Debra A. Stern

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.

Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study

BACKGROUND Together with smoking, the lung function attained in early adulthood is one of the strongest predictors of chronic obstructive pulmonary disease. We aimed to investigate whether lung function in early adulthood is, in turn, affected by airway function measured shortly after birth. METHODS Non-selected infants were enrolled at birth in the Tucson Childrens Respiratory Study between 1980 and 1984. We measured maximal expiratory flows at functional residual capacity (Vmax(FRC)) in 169 of these infants by the chest compression technique at a mean of 2.3 months (SD 1.9). We also obtained measurements of lung function for 123 of these participants at least once at ages 11, 16, and 22 years. Indices were forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of FVC (FEF25-75), both before and after treatment with a bronchodilator (180 microg of albuterol). FINDINGS Participants who had infant Vmax(FRC) in the lowest quartile also had lower values for the FEV1/FVC ratio (-5.2%, p<0.0001), FEF25-75 (-663 mL/s, p<0.0001), and FEV1 (-233 mL, p=0.001) up to age 22, after adjustment for height, weight, age, and sex, than those in the upper three quartiles combined. The magnitude and significance of this effect did not change after additional adjustment for wheeze, smoking, atopy, or parental asthma. INTERPRETATION Poor airway function shortly after birth should be recognised as a risk factor for airflow obstruction in young adults. Prevention of chronic obstructive pulmonary disease might need to start in fetal life.

Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study

BACKGROUND Incidence of asthma increases during early adulthood. We aimed to estimate the contributions of sex and early life factors to asthma diagnosed in young adults. METHODS 1246 healthy newborn babies were enrolled in the Tucson Childrens Respiratory Study. Parental characteristics, early-life wheezing phenotypes, airway function, and bronchial hyper-responsiveness to cold dry air and sensitisation to Alternaria alternata were determined before age 6 years. Physician-diagnosed asthma, both chronic and newly diagnosed, and airway function were recorded at age 22 years. FINDINGS Of 1246 babies enrolled, 849 had follow-up data at 22 years. Average incidence of asthma at age 16-22 years was 12.6 per thousand person-years. 49 (27%) of all 181 cases of active asthma at 22 years were newly diagnosed, of which 35 (71%) were women. Asthma remittance by 22 years was higher in men than in women (multinomial odds ratio [M-OR] 2.0, 95% CI 1.2-3.2, p=0.008). Age at diagnosis was linearly associated with the ratio of forced expiratory volume at 1 s to forced vital capacity at age 22 years. Factors independently associated with chronic asthma at 22 years included onset at 6 years (7.4, 3.9-14.0) and persistent wheezing (14.0, 6.8-28.0) in early life, sensitisation to A alternata (3.6, 2.1-6.4), low airway function at age 6 years (2.1, 1.1-3.9), and bronchial hyper-responsiveness at 6 years (4.5, 1.9-10.0). Bronchial hyper-responsiveness (6.9, 2.3-21.0), low airway function at 6 years (2.8, 1.1-6.9), and late-onset (4.6, 1.7-12.0) and persistent wheezing (4.0, 1.2-14.0) predicted newly diagnosed asthma at age 22 years. INTERPRETATION Asthma with onset in early adulthood has its origins in early childhood.

Association of interleukin-2 and interferon-γ production by blood mononuclear cells in infancy with parental allergy skin tests and with subsequent development of atopy

The mechanisms regulating the onset of atopic sensitization in human beings are not yet fully clarified. We assessed the capacity of mitogen-stimulated umbilical and peripheral blood mononuclear cells to produce interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) at birth and at 9 months of age in 159 infants. Mononuclear cell production of both IFN-gamma and IL-2 at 9 months, but not at birth, was found to be inversely related to parental immediate skin test reactivity to seven local aeroallergens. Skin test reactivity at the age of 6 years was also inversely related to IFN-gamma and IL-2 production at 9 months of age. However, no relationship was evident between total serum IgE levels at 6 years and production of these cytokines at 9 months. The proportions of circulating lymphocytes and CD4+ or CD8+ cells were also unrelated to skin test reactivity at the age of 6 years. These data suggest that mechanisms regulating skin test reactivity to inhaled allergens may involve deficient IFN-gamma production, deficient IL-2 production, or both during or preceding the time of initial sensitization and that additional mechanisms are involved in regulating total serum IgE level.

IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

Genetic factors are known to strongly influence susceptibility to allergic inflammation. The Th2 cytokine IL-13 is a central mediator of allergy and asthma, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13+2044GA is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044GA on the functional properties of IL-13 by directly comparing the activity of WT IL-13 and IL-13 R130Q on primary human cells involved in the effector mechanisms of allergic inflammation. Our results show that IL-13 R130Q was significantly more active than WT IL-13 in inducing STAT6 phosphorylation and CD23 expression in monocytes and hydrocortisone-dependent IgE switching in B cells. Notably, IL-13 R130Q was neutralized less effectively than WT IL-13 by an IL-13R2 decoy. Decreased neutralization of the minor variant could contribute to its enhanced in vivo activity. Neither IL-13 variant was able to engage T cells, which suggests that increased allergic inflammation in carriers of IL13+2044A depends on enhanced IL-13-mediated Th2 effector functions rather than increased Th2 differentiation. Collectively, our data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy.

Cord blood 25-hydroxyvitamin D levels are associated with aeroallergen sensitization in children from Tucson, Arizona

BACKGROUND The association between vitamin D status at birth and childhood allergic outcomes is uncertain. The desert climate of Tucson offers a unique setting for studying the health effects of higher exposure to vitamin D. OBJECTIVE To assess the relationship between cord blood 25-hydroxyvitamin D (25[OH]D) levels and allergic outcomes through age 5 years. METHODS Cord blood 25(OH)D levels were measured in 219 participants in the Tucson Infant Immune Study, a population-based birth cohort. Plasma total IgE and specific IgE levels to 6 aeroallergens were measured at 1, 2, 3, and 5 years. Skin prick test (SPT) positivity (wheal diameter ≥ 3 mm) and physician-diagnosed active allergic rhinitis and asthma were assessed at age 5 years. Longitudinal models were used to assess the relationship between 25(OH)D and IgE levels. Logistic regression models were used to assess the relationship of 25(OH)D level with SPT positivity, allergic rhinitis, and asthma. RESULTS The median cord blood 25(OH)D level was 64 nmol/L (interquartile range, 49-81 nmol/L). Relative to the reference group (50-74.9 nmol/L), both low (<50 nmol/L) and high (≥ 100 nmol/L) levels were associated with increased total IgE (coefficient = 0.27, P = .006 and coefficient = 0.27, P = .04, respectively) and detectable inhalant allergen-specific IgE (odds ratio = 2.4, P = .03 and odds ratio = 4.0, P = .01, respectively) through age 5 years. High 25(OH)D levels were also associated with increased SPT positivity (odds ratio = 4.0, P = .02). By contrast, the 25(OH)D level was not significantly associated with allergic rhinitis or asthma. CONCLUSION Both low and high levels of cord blood 25(OH)D were associated with increased aeroallergen sensitization. The association between vitamin D status and actual allergic diseases merits further study.

Differential immune responses to acute lower respiratory illness in early life and subsequent development of persistent wheezing and asthma

BACKGROUND Recent epidemiologic evidence suggests that 2 wheezing syndromes coexist in early life: transient wheezing, limited to early childhood, and persistent wheezing, which starts in early childhood and persists beyond that age. OBJECTIVE Whether the nature of the immune response occurring during acute lower respiratory illnesses (LRIs) in infancy differs between these 2 groups of wheezers has yet to be determined. METHODS We compared total serum IgE levels and peripheral blood eosinophil counts obtained during the acute phase of the first LRI with those obtained during the convalescent phase or with well-baby samples in persistent (n = 49) and transient early wheezers (n = 88), as well as in children who had only nonwheezing LRIs (n = 43) during the first 3 years of life. RESULTS Total serum IgE levels were significantly higher (P =.008) during the acute phase compared with the convalescent phase of the LRI in persistent wheezers, a response not observed in transient early wheezers (P =.7). Peripheral blood eosinophil counts were significantly reduced during the acute phase of the LRI (P =.009) in transient early wheezers, a response not observed among persistent wheezers (P =.7). Acute responses in children who had nonwheezing LRIs only were similar to those seen in transient early wheezers. CONCLUSION Alterations in acute immune response to viral infection may be detected at the time of the first wheezing episode in subjects who will go on to have persistent wheezing symptoms.

TGF-β in human milk is associated with wheeze in infancy

Abstract Background Cytokines secreted in human milk might play important roles in newborn health and in the development of infant immune responses. We investigated the relationship of the concentration and dose of cytokines in human milk to infant wheeze at 1 year of age. Objective Our objective was to test whether the cytokines in milk could account for some of the apparent protective effect of breast-feeding against wheeze in the first year of life. Methods Data on breast-feeding and infant wheeze were collected prospectively from birth to 1 year from 243 mothers participating in the Infant Immune Study in Tucson, Arizona. Breast milk samples obtained at a mean age of 11 days postpartum were assayed by means of ELISA for concentrations of TGF-β1, IL-10, TNF-α, and the soluble form of CD14. The dose of each cytokine was assessed for a relationship with wheeze in bivariate and logistic regression analyses. Results Increasing duration of breast-feeding was significantly associated with a decreased prevalence of wheeze ( P = .039). There was wide variability in levels of each cytokine in milk, as well as variability between women in the amount of each cytokine produced. There was a significant inverse association between the dose of TGF-β1 received through milk with the percentage of wheeze ( P = .017), and the relationship was linear ( P = .006). None of the other cytokines showed a linear relationship with wheeze. In multivariate analyses the risk of wheeze was significantly decreased (odds ratio, 0.22; 95% CI 0.05-0.89; P = .034) with increasing TGF-β1 dose (long breast-feeding and medium-high TGF-β1 level compared with short breast-feeding and low TGF-β. Conclusion This analysis shows that the dose of TGF-β1 received from milk has a significant relationship with infant wheeze, which might account for at least some of the protective effect of breast-feeding against wheeze.

Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels. Group Health Medical Associates.

BACKGROUND--The role of lower respiratory tract illnesses (LRIs) in the development of allergies is not well understood. The relation of wheezing and non-wheezing LRIs to serum IgE levels and atopy was studied in 888 children. METHODS--Total serum IgE levels were measured at birth, nine months and six years of age; and interferon gamma production by blood mononuclear cells was measured at birth and nine months. Atopy was determined by skin prick tests at age six. Wheezing and non-wheezing LRIs up to age three were diagnosed by a physician. RESULTS--Cord serum IgE levels were similar between all LRI groups and the no LRI group. Children who had wheezing LRIs until the age of three had IgE levels at nine months and at six years within normal ranges for age. In contrast, children who had a non-wheezing LRI before the nine month IgE sample had lower IgE levels at nine months and six years (geometric mean 1.8 IU/ml and 9.9 IU/ml, respectively) compared with children who had no LRIs (3.9 IU/ml and 38.3 IU/ml, respectively). Children who had non-wheezing LRIs after the nine month IgE sample had normal nine month IgE levels (3.2 IU/ml) but decreased IgE levels at six years of age (15.7 IU/ml). Children with more than one non-wheezing LRI before the age of three were less likely to be atopic than those with no LRI (odds radio 0.2). Interferon gamma production was higher in the non-wheezing LRI group at nine months than in the no LRI or wheezing LRI groups. CONCLUSIONS--Non-wheezing LRIs are associated with subsequent depression of IgE levels and reduced skin test reactivity.

Relationship of total serum IgE levels in cord and 9‐month sera of infants

To characterize IgE levels at birth and changes in those levels during the first year of life and to identify Factors that might influence IgE levels in infancy, we measured IgE levels in 1074 umbilical cord sera and in 697 sera obtained at 9 months of age in a healthy population of infants enrolled at birth into the Childrens Respiratory Study in Tucson, Arizona, U.S.A. Serum IgE levels at birth and 9 months were log normally distributed with geometric means of 0.09 and 3.87 IU/ml, respectively. Cord serum IgE levels were unaffected by maternal smoking. Levels varied according to month of birth with a nadir in September. Cord and 9‐month serum IgE levels were higher in boys than in girls, Hispanics compared with Anglos, and infants who developed eczema compared with those who did not, but the mean increases in log IgE from birth to 9 months were not significantly affected by these factors. A significant correlation between IgE levels at cord and 9 months was observed (r= 0.44; P < 0.0001). Also, mean log IgE levels at 9 months in infants grouped according to cord serum IgE levels maintained the same rank order of mean values as the cord groups. These data indicate that 9‐month IgE levels are influenced by cord serum IgE levels and that the main influence of gender, ethnicity and susceptibility to eczema on IgE levels occurs before birth.