Carel Thijs

IL13 , CD14, pet and tobacco smoke influence atopy in 3 Dutch cohorts; The Allergenic study

Studying gene–environment interactions may elucidate the complex origins of atopic diseases but requires large study populations. Pooling data from several cohort studies may help but may also obscure findings. Gene–environment interactions in atopy development were studied and the benefits of pooling data were evaluated. Haplotype-tagging polymorphisms in the genes interleukin (IL)13 and CD14 were genotyped in 3,062 children from the following birth cohorts: the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study; the Prevention of Asthma in Children (PREVASC) study; and the Child, Parent, Health, Focus on Lifestyle and Predisposition (KOALA) study, and tested for association with total and specific immunoglobulin (Ig)E and interaction with tobacco smoke and pet exposure at ages 1, 2, 4 and 8u2005yrs by analysis of variance, Chi-squared tests and regression analyses. At all ages, in IL13, minor alleles of rs1295685 and rs20541 were significantly associated with elevated IgE levels in pooled analyses. In CD14, the rs2569190-TT and rs2569191-CC genotypes associated with lower IgE and decreased risk of sensitisation at 4 and 8u2005yrs in children exposed to pets, with an opposite effect in nonexposed children. Findings for IL13 and CD14 were comparable in separate cohorts. The present study indicates that atopy is importantly influenced by interleukin 13 at age 1–8u2005yrs and by CD14 in interaction with pet exposure at ages 4 and 8u2005yrs. Additionally, pooled data improved effect estimates and genetic effects could be detected in interaction with important environmental factors.

Essential fatty acids in breast milk of atopic mothers : comparison with non-atopic mothers, and effect of borage oil supplementation

Objective: To evaluate whether levels of n-6 long chain polyunsaturated fatty acids (LCPs) in human breast milk are related to the mother’s atopic constitution, and whether a decreased level can be restored by gamma-linolenic acid supplementation.Design: Cross-sectional study and dietary supplementation trial.Subjects: 20 atopic mothers and 20 non-atopic mothers (controls), all lactating.Setting: General population.Interventions: The atopic mothers were randomly assigned to low (n=10) or high (n=10) dosage oral supplementation with oral borage oil for one week (230 or 460u2005mg gamma-linolenic acid (18:3n-6) per day).Main outcome measures: Essential fatty acid composition of the breast milk total fat fraction, determined by gas liquid chromatography.Results: Arachidonic acid (20:4n-6) was lower in breast milk of atopic mothers compared with non-atopic mothers (0.39u2005wt% vs 0.46u2005wt%, difference −0.07%u2005wt% (95% confidence limits −0.13, −0.01u2005wt%; P<0.05). The ratio between linoleic acid and the sum of n-6 derivatives did not differ between these groups, indicating no difference in delta-6-desaturase (D6D) activity. Supplementation of the atopic mothers significantly increased the levels of gamma-linolenic acid and dihomo-gamma-linolenic acid in breast milk in a dose-related way, but the level of arachidonic acid was not increased.Conclusion: We found a decreased level of arachidonic acid in breast milk in atopic compared to non-atopic mothers, but no indication that the rate-limiting enzymatic step (D6D) is involved. Supplementation increased the precursor pool but did not restore the level of arachidonic acid. We conclude that atopy is related to a metabolic disturbance beyond the D6D enzymatic step. A low level of arachidonic acid in breast milk may be a risk factor for the development of atopy in the infant, especially when the possible underlying metabolic disturbance of EFA metabolism is inherited by the child.Sponsorship: F Hoffman-La Roche (Basel, Switzerland) and Friesland Dairy Foods (Leeuwarden, The Netherlands).European Journal of Clinical Nutrition (2000) 54, 234–238

Diphtheria, Pertussis, Poliomyelitis, Tetanus, and Haemophilus influenzae Type b Vaccinations and Risk of Eczema and Recurrent Wheeze in the First Year of Life: The KOALA Birth Cohort Study

OBJECTIVES. Among potential etiologic factors for atopic manifestations, infant vaccinations have recently been discussed. We evaluated in a prospective design whether infants who were unvaccinated or vaccinated according to incomplete vaccination schedules in the first 6 months of age were at decreased risk for eczema and recurrent wheeze in the first year of life. METHODS. Information on vaccinations against diphtheria, pertussis, poliomyelitis, tetanus; Haemophilus influenzae type b vaccine; and eczema and recurrent wheeze was collected by repeated questionnaires in 2764 families participating in the KOALA Birth Cohort Study in the Netherlands. A standard vaccination schedule referred to 3 diphtheria, pertussis, poliomyelitis, tetanus, and Haemophilus influenzae type b vaccinations in the first 6 months with the first given in months 1 to 3; an incomplete vaccination schedule was defined as any other vaccination schedule. Exclusion criteria were prematurity (gestational age <37 weeks) and congenital abnormalities related to immunity (such as Down syndrome). Multiple logistic regression models were fitted to adjust for confounding factors. RESULTS. During the first year of life, the incidence of eczema was 23% (584 of 2537 infants) and of recurrent wheeze, the incidence was 8.5% (203 of 2402 infants). At age 6 months, 1969 (77%) of 2545 infants had been vaccinated according to a standard schedule, 393 (15%) vaccinated according to an incomplete schedule, and 182 (7%) never vaccinated. Compared with infants with standard vaccination schedules, infants with incomplete schedules did not differ significantly in eczema risk or recurrent wheeze. This was also true for infants who had never been vaccinated. CONCLUSION. This study shows that the risk of eczema or recurrent wheeze at 1 year of age does not differ between infants with different vaccination status at the age of 6 months.

Interaction of T-cell and antigen presenting cell co-stimulatory genes in childhood IgE

It is likely that multiple genes contribute to immunoglobulin (Ig)E production. Co-stimulatory molecules are crucial for the cross-talk between antigen presenting cells and T-lymphocytes which drives the IgE response. We evaluated gene–gene interactions of haplotype tagging polymorphisms in a pathway of 24 co-stimulatory genes in relation to serum IgE levels. We assessed this at ages 1–2u2005yrs and 6–8u2005yrs in 3,062 Dutch children from a pooled data set of three birth cohorts: PIAMA (Prevention and Incidence Asthma and Mite Allergy), PREVASC (Prevention of Asthma in Children) and KOALA (Child, parents and health: lifestyle and genetic constitution). Single- and multi-locus associations with serum IgE levels (3rd versus 1st tertile) were evaluated by Chi-squared tests and the multifactor dimensionality reduction (MDR) method in the following co-stimulatory genes: VTCN1, TNFRSF4, TNFRSF18, TNFRSF14, TNFSF18, TNFSF4, CD28, CTLA4, ICOS, PDCD1, BTLA, CD80, CD86, HLA-G, CD274, PDCD1LG2, CD276, LILRA4, LILRB1, LILRB2, LILRB4, CD40, ICOSLG, and CD40LG. We found multiple statistically significant single-locus (S) and multi-locus (M) associations for the genes VTCN1SM, TNFSF18SM, TNFSF4S, CD28S, CTLA4M, ICOSS, BTLAM, CD80M, CD86SM, CD274SM, PDCD1LG2M, LILRA4SM, LILRB4M, and CD40SM with serum IgE. Two-locus interactions of CD86 with VTCN1 and CD274 with LILRA4 were confirmed by logistic regression. In conclusion, serum IgE levels are regulated by multiple gene–gene interaction effects in the co-stimulatory pathway. We suggest using research strategies that model multiple gene–gene interactions in genetic studies.