Asthma, eczema and other allergic disorders are common among children in industrialized countries, and their frequency is increasing. Changes in diet provide one possible explanation for this increase, but the results of dietary intervention trials in older children have been disappointing, and it has been suggested that diet during pregnancy and infancy may be critical to the development of atopy(1). In particular it has been suggested that the age of introduction of solids, duration of breastfeeding, and the balance of n-3/n-6 PUFAs in the pregnancy and infant diet may be important. Traditionally, the advice given on feeding infants at high risk of atopy is that to minimize risk they should be breastfed for at least six months, and that solid foods should be avoided for at least 4-6 months, with possible further delays in the introduction of particularly allergenic foods such as egg and peanuts(2-4). However, the efficacy of all aspects of this advice is questionable. There are a number of mechanisms by which early diet could be associated with the development of atopy. There could be a causal relationship, whereby early introduction of solid foods either induces an allergic response, or alternatively induces immune tolerance and so reduces the risk of allergy/atopy. It is possible that atopic parents, or parents noticing early symptoms of allergy in their child might delay the introduction of solids, generating a spurious association between the early introduction of solids and allergy/atopy (reverse causation). It is also possible that prolonged breastfeeding or delayed introduction of solids might increase the rates of allergy/atopy by affecting the development of mature immune response mechanisms in the infant - either by a direct reduction in exposure to immune stimulants such as bacteria, or in the case of breastfeeding by passive transfer or immune responses from the mother (hygiene hypothesis). There are relatively few studies of the associations of early diet with eczema and asthma and the results are very variable. Some studies have found early introduction of solids to be associated with wheezing and eczema, others have found no association, and some have found later introduction of particular solids to increase the risk of eczema and food sensitization (5,6).

One possible reason for the variability in the results of these studies is interaction of these dietary factors with the child's genotype. Loss of function mutations in the filaggrin gene have been shown to confer a greatly increased susceptibility to eczema, eczema plus asthma, and allergic sensitisation(7). This genotype has been shown to interact with environmental factors, with exposure to cats only being a risk factor for infant eczema among FLG deficient infants(8) Filaggrin has been detected in both human oral cavity and pharynx and rodent gut (9), and indeed the gut has been characterised as a key site for peanut absorption and sensitisation (10). However, as far as we are aware there is no data on how filaggrin genotype might interact with early dietary factors to determine the risk of allergic and atopic disorders.

Atopic sensitisation and inflammation are related to plasma levels of the 2-series prostaglandins and 4-series leukotrienes, which are derived from arachidonic acid(9). Common polymorphisms in the fatty acid delta-5 delta-6 desaturase gene cluster FADS1 and FADS2 have been linked with both altered plasma levels of arachidonic acid and clinical symptoms of adult atopy(10). There is no data on how FADS genotype is associated with the risk of wheeze and eczema in children and infants, nor on how this genotype may interact with early dietary factors such as PUFA intake.

Proposed project:

We propose to investigate the relationship between early dietary factors and atopic outcomes in the ALSPAC cohort, considering possible interactions with filaggrin and FADS genotype. Statistical analyses will take account of the possibility of reverse causation.

Data requested

1. Outcome variables:

Wheeze in the first 3 years of life (assessed by questionnaire at 6m, 18m, 30m and 42m)

Wheeze at 7 1/2 years of life (self-reported)

Questionnaire data on doctor-diagnosed asthma at 7 years

Lung function by BHR at 8 years (clinic assessment)

Results of skin prick tests at 7 years (clinic assessment)

Eczema assessed by questionnaire at 6, 18, 39, 42, 57 and 81 months of age.

Flexural dermatitis assessed by observation annually from 7y to 11y (clinic assessment).

2. Infant dietary predictor variables (all assessed by questionnaire at 6m and 15m):

Duration of breastfeeding

Age of introduction of formula milk.

Age of introduction of any solids.

Number of solids introduced at 4m and 6m.

Age of first introduction of egg, fish, meat, fruit, vegetables

Pregnancy dietary predictor variables (assessed by FFQ at 32 wks gestation):

PUFA intake in pregnancy

fish intake in pregnancy

3. Other predictor variables:

Fillagrin genotype

FADS genotype

4. Confounding variables:

Maternal education (assessed by questionnaire at 32 wks gestation)

Maternal age (assessed by questionnaire)

Smoking in pregnancy (assessed by quesitionnaire at 32 wks gestation)

Maternal parity (assessed by questionnaire)

Pet exposure (assessed by questionnaire)

Gestation (assessed by questionnaire)

Sex

ETS in first four years (assessed by questionnaire)

Crowding (assessed by questionnaire)

Child's BMI

Parental atopy (assessed by questionnaire)

References

1. Devereux G. The increase in the prevalence of asthma and allergy: food for thought. Nature Reviews Immunology 2006;6:869-874.

2. Pediatric Nutrition Handbook. 2004 Elk Grove, IL: American Academy of Pediatrics.

3. World Health Organisation. Fifty-Fourth World Health Assembly. WHA54.2 Agenda Item 13.1. Infant and Young Child Nutrition. 2004. Geneva, Switzerland: World Health Organization.

4. Murano A et al. Dietary prevention of allergic diseases in infants and small children: part III - critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatric Allergy and Immunology, 2004;15:291-307.

5. Tarini B et al. Systematic review of the relationship between early introduction of solid foods to infants and the development of allergic disease. Archives of Pediatric and Adolescent Medicine 2006;160:502-507.

6. Zutavern A. et al. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitisation at the age of 6 years. Results from prospective birth cohort study LISA. Pediatrics 2008;121:e44-e52.

7. Henderson J et al. The burden of disease associated with filaggrin mutations: A population-based longitudinal birth cohort study. Journal of Allergy and Clinical Immunology 2008 (In Press).

8. Bisgaard H et al. Gene-environment interaction in the onset of eczema in infancy: Filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PloS Med 2007;5:e131.

9. Makino T et al. Expression of hornerin in stratified squamous epithelium in the mouse: a comparative analysis with profilaggrin. J Histochem Cytochem 2003;51:485-492.

10. Anonymouse. Absorption of peanuts. N Engl J Med 1981;304:359-360.

11. Behrendt H et al. Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergen sensitization. Int Arch Allergy Immunol 2001;124:121-125.

12. Schaeffer L et al. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids. Human Mol Gen 2006;15:1745-1756.