Childhood lung function and the association with ß2-adrenergic receptor haplotypes.

AIM: To determine associations between ADRB2 polymorphisms and lung function through childhood, and possible modification by gender, pet keeping or tobacco smoke. METHODS: Four ADRB2 single nucleotide polymorphisms (rs1042711, rs1042713, rs1042714 and rs1800888) were genotyped in 953 children from the prospective birth cohort 'Environment and Childhood Asthma' study and analysed for association with flow-volume parameters at birth (tidal breathing) and at 10 years of age (maximally forced), stratified by environmental exposures. RESULTS: The risk of reduced lung function was reduced in 10-year-old children carrying the most common ADRB2 haplotype (CGGC) (OR 0.45 (95% CI 0.25, 0.82)), whereas there was no association between lung function at birth and ADRB2 haplotypes. Tobacco smoke exposure, gender and pet keeping did not significantly interact with the haplotypes in influencing lung function. CONCLUSION: This study demonstrates a possible protective effect by the ADRB2 haplotype I (CGGC) on reduced FEV1 in 10-year-old children, whereas no ADRB2 geno-/haplotypes were significantly associated with neonatal lung function. The ADRB2 gene thus appears to contribute to lung function development in childhood, independently of smoking, pets and gender.

Pet keeping and tobacco exposure influence CD14 methylation in childhood.

BACKGROUND: Several CD14 gene-environment interactions in relation to the development of allergic diseases have been reported, but the underlying biological mechanisms are unclear. We recently showed that CD14 methylation increased during childhood, parallelling a decreased impact of CD14 polymorphisms on soluble CD14 levels. Here, we aim to explore whether environmental stimuli during childhood affects CD14 methylation, thereby providing a biological mechanism through which environment may modulate genetic effect. METHODS: CD14 methylation levels were quantified in 157 children from the prospective Environment and Childhood Asthma birth cohort at ages 2 and 10. Associations between CD14 methylation levels and house dust levels of endotoxin, ß(1,3)-glucans (at 2 yr only), allergens (dog, cat, and house dust mite), pet keeping and tobacco smoke exposure (TSE; questionnaire data) at 2 and 10 yr were explored. RESULTS: Children in homes without pets had larger increases in CD14 methylation through childhood (2-10 yr) compared with children with pets (2.1% increase (p = 0.003) vs. 0.4% decrease (n.s.), global p = 0.04). At 10 yr of age, lower CD14 methylation values were found in children with pets compared with children without pets at both 2 and 10 yr (5.4% vs. 7.5% [p = 0.02]). A similar trend was detected for TSE; children not exposed show larger increases in CD14 methylation, most pronounced in school-age girls exposed vs. not exposed to tobacco (5.5% vs. 7.5% methylation, p = 0.037). CONCLUSION: Pet keeping and TSE appears to limit increase in CD14 methylation from 2 to 10 yr of age. This may partly explain the diverging CD14 allele associations with allergic diseases detected in different environments.

Alpha-nicotinic acetylcholine receptor and tobacco smoke exposure: effects on bronchial hyperresponsiveness in children.

BACKGROUND: The CHRNA 3 and 5 genes on chromosome 15 encode the alpha subunits of the nicotinic acetylcholine receptor, mediating airway cholinergic activity. Polymorphisms are associated with cigarette smoking, chronic obstructive pulmonary disease, and lung cancer. AIMS: To determine possible associations between CHRNA 3/5 SNP rs8034191 and asthma or lung function in children in one local and one replicate multinational population, and assess if tobacco smoke modified the associations. MATERIALS AND METHODS: The rs8034191 SNP genotyped in 551 children from the environment and childhood asthma (ECA) birth cohort study in Oslo, Norway, and in 516 families from six European centers [the Genetics of Asthma International Network (GAIN) study] was tested for genotypic or allelic associations to current or history of asthma, allergic sensitization (≥ one positive skin prick tests), bronchial hyperresponsiveness (BHR), and lung function (FEV(1%) of predicted and FEV(1) /FVC ratio over/ below the 5th percentile). RESULTS: Although the TT and CT genotypes at SNP rs 8034191 were overall significantly associated with BHR (OR = 3.9, 95% CI 1.5-10.0, p = 0.005), stratified analyses according to exposure to maternal smoking in-utero or indoor smoking at 10 yrs of age showed significant association (OR = 4.4, 95% CI 1.5-12.6, p = 0.006 and OR 5.6, 95% CI 1.7-18.5, p = 0.004, respectively) only in the non-exposed and not in exposed children. The SNP-BHR association was replicated in the non-tobacco-smoke-exposed subjects in one of the GAIN centers (BHR associated with the T allele (p = 0.034)), but not in the collated GAIN populations. Asthma, allergic sensitization, and lung function were not associated with the rs8034191 alleles. CONCLUSION: An interaction between tobacco smoke exposure and a CHRNA3/5 polymorphism was found for BHR in children, but CHRNA3/5 was not associated with asthma or lung function.

CD14 polymorphisms and serum CD14 levels through childhood: a role for gene methylation?

BACKGROUND: CD14 is a pattern-recognition receptor for environmental LPS, and engagement of the CD14-LPS complex activates innate host defense mechanisms. Single nucleotide polymorphisms (SNPs) in the CD14 gene have been associated with soluble CD14 (sCD14) levels, but inconsistencies between studies suggest the presence of regulatory mechanisms hitherto not well understood. OBJECTIVE: We sought to investigate possible associations between CD14 SNPs and sCD14 levels at different time points in childhood (at birth [cord blood] and 2 and 10 years) and to explore whether these associations were related to CD14 gene methylation. METHODS: Four SNPs, rs2569191 (-1145GA), rs5744455 (-550CT or -651CT), rs2569190 (-159CT or -260CT), and rs4914 in CD14 were genotyped in 762 children from the Environmental and Childhood Asthma study. Genotype frequencies were analyzed for association with sCD14 levels in 660 babies, 346 children at age 2 years, and 360 children at age 10 years. In a subgroup of 157 children with DNA available at both 2 and 10 years of age, CD14 methylation patterns were determined and analyzed against detected CD14 gene-sCD14 associations. RESULTS: rs2569191, rs5744455, and rs2569190 were associated with sCD14 levels at birth and 2 years, but only rs5744455 was associated with sCD14 levels at 10 years. CD14 methylation increased significantly from age 2 to 10 years, and the level of methylation was inversely correlated with sCD14 levels at 10 years. CONCLUSION: The reduced effect of CD14 polymorphisms on sCD14 levels from early to late childhood paralleled a small but significant increase in CD14 methylation during the same period.

Advanced glycation end products in pregnancies complicated with diabetes mellitus or preeclampsia.

OBJECTIVE: Preeclampsia (PE) and diabetes mellitus (DM) are associated with oxidative stress. DM is complicated with formation of advanced glycation end products (AGEs), which are associated with oxidative stress. We hypothesized that elevated serum AGE would be found in pregnancies complicated by PE or DM. METHODS: Circulating AGEs, 8-isoprostane, vitamin E, and antioxidant capacity were analyzed from study patients. RESULTS: Serum AGE was elevated both in patients with type 1 DM and gestational DM, but not in PE, compared with controls. 8-isoprostane was elevated in patients with type 1 DM and PE compared with controls. CONCLUSION: AGEs and 8-isoprostane are not elevated in parallel in pregnancies complicated with PE or DM, suggesting biological heterogeneity.