Serum total IgE levels and CD14 on chromosome 5q31.
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Alleles↗
Biomedical subjects
F D Martinez
Publications and source records attributed to F D Martinez.
Role of respiratory infection in onset of asthma and chronic obstructive pulmonary disease.
There is renewed interest in the possible role of events occurring during early life in determining predisposition to asthma and allergies. Among these events, respiratory illnesses associated with viral infections have been the matter of considerable research interest. There is now evidence suggesting that an immune response to viral infection in early life that is skewed toward an IgE- or an eosinophil-mediated slant is predictive of persistent wheezing symptoms up to the age of 6 years. Genetic and environmental factors (specifically bacterial infection burden) may be important determinants of the maturation of immune responses from a default 'Th-2-like' at birth to mature, non-Th-2-like responses. Homing of Th-2-like responses to the lung may be determined in part by inheritance of bronchial hyperresponsiveness, and in part by the progressive nature of chronic, uncontrolled airway inflammation. The main risk factor for the development of wheezing episodes in children who are not predisposed to allergic asthma is diminished airway function, which can also be detected shortly after birth. These children may stop wheezing later during childhood, but their levels of lung function track with age. It is tempting to speculate that chronic obstructive pulmonary disease may occur more frequently in these children.
Animals↗
Recognizing early asthma.
Asthma symptoms often develop during the first years of life. Longitudinal studies show that at least 40% of children with wheezing lower respiratory illnesses (LRIs) during the first 3 years of life still have wheezing episodes at 6 years of age. Thus, it is important to identify children at risk of developing asthma, and to distinguish these from those in whom early wheezing is likely to be transient. This is complicated, however, by the variable nature of asthma and the lack of specific and sensitive markers. Genetic markers and epidemiologic risk factors for asthma have been identified, but cannot be used to predict the development of asthma in an individual patient. Similarly, infants who subsequently develop asthma in childhood have higher serum immunoglobulin E (IgE) and peripheral eosinophil counts than those who do not develop asthma, but, again, these factors are not sufficiently sensitive and specific to allow identification of children at risk of developing asthma. An algorithm is presented that outlines possible criteria to determine the risk of developing asthma in infants.
Algorithms↗
Association of radiologically ascertained pneumonia before age 3 yr with asthmalike symptoms and pulmonary function during childhood: a prospective study.
Epidemiologic evidence suggests an association between reports of pneumonia in early life and the subsequent development of diminished lung function. However, no studies are available in which the diagnosis of pneumonia was based on radiologic evidence. Lower respiratory illnesses with or without a radiologically confirmed diagnosis of pneumonia were assessed in a study of 888 children enrolled at birth. Pulmonary function tests, markers of atopy, asthma diagnosis, and prevalence of respiratory symptoms were assessed at different ages between birth and 11 yr. Incidence of pneumonia during the first 3 yr of life was 7.4%. Respiratory syncytial virus was the most frequent agent identified both in children with pneumonia and in those with lower respiratory tract illness (LRI) without pneumonia (36.4% versus 35.6%, respectively). Children with a diagnosis of pneumonia were more likely to have physician-diagnosed asthma and current wheezing at ages 6 and 11 yr than were those who had no LRIs. When compared with children without LRIs, those with a diagnosis of pneumonia had lower levels of maximal flows at FRC at mean age of 2 mo (albeit not significantly) and at age 6 yr, and lower levels of FEV1 and FEF25-75 at age 11 yr. These deficits were independent of known confounders, including wheezing at the time of study, and were partly and significantly reversed after administration of a bronchodilator. We conclude that children with radiologically confirmed pneumonia have diminished airway function that is probably present shortly after birth. These deficits are at least in part due to alterations in the regulation of airway muscle tone.
Aging↗
Two subphenotypes of childhood asthma that differ in maternal and paternal influences on asthma risk.
Asthma is a phenotypically heterogeneous disease. Two subgroups are defined here based initially on skin test reactivity to the allergen Alternaria at age 6 from among a large population of children born and raised in the Southwestern desert environment of Tucson, Arizona. When compared with asthma among Alternaria-positive subjects, asthma among Alternaria-negative subjects was associated with lower levels of total serum IgE, no relation to local aeroallergen skin tests, a younger age at diagnosis, greater remittance by age 11, and more frequent wheezing lower respiratory illnesses (LRIs) in the first year of life. Despite the difference in total serum IgE, however, IgE concentrations were significantly higher in each asthma group compared with its respective control group. Asthma in each parent contributed approximately equivalent risk for Alternaria-positive asthma in the child. However, neither parental skin test sensitization nor total serum IgE levels provided risk for asthma in the child. Inheritance patterns for Alternaria-negative asthma revealed a contribution from maternal but not paternal asthma. Thus, dividing asthma in children at age 6 into Alternaria-positive and Alternaria-negative groups identifies subphenotypes that are further distinguished by differences in phenotypic markers and parental influences.
Alternaria↗
Familial aggregation and segregation analysis of eosinophil levels.
The number of circulating eosinophils is associated with the risk of asthma in population samples. Therefore, eosinophil levels may be an intermediate phenotype for asthma amenable to genetic analysis. We examined familial aggregation of the number of eosinophils x 10(6) L(-1) and the percentage of eosinophils based on a 300 count differential in 644 Hispanic and non-Hispanic white families, with 2, 097 subjects, enrolled in the Tucson Children's Respiratory Study. Both measures were adjusted for age, season and year at the time blood was drawn, sex, and ethnicity. Segregation analysis was conducted in the 458 non-Hispanic white families, as there were no significant familial correlations in the Hispanic families, and there was significant heterogeneity by ethnic group. Familial correlations (rho) in the non-Hispanic white families were as follows: mother-father, 0.05; mother-child, 0.18 (p < 0.001); father-child, 0.07; sibling-sibling, 0.31 (p < 0.001). Without covariates analyses indicated a polygenic/multifactorial mode of inheritance. After adjusting for current and past asthma an oligogenic mode of inheritance was suggested, plus additional residual familial components that were mainly maternally mediated. This study supports the notion of multiple, relatively common genes interacting to determine genetic susceptibility to asthma. Holberg CJ, Halonen M, Wright AL, Martinez FD. Familial aggregation and segregation analysis of eosinophil levels.
Adult↗
A Polymorphism* in the 5' flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E.
Total serum immunoglobulin (Ig)E levels are genetically regulated, but the mechanism of inheritance is not well understood. Cytokines produced by T-helper (Th)1 and Th2 lymphocytes control IgE synthesis. Bacterial antigens may favor the development of Th1 cells from naive CD4-positive T cells through a CD14-dependent pathway. CD14 is constitutively expressed on the surface of monocytes and macrophages, and is also present in serum in a soluble form (sCD14). The CD14 gene maps to chromosome 5q31.1, a candidate region for loci regulating total serum IgE. We hypothesized that genetic variants in the CD14 gene could influence Th-cell differentiation and thus total serum IgE. We identified a C-to-T transition at base pair -159 from the major transcription start site (CD14/-159). Among 481 children recruited from a general population sample, frequency of allele C was 51.4%. TT homozygotes had significantly higher sCD14 levels than did carriers of both the CC and CT genotypes (P = 0.01). TT homozygotes also had significantly lower levels of IgE than did carriers of the other two genotypes, but differences were significant only among children who were skin test-positive to local aeroallergens (P = 0.004). There was no association between CD14/-159 and either interleukin (IL)-4 or interferon (IFN)-gamma responses by peripheral blood mononuclear cells. However, IFN-gamma and IL-4 responses were positively and negatively correlated, respectively, with serum sCD14 levels. We conclude that CD14/-159 plays a significant role in regulating serum sCD14 levels and total serum IgE levels.
Base Sequence↗
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.
Acute Disease↗
The genetics of asthma. Implications of association studies in asthma.
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Asthma↗
Gene by environment interactions in the development of asthma.
Present knowledge suggests that asthma is a heterogeneous condition. Different genetic backgrounds may or may not express themselves as asthma-like symptoms, depending on both the nature and the timing of exposures in the individual. Although particular attention has been paid to environmental factors that may increase the risk of asthma, it is equally important to understand 'protective' exposures that may have decreased during the last decades and may thus explain the reported increases in asthma prevalence. Among these 'protective' factors are certain infections and the role they may have in the inception of allergics and asthma, particularly when they occur at critical times in the development of the immune system.
Allergens↗
Differences in familial segregation of FEV1 between asthmatic and nonasthmatic families. Role of a maternal component.
Studies have demonstrated familial aggregation of lung function. This study employed segregation analysis to investigate the mode of inheritance of FEV1 using regressive models for continuous traits. The study population comprised 309 families (1,163 individuals) enrolled in the Tucson Children's Respiratory Study who had both parents and at least one child with FEV1 data. Results showed significant genetic heterogeneity among the 87 families (328 individuals) with at least one member with asthma and the 222 families (835 individuals) with no asthmatic members. In families with no asthmatic members, all statistical models were rejected, indicating the absence of a major gene controlling lung function. However, a significant familial component indicated a strong polygenic/multifactorial mode of inheritance. In families with asthmatic member(s), results suggested polygenic/multifactorial inheritance with weak evidence for a Mendelian component expressed in a recessive fashion. However, while both father-offspring and mother-offspring correlations were statistically significant in families with no asthmatic members, only the mother-offspring correlation was significant in families with asthmatic members. The data suggest that lung function is inherited as a polygenic/multifactorial trait, but in asthmatic families a major element of intergenerational correlation is associated with a maternal influence, which may be genetically or environmentally mediated.
Adult↗
Linkage of circulating eosinophils to markers on chromosome 5q.
Although peripheral blood eosinophilia is strongly associated with the risk of developing asthma, genetic determinants of eosinophilia have not been extensively studied. We used sib-pair analysis to assess linkage of circulating eosinophils (as a percent of total white blood cells [WBC]) to nine markers located in chromosome 5q31-33. The study was divided into two phases. Of 246 sib pairs available for the first phase, 35 were classified as low concordant (LC) (both sibs had <= 2% circulating eosinophils), 18 were defined as high concordant (HC) (both sibs had 5% or more circulating eosinophils), and 26 were defined as discordant (one sib had <= 2% and the other sib had 5% or more circulating eosinophils). Significant evidence for linkage among low concordant sib pairs was found for several markers in the region under study, with a peak for marker D5S500 (proportion of alleles shared identical by descent [ibd] = 0.68 +/- 0.05 [mean +/- SE], p = 0.0004). A cross-validating study was done in which an additional 19 sib pairs that were low concordant for circulating eosinophils were studied. Evidence for linkage was also observed in this subset. Results were independent of current wheezing, total serum IgE levels, and other potential confounders. A multipoint analysis done for all low-concordant sib pairs available showed that the maximal logarithm of the odds favoring genetic linkage (LOD) score (2.4, p = 0.0004) was observed in correspondence with marker D5S658. We conclude that a locus or loci may be present in chromosome 5q31-33 that controls for circulating eosinophils as a proportion of total WBC.
Alleles↗
Types of asthma and wheezing.
There is now convincing evidence that childhood asthma is a spectrum of different conditions that are manifested by recurrent symptoms of bronchial obstruction. Risk factors such as age, genetic background, degree of maturation at birth and allergic sensitization, amongst others, are important in determining asthma-like manifestations at different times during childhood. Although efforts have been made to differentiate "wheezing syndromes" occurring during childhood, these efforts have been made more difficult by the significant degree of overlap between them. Nevertheless, the evidence suggests that recurrent obstructive symptoms remit in a large number of children who develop these symptoms during the first 3 yrs of life, and low lung function seems to be the main risk factor for these transient episodes. On the other hand, children who will go on to develop persistent wheezing beyond infancy and early childhood usually have a family history of asthma and allergies and present with allergic symptoms very early in life. Recent studies suggest that the latter also show acute immune responses to viruses that are different from those of transient wheezers. Identification of specific inflammatory markers for persistent wheezing at the time of the first lower respiratory symptoms may be a necessary step for the establishment of successful strategies for the prevention of asthma in the future.
Asthma↗
Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing.
The beta2-adrenergic receptor (beta2AR) agonists are the most widely used agents in the treatment of asthma, but the genetic determinants of responsiveness to these agents are unknown. Two polymorphic loci within the coding region of the beta2AR have been recently described at amino acids 16 and 27. It has been reported that glycine at codon 16 (Gly-16) is associated with increased agonist-promoted downregulation of the beta2AR as compared with arginine-16 (Arg-16). The form of the receptor with glutamic acid at codon 27 (Glu-27), on the other hand, has been shown to be resistant to downregulation when compared with glutamine-27 (Gln-27), but only when coexpressed with Arg-16. To assess if different genotypes of these two polymorphisms would show differential responses to inhaled beta2AR agonists, we genotyped 269 children who were participants in a longitudinal study of asthma. Spirometry was performed before and after administration of 180 microg of albuterol, and a positive response was considered an increase of >15.3% predicted FEV1. There was marked linkage disequilibrium between the two polymorphisms, with 97.8% of all chromosomes that carried Arg-16 also carrying Gln-27. When compared to homozygotes for Gly-16, homozygotes for Arg-16 were 5.3 times (95% confidence interval 1.6-17.7) and heterozygotes for beta2AR-16 were 2.3 times (1.3-4.2) more likely to respond to albuterol, respectively. Similar trends were observed for asthmatic and nonasthmatic children, and results were independent of baseline lung function, ethnic origin, and previous use of antiasthma medication. No association was found between the beta2AR-27 polymorphism and response to albuterol. These results may explain some of the variability in response to therapeutic doses of albuterol in children.
Adrenergic beta-Agonists↗
The relationship between impaired lung growth and onset of bronchial asthma in early life.
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Adolescent↗
Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood.
BACKGROUND: There is increasing evidence that wheezing during childhood may be a heterogeneous condition, and that different forms of wheezing may be associated with different risk factors and prognosis. The aim of this study was to determine if measures of airway lability and of atopy could identify distinct wheezing phenotypes during childhood. METHOD: In a cohort of children followed from birth peak flow variability (n = 600) was evaluated and methacholine challenge responsiveness (n = 397) was measured at age 11 in relation to wheezing before the age of three, and at age six and 11 years total serum IgE and skin test reactivity to allergens were determined. RESULTS: Neither positive peak flow variability nor methacholine hyperresponsiveness measured at age 11 were associated with wheezing occurring only during the first three years of life. Both methacholine hyperresponsiveness and positive peak flow variability were associated with wheezing at both ages six and 11 (OR 5.1 (95% CI 2.4 to 10.6) and 2.3 (1.2 to 4.5), respectively). In addition, positive peak flow variability was associated with wheezing up to the age of six but not at age 11 in non-atopic children (OR 2.9 (95% CI 1.0 to 8.8)). Methacholine hyperresponsiveness measured at age 11 was more frequently observed in boys (OR 2.1 (95% CI 1.2 to 3.5)) and was strongly associated with serum IgE levels measured at ages six and 11 (p < 0.001) and with positive skin test reactivity (OR 4.5 (95% CI 2.0 to 10.1)). Peak flow variability was unrelated to sex or markers of atopy (IgE and skin test reactivity). CONCLUSIONS: Methacholine responsiveness and peak flow variability assessed at age 11, together with markers of atopy (IgE and skin test reactivity to allergens) identify three different wheezing phenotypes in childhood: "transient early wheezing" limited to the first three years of life and unrelated to increased airway lability; "non-atopic wheezing" of the toddler and early school years associated with positive peak flow variability but not with methacholine hyperresponsiveness; and "IgE-associated wheeze/asthma" associated with persistent wheezing at any age and with methacholine hyperresponsiveness, peak flow variability, and markers of atopy.
Adolescent↗
Alternaria as a major allergen for asthma in children raised in a desert environment.
The relationships of asthma and allergic rhinitis with individual immediate skin test responses were examined for preferential associations and for changes with age in children raised in a semiarid environment. Prevalence of physician-diagnosed asthma was 9.8% at age 6 (n = 948) and 15.5% at age 11 (n = 895). Immediate skin test responses to Bermuda grass were the most prevalent among children with allergic rhinitis and control subjects, whereas responses to the mold, Altenaria alternata, were the most prevalent among asthmatics. Skin test responses for crude house dust, Dermatophagoides farinae, and cat had low prevalences in all groups. By logistic regression, Alternaria was the only allergen independently associated with increased risk for asthma at both ages 6 and 11. Allergic rhinitis showed independent association with sensitization to Bermuda grass and mulberry tree pollen at age 11 but did not show an independent relation to any single allergen at age 6. Logistic regression further revealed that persistent asthma (diagnosed before age 6) was independently associated with Alternaria skin tests at both ages 6 and 11, whereas new asthma (diagnosed after age 6) was associated with Alternaria skin tests at age 6 but not at age 11. We conclude that Alternaria is the major allergen associated with the development of asthma in children raised in a semiarid environment and that skin test responses at age 6 are more closely linked to asthma than those at age 11.
Allergens↗
Complexities of the genetics of asthma.
The task of deciphering the genetics of asthma is very complex. Recent studies of the familiar segregation of asthma showed that no single gene accounts for a major part of the expression of the disease, and that a polygenic model with some evidence of an oligogenic influence (i.e., a handful of loci being responsible for most of the genetic control) provided the best fit to the data. Although a final common pathway of recurrent bronchial obstruction is present in most cases of asthma, the disease shows marked phenotypic variability, suggesting etiologic heterogeneity and strong environmental influences. In an effort to circumvent these obstacles, linkage studies for genes controlling for apparently simpler phenotypes have been attempted. Total serum immunoglobulin E (IgE) levels, for example, show strong familiar aggregation and are known to be strongly correlated with asthma risk. Recent epidemiologic studies have suggested, however, that the inherited component of total serum IgE may be of little relevance as a determinant of asthma. Sensitization to certain aeroallergens is also associated with increased prevalence of asthma and is likely to have a genetic component, but the aeroallergens involved vary markedly with locale. In addition, sensitization to aeroallergens occurring at an early age is more strongly associated with asthma risk than late allergic sensitization, suggesting genetic heterogeneity. Therefore, studies of the genetics of phenotypes known to be strongly associated with asthma may clarify the causal role (if any) of the genes regulating their expression in the pathogenesis of asthma.
Allergens↗