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1.  IL10 Gene Polymorphisms Are Associated With Asthma Phenotypes in Children 
Genetic epidemiology  2004;26(2):155-165.
IL10 is an anti-inflammatory cytokine that has been found to have lower production in macrophages and mononuclear cells from asthmatics. Since reduced IL10 levels may influence the severity of asthma phenotypes, we examined IL10 single-nucleotide polymorphisms (SNPs) for association with asthma severity and allergy phenotypes as quantitative traits. Utilizing DNA samples from 518 Caucasian asthmatic children from the Childhood Asthma Management Program (CAMP) and their parents, we genotyped six IL10 SNPs: 3 in the promoter, 2 in introns, and one in the 3′ UTR. Using family-based association tests, each SNP was tested for association with asthma and allergy phenotypes individually. Population-based association analysis was performed with each SNP locus, the promoter haplotypes and the 6-loci haplotypes. The 3′ UTR SNP was significantly associated with FEV1 as a percent of predicted (FEV1PP) (P=0.0002) in both the family and population analyses. The promoter haplotype GCC was positively associated with IgE levels and FEV1PP (P=0.007 and 0.012, respectively). The promoter haplotype ATA was negatively associated with lnPC20 and FEV1PP (P=0.008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children.
PMCID: PMC3705717  PMID: 14748015
interleukin 10 (IL10); single nucleotide polymorphism (SNP); genetic association; family-based association test (FBAT); haplotype; promoter; 3′; untranslated region (3′UTR)
2.  Perinatal Predictors of Atopic Dermatitis Occurring in the First Six Months of Life 
Pediatrics  2004;113(3 Pt 1):468-474.
Previous studies of predictors of atopic dermatitis have had limited sample size, small numbers of variables, or retrospective data collection. The purpose of this prospective study was to investigate several perinatal predictors of atopic dermatitis occurring in the first 6 months of life.
We report findings from 1005 mothers and their infants participating in Project Viva, a US cohort study of pregnant women and their offspring. The main outcome measure was maternal report of a provider’s diagnosis of eczema or atopic dermatitis in the first 6 months of life. We used multiple logistic regression models to assess the associations between several simultaneous predictors and incidence of atopic dermatitis.
Cumulative incidence of atopic dermatitis in the first 6 months of life was 17.1%. Compared with infants born to white mothers, the adjusted odds ratio (OR) for risk of atopic dermatitis among infants born to black mothers was 2.41 (95% confidence interval [CI]: 1.47, 3.94) and was 2.58 among infants born to Asian mothers (95% CI: 1.27, 5.24). Male infants had an OR of 1.76 (95% CI: 1.24, 2.51). Increased gestational age at birth was a predictor (OR: 1.14; 95% CI: 1.02, 1.27, for each 1-week increment), but birth weight for gestational age was not. Infants born to mothers with a history of eczema had an OR of 2.67 (95% CI: 1.74, 4.10); paternal history of eczema also was predictive, although maternal atopic history was more predictive than paternal history. Several other perinatal, social, feeding, and environmental variables were not related to risk of atopic dermatitis.
Black and Asian race/ethnicity, male gender, higher gestational age at birth, and family history of atopy, particularly maternal history of eczema, were associated with increased risk of atopic dermatitis in the first 6 months of life. These findings suggest that genetic and pre- and perinatal influences are important in the early presentation of this condition. Pediatrics
PMCID: PMC1488729  PMID: 14993536
atopic dermatitis; eczema; perinatal; infancy; gestational age; race/ethnicity; gender; BMI, body mass index; OR, odds ratio; CI, confidence interval; IgE, immunoglobulin E
3.  Nuclear Factor Kappa B Activation in Human Cord Blood Mononuclear Cells 
Pediatric research  2004;56(2):212-218.
The immunologic signals participating in immune responses early in life have not been completely elucidated. Regarding the characterization of neonatal cells, little is known concerning the activity of transcription factor nuclear factor kappa B (NF-κB), which regulates inflammatory genes and cytokine production. The aim of this study was to characterize NF-κB activation in cord blood mononuclear cells (CBMC). We analyzed the potential association of NF-κB activity with lymphocyte proliferation and influences on cytokine secretion in the early immune system. To determine the contribution of a disease whereby inheritance may impact neonatal immunity, we assessed the influence of maternal allergic disease on NF-κB regulation and cytokine secretion. CBMC from healthy newborns were isolated and stimulated with mitogen (n = 28). Nuclear extracts were analyzed by electrophoretic mobility shift assay, cytokine secretion by ELISA. FISH analysis excluded relevant maternal contamination of CBMC. All samples showed a positive lymphoproliferative response, and NF-κB activity was both increased and decreased after mitogen stimulation. Increased NF-κB activation was significantly associated with decreased TNF-α secretion (median 6.1 versus 50.3 pg/mL) in unstimulated CBMC. Mitogen stimulation resulted in increased NF-κB activity with a trend to increased IL-13 production. Maternal allergic disease was associated with higher TNF-α (median 982 versus 173 pg/mL) and IL-13 secretion (median 1328 versus 1120 pg/mL) after mitogen stimulation. Together, NF-κB activity is differentially activated in cord blood and associated with a distinct cytokine pattern. Whether differential NF-κB activity in cord blood is related to the subsequent development of immune diseases requires further investigation.
PMCID: PMC1488728  PMID: 15181194
CBMC, cord blood mononuclear cells; EMSA, electrophoretic mobility shift assay; IFN-γ, interferon gamma; NF-κB, nuclear factor kappa B; PHA, phytohemagglutinin; SI, stimulation index; Th, T helper; TNF-α, tumor necrosis factor alpha
4.  Endotoxin Exposure and Eczema in the First Year of Life 
Pediatrics  2004;114(1):13-18.
Exposure to endotoxin in early life has been proposed as a factor that may protect against the development of allergic diseases such as eczema. The objective of this study was to examine the relation between endotoxin exposure in early life and eczema in the first year of life in children with parental history of asthma or allergies.
This study used a prospective birth cohort study of 498 children who had a history of allergy or asthma in at least 1 parent and lived in metropolitan Boston. A subset of 401 living rooms had house dust samples adequate for analysis of endotoxin.
In multivariate analyses adjusting for gender, income, and season of birth, endotoxin levels in the living room at 2 to 3 months of age was inversely associated with physician- or nurse-diagnosed eczema in the first year of life (odds ratio [OR] for each quartile increment: 0.76; 95% confidence interval [CI]: 0.61–0.96). Exposure to a dog in the home at age 2 to 3 months was also inversely associated with eczema in the first year of life, but the CI widened when endotoxin was included in the multivariate model (OR: 0.54; 95% CI: 0.27–1.09). Other variables associated with eczema in the first year of life included paternal history of eczema (OR: 1.91; 95% CI: 1.03–3.55) and maternal specific immunoglobulin E positivity to ≥1 allergen (OR: 1.61; 95% CI: 1.01–2.56).
Among children with parental history of asthma or allergies, exposure to high levels of endotoxin in early life may be protective against eczema in the first year of life. In these children, paternal history of eczema and maternal sensitization to at least 1 allergen are associated with an increased risk of eczema in the first year of life.
PMCID: PMC1242194  PMID: 15231902
Ig, immunoglobulin; OR, odds ratio; CI, confidence interval; Th2, T-helper cell type 2
5.  TLR2 and TLR4 Stimulation Differentially Induce Cytokine Secretion in Human Neonatal, Adult, and Murine Mononuclear Cells 
Toll-like receptor 2 (TLR2) and TLR4 signaling may induce differential secretion of T helper 1 (Th1) and Th2 cytokines, potentially influencing the development of autoimmune or atopic diseases. To date, the influence of the type of stimulus, timing, and dose of TLR2 and TLR4 ligands on cytokine secretion has not been well established. We tested whether the innate stimuli peptidoglycan (Ppg, TLR2 agonist) and lipid A (LpA, TLR4 agonist) differentially affect the secretion of interleukin-13 (IL-13) (Th2) and interferon-γ (IFN-γ) (Th1). Further, we examined the influence of the maturity of the immune system, species, dose, and timing of stimuli in human cord and adult peripheral blood mononuclear cells (PBMC) and murine cells in vitro and in vivo. Stimulation with Ppg induced the secretion of both IL-13 and IFN-γ, influenced by time and dose in neonates, adults, and mice. In contrast, stimulation with LpA induced primarily time-independent and dose-independent production of IFN-γ. Pulmonary administration of Ppg in vivo in mice resulted in secretion of IL-13, whereas administration of LpA resulted in secretion of IFN-γ in bronchoalveolar lavage (BAL). Therefore, TLR2 and TLR4 stimuli differentially influence IL-13 and IFN-γ secretion in neonates, adults, and mice, supporting a critical role for innate stimuli in the modulation of cytokine responses.
PMCID: PMC2052924  PMID: 15450130
6.  Association between hemochromatosis genotype and lead exposure among elderly men: the normative aging study. 
Environmental Health Perspectives  2004;112(6):746-750.
Because body iron burden is inversely associated with lead absorption, genes associated with hemochromatosis may modify body lead burden. Our objective was to determine whether the C282Y and/or H63D hemochromatosis gene (HFE) is associated with body lead burden. Patella and tibia lead levels were measured by K X-ray fluorescence in subjects from the Normative Aging Study. DNA samples were genotyped for C282Y and H63D using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). A series of multivariate linear regression models were constructed with bone or blood lead as dependent variables; age, smoking, and education as independent variables; and C282Y or H63D as independent risk factors and/or effect modifiers. Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In the crude analysis, mean tibia, patella, and blood lead levels were consistently lower in carriers of either HFE variant compared with levels in subjects with wild-type genotypes. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele was an independent predictor of significantly lower patella lead levels (p < 0.05). These data suggest that HFE variants have altered kinetics of lead accumulation after exposure. Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores.
PMCID: PMC1241970  PMID: 15121519

Results 1-6 (6)