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Christian Bieli,
Waltraud Eder,
Remo Frei,
Charlotte Braun-Fahrländer, Walt Klimecki,
Marco Waser,
Josef Riedler,
Erika von Mutius,
Annika Scheynius,
Göran Pershagen,
Gert Doekes,
Roger Lauener,
Fernando D Martinez
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ABSTRACT: Consumption of farm milk in early life is associated with less asthma and allergies.
We hypothesized that genetic variation in the innate immunity receptor CD14 might modify the association between farm milk consumption and asthma and atopy.
Questionnaire data, serum IgE levels, and genotypes for 4 single nucleotide polymorphisms in CD14 were assessed in farmers' and nonfarmers' children from 2 European populations (Allergy and Endotoxin study, n = 576; Prevention of Allergy Risk factors for Sensitization in children related to Farming and Anthroposophic Lifestyle study, n = 1539). In a subsample (n = 222) CD14 gene expression was measured in peripheral blood leukocytes. The effects of farm milk and CD14 genotypes on asthma, allergies, and CD14 expression and their interactions were investigated.
We found a significant interaction between genetic variation in CD14/-1721 and farm milk consumption. Adjusted odds ratios for the association between farm milk and asthma varied between the genotypes: AA, 0.18 (95% CI, 0.07-0.47); AG, 0.47 (95% CI, 0.26-0.86); and GG, 0.98 (95% CI, 0.46-2.08). Similar patterns were observed for symptoms of allergic rhinoconjunctivitis and pollen sensitization. CD14/-1721 also modified the association between farm milk and CD14 gene expression (adjusted geometric means ratios: AA, 1.61 (95% CI, 0.98-2.66); AG, 1.11 (95% CI, 0.71-1.72); and GG, 0.76 (95% CI, 0.39-1.48).
The protective effect of farm milk consumption on allergic diseases is stronger in children carrying the A allele in CD14/-1721 than in children homozygous for the G allele. This might be mediated through farm milk-induced upregulated CD14 gene expression.
Our results support the hypothesis that the inverse association between farm milk consumption and allergic diseases is mediated by CD14-activated innate immune mechanisms.
The Journal of allergy and clinical immunology 01/2008; 120(6):1308-15. · 9.17 Impact Factor
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ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) is involved in intracellular folate homeostasis and metabolism. We assessed 2 polymorphisms in the MTHFR gene (C677T and A1298C) in relation to colorectal adenoma recurrence and conducted analyses to investigate their joint effects with plasma and dietary markers of folate status.
We prospectively analyzed data from 1598 individuals genotyped for the C677T polymorphism and 1583 with data on A1298C.
Among nonusers of multivitamin supplements, compared with wild-type carriage, higher odds of recurrence were observed for those with the 677 TT variant (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.04-2.63) and a nonsignificant increase was observed among those with the 1298 CC variant (OR, 1.50; 95% CI, 0.93-2.40). Diplotype analyses among nonusers of multivitamins showed that individuals who carry the MTHFR 677TT_1298AA or 677CC_1298CC combination were significantly more likely to have a recurrence compared with those with the double wild-type (OR, 2.05 for TT_AA and 1.85 for CC_CC). Higher odds of recurrence were observed among participants with low folate intake or plasma folate and the 677 TT or 1298 CC variants compared with those with lower levels and the wild-type or heterozygous genotypes. Stronger associations were shown for the combination of high homocysteine and the 677 TT variant (OR, 2.29; 95% CI, 1.00-5.26) but not the 1298 CC variant (OR, 1.09; 95% CI, 0.39-3.01).
We propose that the effect of the MTHFR genotypes on increasing risk of adenoma recurrence in the presence of a low folate status is through their increase in homocysteine concentrations, which in turn could result in DNA hypomethylation via pathways involving S-adenosylhomocysteine.
Gastroenterology 12/2006; 131(6):1706-16. · 11.68 Impact Factor
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ABSTRACT: Most complex diseases are the result of interactions between polymorphisms in the genome and environmental exposures.
We sought to investigate the previously reported association between a polymorphism in the promoter region of CD 14 (CD 14/-260 C-->T) and serum IgE levels in relation to the environment to which children are exposed.
In 624 children living in 2 rural communities in Europe, we compared total and specific serum IgE levels between the genotypes of CD 14/-260 in relation to exposure to animals and in relation to house dust endotoxin.
We found that the C allele of CD 14/-260 was associated with higher levels of both total and specific serum IgE to aeroallergens in children with regular contact with pets, whereas an association in the opposite direction was found in children with regular contact with stable animals. This modifying effect of animal exposure was not explained by levels of house dust endotoxin. However, in children with high levels of house dust endotoxin, the C allele was associated with less specific IgE, independently from animal exposure.
Because CD 14 is a pattern recognition receptor for microbial molecules, the results suggest that the type and concentrations of such molecules present in the environment strongly determine the direction of the association between CD 14/-260 and serum markers of atopy.
Journal of Allergy and Clinical Immunology 10/2005; 116(3):601-7. · 11.00 Impact Factor
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ABSTRACT: The finding that the prevalence of asthma and allergies is less frequent in children raised on animal farms has led to the conjecture that exposure to microbial products modifies immune responses. The toll-like receptors (TLRs) represent an evolutionarily conserved family of innate immunity receptors with microbial molecules as ligands.
We reasoned that polymorphisms in genes encoding TLRs might modulate the protective effects observed in farming populations.
Farmers' and nonfarmers' children living in rural areas in Austria and Germany and who were enrolled in the cross-sectional ALEX study were genotyped for single nucleotide polymorphisms in the TLR2 and TLR4 genes. The frequencies of asthma, allergic rhinitis, and atopic sensitization were compared between the genotypes in relation to exposure to farming and endotoxin.
Among farmers' children, those carrying a T allele in TLR2/-16934 compared with children with genotype AA were significantly less likely to have a diagnosis of asthma (3% vs 13%, P = .012), current asthma symptoms (3% vs 16%, P = .004), atopic sensitization (14% vs 27%, P = .023), and current hay fever symptoms (3% vs 14%, P = .01). The association between TLR2/-16934 and asthma among children of farmers was independent of atopy. No such association was found among children from the same rural communities but not living on farms.
Our results suggest that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies in children of farmers.
Journal of Allergy and Clinical Immunology 04/2004; 113(3):482-8. · 11.00 Impact Factor
