, 11, 12 endotoxin exposure,13, 14, 15 immunizations,16, 17, 18, 19 diet,20, 21, 22, 23 and exposure to parasitic24, 25, 26 and viral27, 28, 29 infections have all been implicated in the epidemic. These exposures could act directly on the immune system or end organs to elicit or attenuate sensitization and disease, but they might also result in epigenetic changes that could tilt the immunophenotypic balance in favor of allergic disease. One particular dietary component that could directly influence the propensity for epigenetic modifications is folic acid, which serves as a source for methyl donors for DNA methylation. In fact, a methyl donor–enriched diet that included folic acid enhanced allergic humoral responses and lung inflammation in a mouse model,30 suggesting that epigenetic changes can indeed promote the development of allergic disease.

Although the findings from this mouse model are intriguing, it is unclear how they might translate to human subjects. On the one hand, the concomitant increase in allergic diseases31, 32 and serum folate levels33 in the United States suggests that the relatively recent enrichment of the US diet with folic acid might be a risk factor for allergic disease, an observation that would be consistent with the findings in mice. On the other hand, lower folic acid levels have been implicated in a variety of inflammation-mediated diseases, such as cardiovascular disease34, 35, 36, 37 and rheumatoid arthritis,38, 39 and therefore it is possible that folate might mitigate against, rather than promote, allergic diseases, which are also inflammation mediated.

To gain insight into the role of folate in the development of allergic disease, we examined relationships between serum folate levels and measures of atopy and airways disease in the 2005-2006 National Health and Nutrition Examination Survey (NHANES) population.

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Methods 

The 2005-2006 NHANES dataset40 was used to examine relationships between serum folate levels and measures of atopy, wheeze, and asthma. The NHANES is a nationally representative survey of the noninstitutionalized US civilian population. The NHANES uses a complex multistage probability design to select a representative population and oversamples certain underserved groups to increase the precision of estimates generated during analysis. The NHANES was approved by the institutional review board of the National Center for Health Statistics, Centers for Disease Control and Prevention, and informed consent was obtained from all participants.

All participants who had serum folate and total IgE levels measured were included in the analyses, which resulted in a final sample size of 8083. Ages ranged from 2 years to greater than 85 years. Sociodemographic values, serum folate levels, total and specific IgE levels, respiratory disease questionnaire data, and medical conditions questionnaire data were included in the dataset. A participant was considered to have had wheeze in the preceding 12 months if he or she responded affirmatively to the following question: “In the past 12 months, have you had wheezing or whistling in your chest?” A participant was considered to have doctor-diagnosed asthma if he or she responded affirmatively to the following question: “Has a doctor or other health professional ever told you that you have asthma?”

Laboratory evaluations 

Serum total IgE levels were measured with the ImmunoCAP system (Phadia, Uppsala, Sweden). Cat-, dog (e5)–, Dermatophagoides farinae–, Dermatophagoides pteronyssinus–, Alternaria species–, and cockroach-specific IgE levels were also measured with the ImmunoCAP system. A level of 0.35 kU/L or greater was considered positive, and atopy was defined as at least 1 positive allergen-specific IgE measurement. Serum folate levels were measured by means of radioassay with the Quantaphase II Folate kit (Bio-Rad Laboratories, Hercules, Calif).

Statistical analyses 

Statistical analyses were performed with StataSE 8.0 software (StataCorp, College Station, Tex). The primary sampling units and strata were taken into account using the variables provided in the NHANES dataset to account for the complex survey design. Sampling weights provided by the NHANES were used to generate estimates that are representative of the US noninstitutionalized civilian population.

Relationships between variables of interest were examined by using logistic or linear regression methods that accounted for the sampling design and the weighting of the observations in the NHANES dataset. Bivariate analyses of folate and the outcome variables of interest were used to examine trends in outcomes across a continuous measure of serum folate, as well as quintiles of folate. A test for trend was performed by using either the continuous folate variable or the variable for quintiles of folate, without inclusion of dummy variables. Multivariate models were adjusted for age, sex, race/ethnicity, and poverty income ratio, which is the ratio of family income to the poverty threshold. ANOVA was used to compare serum folate levels among race/ethnicity subgroups. A 2-tailed P value of less than .05 was considered statistically significant.

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Results 

The study population reflected the national representation of the survey design and consisted of approximately equal proportions of male and female subjects with a mean age of 38 years (Table I). The population was predominantly non-Hispanic white, with 13% self-identified as Mexican American or another Hispanic ethnicity, and 12% non-Hispanic black. Approximately 14% of the population had doctor-diagnosed asthma, with 15.7% reporting wheeze in the previous 12 months. Twenty-seven percent had a total IgE level of greater than 100 kU/L, and 32% were atopic, having at least 1 positive allergen-specific IgE level.

Table I. Sociodemographic characteristics
Characteristic
Sex
Male48.9%
Female51.1%
Age (y), mean ± SE38.3 ± 0.8
Race/ethnicity
Non-Hispanic white69.7%
Hispanic12.9%
Non-Hispanic black11.8%
Other5.6%
Income (n = 8004)
<$20,00015.9%
≥$20,00083.9%
Refused/do not know1.2%
Asthma, doctor diagnosed (n = 8074)∗14.4%
Wheezing, past 12 mo (n = 8080)15.7%
High total IgE (>100 kU/L; n = 8083)27.4%
Allergen-specific IgE, positive
Dust mite (n = 8082)20.0%
Cat (n = 8082)11.6%
Dog (n = 8079)11.4%
Cockroach (n = 8072)10.0%
Alternaria species (n = 8053)8.4%
Atopy (≥1 positive; n = 8052)32.4%

∗The number of participants with complete data is indicated in parentheses after each variable.

Serum folate levels ranged from 0.7 to 171.0 ng/mL and were stratified by quintile. The quintile cutoff points were as follows: quintile 1, 0.7 to 8.1 ng/mL; quintile 2, 8.2 to 10.9 ng/mL; quintile 3, 11.0 to 13.8 ng/mL; quintile 4, 13.9 to 17.9 ng/mL; and quintile 5, 18.0 to 171.0 ng/mL. Non-Hispanic black and Hispanic subjects had lower serum folate levels than non-Hispanic white subjects (mean serum folate levels, 12.0, 12.5, and 15.0 ng/mL, respectively; P < .001). Adjustment for income did not alter these racial/ethnic associations with serum folate levels, but higher income tended to be associated with higher serum folate levels. Specifically, serum folate levels were estimated to be 2.8 ng/mL lower among non-Hispanic black subjects than among non-Hispanic white subjects and 2.1 ng/mL lower among Hispanic subjects than among non-Hispanic white subjects (Table II).

Table II. Race/ethnicity, poverty, and serum folate levels
CharacteristicDifferences in serum folate levels (ng/mL [95% CI])P value
Race/ethnicity (reference = Non-Hispanic white)
Non-Hispanic black−2.8 (−3.5 to −2.0)<.001
Hispanic−2.1 (−3.1 to −1.1).006
Other−1.4 (−3.1 to 0.4).10
Poverty index ratio∗0.2 (−0.1 to 0.5).04

∗Ratio of family income to poverty threshold.

Total IgE levels decreased across quintiles of serum folate levels (P < .001 for trend, Fig 1). After adjusting for age, sex, race/ethnicity, and poverty index ratio, higher serum folate levels remained statistically significantly associated with lower total IgE levels (data not shown). Relationships between serum folate levels and high total IgE levels (>100 kU/L) and atopy (≥1 positive allergen-specific IgE level) were also examined. The odds of both a high total IgE level and atopy decreased across quintiles of serum folate in unadjusted analyses (P < .001 for trend), as well as multivariate analyses that adjusted for age, sex, race/ethnicity, and poverty index ratio (Table III).

  • View full-size image.
  • Fig 1. 

    Distribution of serum total IgE levels across quintiles of serum folate. Outside values are not shown. Geometric mean total IgE levels for each quintile of serum folate are as follows: 53.6, 44.9, 45.1, 38.7, and 34.5 kU/L, respectively. P < .001 for trend.

Table III. Relationships among serum folate levels and atopy, asthma, and wheeze
High total IgE (>100 kU/L)Atopy∗Asthma, doctor-diagnosedWheeze, past 12 mo
Serum folate† (ng/mL)Crude ORAdjusted‡ OR (95% CI)Crude ORAdjusted‡ ORCrude ORAdjusted‡ ORCrude ORAdjusted‡ OR
Quintile 1 (0.7-8.1)1.01.01.01.01.01.01.01.0
Quintile 2 (8.2-10.9)0.87 (0.69-1.09)0.94 (0.73-1.21)0.87 (0.72-1.05)0.89 (0.71-1.12)1.03 (0.77-1.39)1.01 (0.76-1.33)0.83 (0.59-1.17)0.81 (0.57-1.15)
Quintile 3 (11.0-13.8)0.82 (0.71-0.94)0.89 (0.77-1.03)0.74 (0.65-0.85)0.76 (0.65-0.88)0.85 (0.66-1.09)0.82 (0.63-1.08)0.82 (0.63-1.06)0.82 (0.64-1.04)
Quintile 4 (13.9-17.9)0.62 (0.48-0.79)0.73 (0.58-0.93)0.72 (0.57-0.92)0.77 (0.59-0.99)0.89 (0.68-1.16)0.83 (0.64-1.07)0.67 (0.48-0.94)0.64 (0.46-0.89)
Quintile 5 (18.0-171.0)0.54 (0.42-0.70)0.70 (0.53-0.92)0.60 (0.49-0.73)0.69 (0.57-0.85)0.84 (0.71-1.01)0.84 (0.70-1.02)0.65 (0.48-0.88)0.60 (0.44-0.82)

Values in boldface are statistically siginificant.

OR, Odds ratio.

∗At least 1 positive specific IgE test result for dust mite, cat, dog, cockroach, or Alternaria species.

†Range of normal serum folate levels: 3 to 26.5 ng/mL.

‡Adjusted for age, sex, race/ethnicity, and poverty index ratio.

An ordinal logistic regression model that accounted for the survey design of the NHANES was constructed to determine whether increasing folate levels were associated with a decreasing number of positive specific IgE test results. The outcome variable was a categorical variable that indicated the number of positive specific IgE test results as follows: 0, 1, 2 to 3, and 4 or more positive allergen-specific IgE results. Sixty-eight percent had none, 9% had 1, 16% had 2 or 3, and 7% had 4 or more positive specific IgE test results. For every 1-unit increase in log10(folate), there was approximately a 50% decrease in the odds of having a greater number of positive specific IgE test results (odds ratio, 0.51 [95% CI, 0.37-0.69]). This marked protective effect of log10(folate) on the number of positive specific IgE test results was also seen between log10(folate) and atopy (odds ratio, 0.27 [95% CI, 0.15-0.47]), whereas the effects of log10(folate) on asthma and wheeze were less strong (see Table E1 in this article's Online Repository at www.jacionline.org).

Higher folate levels were also associated with a lower odds of doctor-diagnosed asthma and wheeze in the previous 12 months in unadjusted analyses (P = .02 and P < .001 for trend, respectively). Higher serum folate levels remained significantly associated with a lower odds of wheeze in the previous 12 months after adjusting for age, sex, race/ethnicity, and poverty index ratio, but the association with doctor-diagnosed asthma was not statistically significant (Table III).

Wheeze was included as a covariate in the final multivariate models to determine whether the effects of serum folate levels on atopy and high total IgE levels were independent of the effect of folate on wheeze (Table IV). In models with high total IgE level or atopy as the outcomes, the addition of wheeze as a covariate did not alter the relationship between serum folate levels and these outcomes because there continued to be a decreasing risk of these outcomes across quintiles of serum folate. Similarly, in the models with wheeze as the outcome, the addition of either high total IgE level or atopy as covariates did not alter the relationship between serum folate levels and wheeze. These findings suggest that the relationships between serum folate level and measures of atopic status (high total IgE level and atopy) are independent of wheeze and vice versa.

Table IV. Multivariate models: Wheeze adjusted for atopy and high IgE level and atopy and high IgE level adjusted for wheeze
Outcome
PredictorsAtopy,∗ OR (95% CI)High IgE∗, (>100 kU/L)Wheeze,∗ OR (95% CI)Wheeze,∗ OR (95% CI)
Folate quintiles† (ng/mL)
Quintile 2 (8.2-10.9)0.89 (0.72-1.09)0.91 (0.71-1.16)0.84 (0.61-1.17)0.84 (0.60-1.17)
Quintile 3 (11.0-13.8)0.75 (0.65-0.86)0.86 (0.75-0.99)0.85 (0.66-1.09)0.83 (0.65-1.07)
Quintile 4 (13.9-17.9)0.76 (0.59-0.98)0.70 (0.64-0.90)0.68 (0.49-0.94)0.69 (0.49-0.97)
Quintile 5 (18.0-171.0)0.68 (0.56-0.84)0.66 (0.50-0.86)0.64 (0.47-0.86)0.64 (0.47-0.87)
Atopy——1.62 (1.28-2.06)—
High IgE level———1.84 (1.50-2.26)
Wheeze1.61 (1.27-2.05)1.84 (1.50-2.26)——

Values in boldface are statistically siginificant.

∗All models are adjusted for age, sex, race/ethnicity, and poverty income ratio.

†Odds ratios (OR) are relative to folate quintile 1.

It is also possible that the effect of serum folate levels on either total IgE levels or atopic status could vary depending on wheezing status or that the effect of serum folate levels on wheezing could vary depending on atopic status. Final multivariate models were stratified by wheezing status, atopic status, and total IgE status, depending on the outcome that was being evaluated, to address these questions. Overall, the risk of the outcomes of interest was lowest at the highest serum folate levels, regardless of atopic, wheezing, or total IgE status, suggesting that neither atopic status nor wheeze modified the relationships between serum folate levels and these outcomes (data not shown).

The effects of age on the relationships between serum folate levels and atopy, high IgE levels, and wheeze were also examined. Across all age groups, higher serum folate levels were associated with a decreased odds of high IgE levels and wheeze, with a trend toward a decreased odds of asthma. Across all age groups, except for those 60 years and older, higher serum folate levels were associated with a decreased odds of atopy. For those 60 years and older, there was no relationship between serum folate levels and atopy (see Tables E1 and E2 in this article's Online Repository at www.jacionline.org).

To determine whether income or race/ethnicity modified the relationship between serum folate levels and our outcomes of interest, we conducted analyses stratified by tertiles of poverty income ratio and by race/ethnicity (Table V). The inverse relationship between serum folate levels and the odds of a high total IgE level, atopy, and wheeze persisted across all tertiles of poverty income ratio, although some of the point estimates lost statistical significance with stratification.

Table V. Relationships between log10(folate) and outcomes stratified by income and race/ethnicity
High IgE level, OR (95% CI)Atopy, OR (95% CI)Wheeze, OR (95% CI)
Poverty income ratio∗
First tertile (0-1.27)0.42 (0.25-0.69)0.55 (0.29-1.06)0.85 (0.31-2.35)
Second tertile (1.28-3.09)0.45 (0.24-0.86)0.42 (0.22-0.79)0.53 (0.24-1.19)
Third tertile (3.10-5.00)0.51 (0.26-0.97)0.54 (0.34-0.88)0.35 (0.17-0.75)
Race/ethnicity
White0.48 (0.29-0.78)0.58 (0.39-0.85)0.33 (0.20-0.54)
Black0.84 (0.53-1.35)0.39 (0.20-0.76)0.83 (0.45-1.54)
Hispanic0.74 (0.35-1.60)1.03 (0.43-2.49)2.87 (0.63-13.12)

All models are adjusted for age and sex.

OR, Odds ratio.

∗Ratio of family income to poverty threshold.

When analyses were stratified by race/ethnicity, the inverse relationships between serum folate and high total IgE levels, atopy, and wheeze were present among non-Hispanic white and black subjects (Table V). The relationships were somewhat stronger among non-Hispanic white than black subjects, but these differences were not statistically significant. Among Hispanic subjects, there was no association between serum folate levels and atopy or wheeze and some suggestion that this group might have a higher risk of wheeze with higher serum folate levels.

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Discussion 

In a representative US population, a higher serum folate level was associated with lower total IgE levels and a lower risk of atopy and wheeze. Although higher serum folate levels have been linked to lower risk of other inflammatory conditions, such as cardiovascular disease35, 36, 37 and rheumatoid arthritis,38 this is the first report, to our knowledge, that links higher serum folate levels to a lower risk of atopy and wheeze. These findings suggest that dietary folic acid and factors affecting its metabolism might play an important role in the development and perpetuation of allergy and asthma.

Two previous epidemiologic studies examined polymorphisms in a folate metabolism gene, methylenetetrahydrofolate reductase (MTHFR), and atopy, asthma, or both. In a cross-sectional population-based Danish study,41 the TT allele of the MTHFR gene, which results in impaired folate metabolism and reduces the intracellular methyl donor pool,42 was associated with a higher prevalence of atopy. By using a dietary questionnaire, that study also indicated that lower intake of dietary factors known to influence methyl donor metabolism (folic acid, methionine, and B vitamins) was associated with a higher risk of atopy in study participants with the TT allele of the MTHFR gene. Findings from this study are consistent conceptually with our study's findings because this study suggests that a lower methyl donor pool, as evidenced by either lower serum folate levels, impaired folate metabolism, or lower dietary intake of cofactors of methyl donor metabolism, is associated with a higher risk of atopy. On the other hand, in a United Kingdom population-based cohort of mothers and children,43 there was no association between MTHFR polymorphisms and atopy or asthma. The reasons for the inconsistent findings of these 2 studies of MTHFR polymorphisms are unclear, but neither study examined relationships between directly measured serum folate levels, which might be a more accurate measure of the methyl donor pool, and asthma or atopy.

Although we examined serum folate levels and not dietary intake of folic acid, greater oral intake of folic acid is associated with higher serum folate levels.33, 44 However, it is important to note that different dietary sources of folic acid affect serum folate levels to varying degrees. For example, supplements appear to have the greatest effect on serum folate levels, followed by enriched ready-to-eat cereals and enriched cereal grain products.44 The lower limit for a normal serum folate level is generally considered to be in the range of 3 to 4.5 ng/mL,33, 45 and approximately 1% of the 2005-2006 NHANES population meets this criterion for a low serum folate level. There is greater debate about the definition of a high serum folate level, although a recent article suggested that a level of greater than 26.5 ng/mL should be considered high.46 In this NHANES population approximately 5% had a serum folate level greater than this threshold value. Thus the findings from our study are relevant for a range of serum folate levels that would be considered normal. Whether future studies provide sufficient data to warrant a revision of the current definition of a normal serum folate level remains to be seen.

We found a lower prevalence of atopy in this NHANES population than reported in the NHANES III.47 Skin testing was performed in the NHANES III, but specific IgE testing was performed in the NHANES 2005-2006. In addition, in the NHANES III the population ranged in age from 20 to 59 years, and in our study the age ranges from 2 to 85 or more years. A combination of a younger study population and use of specific IgE testing on a fewer number of allergens is the most likely explanation for the differences in atopy prevalence between the 2 study populations.

In direct contrast to the 2 epidemiologic studies, a recently published study using a mouse model found that a diet enriched for methyl donors, including folic acid, was a risk factor, rather than a protective factor, for allergy and asthma.30 This positive association between higher dietary folate intake and enhanced allergic immune and inflammatory responses was thought to be mediated by epigenetic modification that was inherited transgenerationally because animals exposed in utero to increased methyl donors, as well as their progeny who were provided normal feed, exhibited increased severity of allergic airway disease. There are several possible explanations for the differences between this mouse study and the epidemiologic studies aside from the obvious differences between mice and human subjects. In this study mice were fed a cocktail of methyl donors and cofactors, including vitamin B12, choline, L-methionine, zinc, and betaine, in addition to folic acid. It is also not clear how this methyl donor–enriched diet affected serum folate levels, and therefore it is possible that the diet resulted in supraphysiologic levels that would rarely, if ever, be observed in human populations. Although our study's findings suggest that low levels of folate might be a risk factor for allergic disease, the mouse study might indicate that very high levels of methyl donors, such as folate, could also be a risk factor for allergic disease and that optimal levels of folate (or methyl donors) fall somewhere in between.

In contrast to gestational exposure, the mice that were provided high methyl donor diets during lactation or early adulthood did not demonstrate a similar increase in disease severity, suggesting that the timing of methyl donor supplementation might play a pivotal role in determining its effect on the development of allergic disease. Because the NHANES is a cross-sectional survey, our study does not address this question of the effect of in utero or early postnatal serum folate levels on the development of allergic sensitization and disease. Rather, the serum folate levels in our study reflect current serum folate levels, which are likely the end result of a combination of current or recent dietary folic acid intake and underlying polymorphisms in genes that are involved in folate metabolism.

Although our study does not address the effects of in utero folate exposure on asthma and atopy, one recent prospective birth cohort study examined the effect of in utero exposure to folic acid supplementation on the risk of respiratory outcomes in the first 18 months of life.48 The investigators found a very small increase in the risk of lower respiratory tract infection and wheeze associated with folic acid supplementation in the first trimester only, and atopic outcomes were not evaluated. More prospective studies are clearly needed, and current birth cohort studies are well positioned to evaluate the effect of in utero or very early life serum folate levels on subsequent risk of allergic sensitization and disease.

A number of epidemiologic studies have described an inverse relationship between folate levels and inflammatory states,36, 37 which is in keeping with our study's findings. Although evidence exists that folic acid supplementation might change serum cytokine levels through nonepigenetic mechanisms,49 changes in DNA methylation have been associated with immune modulation, including the aforementioned mouse study. The precise role of epigenetics in asthma and atopy are poorly understood, but recent studies suggest potential effects on both immunity50, 51, 52, 53 and inflammation.54, 55 In fact, we also found that the relationship between serum folate levels and measures of atopy were independent of wheeze and vice versa. These findings suggest that serum folate levels might indeed have dual and independent functions, potentially reducing the risk of atopy through immunomodulation and also potentially reducing the risk of wheeze through modulation of inflammation.

This study also confirmed previous observations of an association between non-Hispanic black or Hispanic race/ethnicity and lower serum folate levels.33 We also found that the relationships between serum folate levels and the risk of high total IgE levels, atopy, and wheeze were similar across all income levels and among non-Hispanic white and black subjects, suggesting that low serum folate levels might contribute to risk of high total IgE levels, atopy, and wheeze in black and non-Hispanic white populations of all income levels. However, relationships between folate and these outcomes among the Hispanic population are less clear, with folate having little effect on the risk of atopy and wheeze, perhaps even increasing the risk of wheeze in this racial/ethnic group. The reasons behind these differences across racial/ethnic groups are unclear and could be related to dietary, sociocultural, or genetic factors.

Although the inverse association between serum folate levels and atopy and wheeze in this NHANES population is intriguing, the cross-sectional study design limits our ability to conclude that there is a causal relationship between serum folate levels and atopy and wheeze. Because the temporal relationships between serum folate levels and the development of atopy or wheeze are unknown, it is not clear whether high serum folate levels might protect against the development of allergic sensitization or increased total IgE levels, protect against wheeze, or both in a previously sensitized individual. Additional prospective studies will be required to lend insight to the potential role of folic acid supplementation in the primary prevention, treatment, or both of allergic diseases. Ultimately, clinical trials will be needed to draw any firm conclusions about the preventive or therapeutic potential for folic acid in allergic diseases because folic acid supplementation in patients with cardiovascular disease might be related to worse outcomes in some cases.56

In summary, higher serum folate levels are associated with lower total IgE levels and a lower risk of allergic sensitization and wheeze. Future studies are needed to define the temporal relationships among serum folate levels and allergy and asthma and to determine whether these associations, if causal, are mediated by epigenetic changes or by other mechanisms.

Clinical implications

Folic acid status might influence the development and/or the progression of atopy and wheeze.

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Table E1. 

Multivariate models including an interaction term (folate∗age)
Outcome
High IgE levelAtopyWheezeAsthma
log10(folate)0.71 (0.36-1.43)0.27 (0.15-0.47)0.85 (0.40-1.81)0.65 (0.40-1.08)
Age (y)1.01 (0.99-1.02)0.97 (0.96-0.98)1.02 (1.00-1.04)0.99 (0.97-1.01)
log10(folate)∗age0.99 (0.98-1.01)1.02 (1.01-1.03)∗0.99 (0.97-1.01)1.00 (0.99-1.02)

All models are adjusted for sex, race/ethnicity, and poverty.

∗See Table E2, which shows models for atopy as the outcome stratified by age category.

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Table E2. 

Relationship between log10(folate) and atopy stratified by age
Age category (y)OR (95% CI)
<120.71 (0.41-1.25)
12-200.67 (0.29-1.52)
21-390.57 (0.26-1.24)
40-590.81 (0.44-1.50)
≥601.12 (0.55-2.31)

All models are adjusted for sex, race/ethnicity, and poverty.

OR, Odds ratio.

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References 

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 Supported by grants from the National Institute of Allergy and Infectious Diseases (R01AI070630) and the National Institutes of Environmental Health Sciences (DISCOVER Award 5P50ES015903).

 Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

PII: S0091-6749(09)00387-X

doi:10.1016/j.jaci.2009.03.007

The Journal of Allergy and Clinical Immunology
Volume 123, Issue 6 , Pages 1253-1259.e2, June 2009

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