Changes in the facial soft tissue profile after maxillary orthognathic surgery.

OBJECTIVES: To compare the changes of the soft tissue profile in relation to the displacement of the underlying hard structures in maxillary orthognathic surgery and to contribute to the esthetic prediction of the facial profile after surgical procedures. MATERIALS AND METHODS: We analyzed the sagittal changes in the facial soft tissue profile related to surgical changes in skeletal structures after maxillary osteotomy in a retrospective study. The study sample comprised 115 adult patients between the ages of 18-50 years who had undergone maxillary orthognathic surgery and interdisciplinary orthodontic treatment at the Department of Orthodontics, Ludwig-Maximilians University of Munich, Germany. LeFort I osteotomy cases in both maxillary monognathic and bignathic osteotomy procedures were included. All subjects had received rigid fixation. A cephalometric analysis of presurgical and postsurgical cephalograms was performed and the correlations between hard tissue and soft tissue change ratios were evaluated using a bivariate linear regression analysis. A vertical line through the landmark sella (S) perpendicular to the nasion-sella line (NSL) served as the reference plane. RESULTS: The subnasale (Sn) followed the A point (A) by 57%, the soft tissue A point (A') followed the A point (A) by 73% and the upper lip, represented by the landmark labrale superius (Ls) followed the upper incisor (Is) by 73%; all three in a linear correlation with a mean prediction error of nearly 2 mm. CONCLUSION: The scatterplots show a linear correlation with a wide spread for all three pairs of reference points. The wide spread and the high prediction error of almost 2 mm indicate low predictability of the expected lip position and Sn.

Changes in the facial soft-tissue profile after mandibular orthognathic surgery.

OBJECTIVES: To investigate the correlation between soft- and hard-tissue changes after mandibular orthognathic surgery, to generate precise prognostic values for the esthetic treatment outcome of the facial profile. MATERIAL AND METHODS: In this retrospective study, sagittal changes in the facial soft tissue profile in relation to surgical changes in hard structures after mandibular osteotomy were examined. The sample population included 144 reported adult patients aged 17-50 years who had received combined mandibular orthognathic surgery and orthodontic treatment at the Department of Orthodontics, Ludwig-Maximilians University of Munich, Germany. Both mandibular advancement and mandibular setback cases in monognathic and bignathic osteotomy procedures were included. All subjects had undergone rigid fixation. A cephalometric analysis of presurgical and postsurgical cephalograms was performed, and the correlations between hard-tissue and soft-tissue change ratios were evaluated using a bivariate linear regression analysis. RESULTS: The lower lip, represented by the landmark Labrale inferius (Li), followed the lower incisor (Ii) by 77%. The soft-tissue B-point (B') followed the B-point (B) by 97% and the soft-tissue Pogonion (Pg') followed the Pogonion (Pg) by 97% in a linear correlation. CONCLUSION: The scatterplots show a distinct linear correlation and no significant difference in the direction of the movement. A wider spread for the lower lip (Li/Ii) indicates a lower predictability of the expected lip position, whereas a narrow spread of the chin values (B'/B and the Pg'/Pg) reveals a very good predictability of the postoperative chin position. CLINICAL RELEVANCE: This study contributes valid data for the soft-tissue profile prediction in orthognathic surgery.

Direct versus indirect loading of orthodontic miniscrew implants-an FEM analysis.

OBJECTIVE: The mesialization of molars in the lower jaw represents a particularly demanding scenario for the quality of orthodontic anchorage. The use of miniscrew implants has proven particularly effective; whereby, these orthodontic implants are either directly loaded (direct anchorage) or employed indirectly to stabilize a dental anchorage block (indirect anchorage). The objective of this study was to analyze the biomechanical differences between direct and indirect anchorage and their effects on the primary stability of the miniscrew implants. MATERIALS AND METHODS: For this purpose, several computer-aided design/computer-aided manufacturing (CAD-CAM)-models were prepared from the CT data of a 21-year-old patient, and these were combined with virtually constructed models of brackets, arches, and miniscrew implants. Based on this, four finite element method (FEM) models were generated by three-dimensional meshing. Material properties, boundary conditions, and the quality of applied forces (direction and magnitude) were defined. After solving the FEM equations, strain values were recorded at predefined measuring points. The calculations made using the FEM models with direct and indirect anchorage were statistically evaluated. RESULTS: The loading of the compact bone in the proximity of the miniscrew was clearly greater with direct than it was with indirect anchorage. The more anchor teeth were integrated into the anchoring block with indirect anchorage, the smaller was the peri-implant loading of the bone. CONCLUSIONS: Indirect miniscrew anchorage is a reliable possibility to reduce the peri-implant loading of the bone and to reduce the risk of losing the miniscrew. The more teeth are integrated into the anchoring block, the higher is this protective effect. CLINICAL RELEVANCE: In clinical situations requiring major orthodontic forces, it is better to choose an indirect anchorage in order to minimize the risk of losing the miniscrew.

3D surface measurement for medical application--technical comparison of two established industrial surface scanning systems.

In 3D mapping of flexible surfaces (e.g. human faces) measurement errors due to movement or positioning occur. Aggravated by equipment- or researcher-caused mistakes considerable deviations can result. Therefore first the appliances' precision handling and reliability in clinical environment must be established. Aim of this study was to investigate accuracy and precision of two contact-free 3D measurement systems (white light vs. laser). Standard specimens of known diameter for sphere deviation, touch deviation and plane deviation were tested. Both systems are appropriate for medical application acquiring solid data (

[Lip, jaw, and palate clefts. Analysis of unilateral cleft lip using 3-D laser topometry]. / Lippen-Kiefer-Gaumen-Spalten. Individuelle Analyse der Lippenspalte durch 3-D-Lasertopometrie.

INVESTIGATION: In most cases it is not sufficient to use photographs and plaster casts to document and analyze the three-dimensional morphology of lip, jaw, and palate clefts. The aim of this study was to evaluate the applicability of surface scanning with a 3-D laser topography scanner in patients with unilateral cleft lip. PATIENTS AND METHODS: Three-dimensional surface scans of the face were performed pre- and postoperatively in 20 patients (3-35 years of age) with a 3-D laser topography scanner. All patients were suffering from nonoperated, one-sided cleft lip, cleft lip-jaw, or cleft lip-jaw and palate. The digital data sets were metrically analyzed and expressed on the basis of quotients, independent of size factors. RESULTS: Using this 3-D laser scanner it was possible to acquire good quality three-dimensional data sets. Measurements were in the dimension of millimeters. Based on the data sets it was possible to provide the three-dimensional cleft morphology with reproducible landmarks and analyze the data. The postoperative symmetry of the face was controlled and objectively quantified. It is disadvantageous however that numerous views need to be taken to get the full image of the face and that the scanning process takes about 2 s. CONCLUSION: The presented 3-D laser scanner renders a precise 3-D surface analysis of the lip and nose region in cleft patients. For lively infants or uncooperative adults, the system is suitable only to a limited extent due to the time-consuming scanning process.

[Positioning of the premaxilla in cases of bilateral cleft lip, alveolus and palate using Latham's appliance]. / Positionierung der Oberkieferelemente mit der Latham-Appartur bei Patienten mit Lippen-Kiefer-Gaumen-Spalten.

UNLABELLED: SUBJECT MATTER: In cases of bilateral cleft lip, alveolus and palate, preoperative positioning of the premaxilla using Latham's appliance has been described. This method is controversial, since it may cause growth defects. PATIENTS AND METHODS: From 1992 to 2000, Latham's appliance was inserted preoperatively into 20 patients with bilateral lip, alveolus and palate clefts with extreme premaxillary protrusion. Pin fixation ensued at the age of 3 months. After adjustment of the premaxilla, the soft palate was closed and bilateral lip adhesion as well as bilateral gingivoperiosteoplasty were performed directly after the removal of the appliance. Final lip closure took place 4-6 weeks later. At the age of 2 years, the hard palate was closed. Evaluation was based on combined face-maxilla models, standard photographs and, when available, lateral skull x-rays showing the relative position of the segments, the influence of Latham's appliance on the nasal septum and the relation of the upper jaw to the skull base and mandibula. RESULTS: In all cases, a satisfactory alveolar alignment was achieved; thickening and curvature of the nasal septum occurred but receded. Neither growth disturbances nor dental germ damage were seen. In two cases, complications arose from suture dehiscence of the lip adhesion: in one patient, a screw defect caused a loosening of the appliance and there was also a transmigration of the postpremaxillary pin. CONCLUSIONS: On the basis of our experience, the use of Latham's appliance, combined with consistent orthodontic supervision and, if necessary, treatment, represents a practical option for the treatment of bilateral cleft lip, alveolus and palate, especially in cases with extreme protrusion of the premaxilla.

Factor analysis of asthma and atopy traits shows 2 major components, one of which is linked to markers on chromosome 5q.

BACKGROUND: A variety of definitions of asthma and atopy traits have been used in genetic studies. The variables used may be correlated, increasing the likelihood of type I error. OBJECTIVE: We sought to clarify and quantify phenotypes that may be characterized by related traits. Principal components and factor analysis were applied to the correlation matrix of asthma and atopy traits before linkage analysis. METHODS: Factor analysis was performed on 468 Hispanic and non-Hispanic white children enrolled in the Tucson Children's Respiratory Study, with complete information on 24 items, including skin test response to 7 allergens, total serum IgE levels, presence or absence of asthma attacks, wheezing episodes, hay fever, and cough. Factor score coefficients were then applied to all siblings (n = 877), and quantitative factor scores were derived. Single-point and multipoint nonparametric sib-pair analyses were performed to assess linkage to markers on chromosome 5q31-33. Analyses were also performed for individual items. RESULTS: Two main factors were identified: Factor I had high loadings on atopic items, including skin test responses, IgE, and hay fever, and Factor II had high loadings that included asthma diagnosis, wheezing, cough, and Alternaria species skin test response. Factors I and II were correlated at an r value of 0.19. For the quantitative factor scores, significant single-point linkage (P < .0001) was demonstrated only for atopic Factor I, and a peak multipoint LOD score of 2.7 was seen for marker D5S479. Multipoint LOD scores for individual items were 1.1 or less. CONCLUSION: These analyses suggest evidence for a locus or loci mapping to chromosome 5q31-33 associated with this composite atopic phenotype.

Relation between infantile colic and asthma/atopy: a prospective study in an unselected population.

OBJECTIVE: To assess whether children with history of infantile colic may be at increased risk of subsequently developing asthma and/or atopy. METHODS: We used data collected in a large, prospective study from an unselected population. Infantile colic and concurrent feeding method were determined from the 2-month well-infant visit form completed by the physician for 983 children who were enrolled at birth. Markers of atopy (total serum immunoglobulin E and allergy skin prick test), allergic rhinitis, asthma, wheezing, and peak flow variability were the main outcome measures studied at different ages between infancy and 11 years. RESULTS: Ninety (9.2%) children had infantile colic. Prevalence of colic was similar among children fed either breast milk or formula. There was no association between infantile colic and markers of atopy, asthma, allergic rhinitis, wheezing, or peak flow variability at any age. CONCLUSION: Our data cannot support the hypothesis that infantile colic provides increased risk for subsequent allergic disease or atopy.

Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not of atopy.

BACKGROUND: Influence of household pets in the development of childhood asthma or atopy has been controversial. OBJECTIVE: The purpose of this study was to investigate whether pet exposure in early life decreases the subsequent risk of frequent wheezing and/or allergic sensitization. METHODS: This was a prospective observational birth cohort study. The setting was a large health maintenance organization in Tucson, Ariz; the subjects were a population sample of 1246 newborns enrolled at birth and followed prospectively to age 13 years. The main outcome measures were as follows: time to first report of frequent wheezing (>3 episodes in the past year), skin prick test reactivity at 6 years and 11 years of age, and total serum IgE at 9 months, 6 years, and 11 years of age. RESULTS: Children living in households with > or =1 indoor dogs at birth were less likely to develop frequent wheeze than those not having indoor dogs (P =.004). This inverse association was confined to children without parental asthma (hazard ratio = 0.47; P <.001 [Cox regression]) and was not evident for children with parental asthma (hazard ratio = 0.96; P =.87). Adjustment by potential confounders did not change the results. Indoor cat exposure was not significantly associated with the risk of frequent wheezing. Neither cat exposure in early life nor dog exposure in early life was associated with skin prick test reactivity or total serum IgE at any age. CONCLUSION: Dog exposure in early life might prevent the development of asthma-like symptoms, at least in low-risk children with no family history of asthma. Nevertheless, early pet exposure does not seem to significantly influence the development of allergic sensitization.

Familial correlation in the decline of forced expiratory volume in one second.

Studies have shown evidence of significant parent-offspring and sibling correlation in FEV1, but familial aggregation of decline of FEV1 over time has not been reported. Our study population comprised 392 families enrolled in the Tucson Epidemiological Study of Airway Obstructive Diseases. Subjects were older than 18 yr of age and performed at least 3 pulmonary function tests over 5 to 20 yr. The slope of FEV1 was calculated for each subject using simple linear regression. Multiple regression models were used to compute standardized residual slope values adjusted for possible confounders. Familial correlation analysis on residual slope values demonstrated no evidence of spousal or parent-offspring correlation. However, sibling pairs were highly correlated (r = 0.256, p < 0.001, n = 166), especially smoking-concordant pairs (r = 0.483, p < 0.01 for ever-smokers, and r = 0.280, p < 0.05 for never-smokers). The residual slopes of smoking-discordant siblings were not significantly correlated (r = 0.031, p < 0.77). Genetic susceptibility to an accelerated rate of decline associated with smoking may be evidenced in the increased correlation among smoking sibling pairs, and in the lack of correlation among smoking-discordant sibling pairs. High sibling correlation in the absence of parent-offspring correlation is compatible with a recessive model of inheritance.

Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years.

The possibility of a causal relationship is suggested by recent concomitant increases in the prevalence of obesity and asthma. In a general population sample, prevalence and incidence of asthma symptoms, skin tests, and body mass index (BMI) were ascertained at mean ages of 6.3 (n = 688) and 10.9 (n = 600) yr. Lung function, bronchodilator responsiveness, and daily peak flow variability were measured at 11 yr of age. There was no association between BMI at age 6 and wheezing prevalence at any age. Females, but not males, who were overweight or obese at 11 yr of age were more likely to have current wheezing at ages 11 and 13 but not at ages 6 or 8. This effect was strongest among females beginning puberty before the age of 11. Females who became overweight or obese between 6 and 11 yr of age were 7 times more likely to develop new asthma symptoms at age 11 or 13 (p = 0.0002); at age 11 their peak flow variability and bronchodilator responsiveness were significantly more likely to be increased. In females, becoming overweight or obese between 6 and 11 yr of age increases the risk of developing new asthma symptoms and increased bronchial responsiveness during the early adolescent period.

Familial correlation and segregation analysis of forced expiratory volume in one second (FEV1), with and without smoking adjustments, in a Tucson population.

BACKGROUND: Previous researchers have found significant familial aggregation but no evidence of Mendelian inheritance of forced expiratory volume in one second (FEV1) in general population studies. However, the influence of cigarette smoking on familial aggregation of FEV1 has been difficult to assess in these studies. OBJECTIVES: The main objective of our study was to attempt to discern the effects of smoking on familial correlation and segregation models of FEV1. SUBJECTS AND METHODS: In a randomly selected sample of white, non-Mexican American families in Tucson, Arizona, we performed two separate familial correlation and segregation analyses of FEV1, one adjusted for cigarette smoking and one unadjusted for smoking. In both, initial survey measures of FEV1 for 1329 females and 1291 males in 746 families were standardized for gender, age, height and height-squared using piecewise linear regression models. In the smoking-adjusted model, total number of pack-years smoked, current and ex-smoking status, and the interaction between total pack-years and current smoking status were also included. RESULTS: FEV1 was significantly correlated among sibling pairs and parent-offspring pairs (both p < 0.001), regardless of smoking adjustment, but sibling correlation was significantly higher than parent-offspring correlation (p < 0.05), suggesting additional effects beyond common parentage. Spousal correlations were not significant even when both spouses smoked. We found no evidence of major gene segregation of FEV1, with or without smoking adjustment, and all of the segregation models were significantly different from the unrestricted model. CONCLUSIONS: The best-fitting model was an environmental model with three distinct distributions of FEV1 and significant residual familial effects. A significant familial component suggests the presence of polygenic factors and/or effects due to a shared environment (multifactorial). That familial correlations of smoking-adjusted and smoking-unadjusted residuals were not appreciably different suggests that current smoking status and number of pack-years smoked do not account for the observed familial aggregation of FEV1.

Relation of two different subtypes of croup before age three to wheezing, atopy, and pulmonary function during childhood: a prospective study.

OBJECTIVE: Some retrospective evidence suggests that children with a history of croup may be at increased risk of subsequently developing asthma, atopy, and diminished pulmonary function. The objective of this study was to determine the long-term outcome of croup (as diagnosed by a physician) in early life. METHODS: Lower respiratory illnesses (LRIs) in the first 3 years of life were assessed in 884 children who were enrolled in a large longitudinal study of airway diseases at birth. Pulmonary function tests, markers of atopy, and wheezing episodes were studied at different ages between birth and 13 years. RESULTS: Ten percent of children had croup with wheeze (Croup/Wheeze), 5% had croup without wheeze (Croup/No Wheeze), 36% had another LRI (Other LRI), and 48% had no LRI. Respiratory syncytial virus was more frequently isolated in children with Croup/Wheeze and Other LRI than in those with Croup/No Wheeze. There was no association between croup in early life and markers of atopy measured during the school years. Only children with Croup/Wheeze and with Other LRI had a significant risk of subsequent persistent wheeze later in life. Significantly lower levels of indices of intrapulmonary airway function were observed at ages <1 (before any LRI), 6, and 11 years in children with Croup/Wheeze and Other LRI compared with children with No LRI. Conversely, inspiratory resistance before any LRI episode was significantly higher in infants who later developed Croup/No Wheeze than in the other 3 groups. CONCLUSIONS: We distinguish 2 manifestations of croup with and without wheezing. Children who present with croup may or may not be at increased risk of subsequent recurrent lower airway obstruction, depending on the initial lower airway involvement, and preillness and postillness abnormalities in lung function associated with this condition.

Factors influencing the relation of infant feeding to asthma and recurrent wheeze in childhood.

BACKGROUND: The relationship between infant feeding and childhood asthma is controversial. This study tested the hypothesis that the relation between breast feeding and childhood asthma is altered by the presence of maternal asthma. METHODS: Healthy non-selected newborn infants (n = 1246) were enrolled at birth. Asthma was defined as a physician diagnosis of asthma plus asthma symptoms reported on > or = 2 questionnaires at 6, 9, 11 or 13 years. Recurrent wheeze (> or = 4 episodes in the past year) was reported by questionnaire at seven ages in the first 13 years of life. Duration of exclusive breast feeding was based on prospective physician reports or parental questionnaires completed at 18 months. Atopy was assessed by skin test responses at the age of 6 years. RESULTS: The relationship between breast feeding, asthma, and wheeze differed with the presence or absence of maternal asthma and atopy in the child. After adjusting for confounders, children with asthmatic mothers were significantly more likely to have asthma if they had been exclusively breast fed (OR 8.7, 95% CI 3.4 to 22.2). This relationship was only evident for atopic children and persisted after adjusting for confounders. In contrast, the relation between recurrent wheeze and breast feeding was age dependent. In the first 2 years of life exclusive breast feeding was associated with significantly lower rates of recurrent wheeze (OR 0.45, 95% CI 0.2 to 0.9), regardless of the presence or absence of maternal asthma or atopy in the child. Beginning at the age of 6 years, exclusive breast feeding was unrelated to prevalence of recurrent wheeze, except for children with asthmatic mothers in whom it was associated with a higher odds ratio for wheeze (OR 5.7, 95% CI 2.3 to 14.1), especially if the child was atopic. CONCLUSION: The relationship between breast feeding and asthma or recurrent wheeze varies with the age of the child and the presence or absence of maternal asthma and atopy in the child. While associated with protection against recurrent wheeze early in life, breast feeding is associated with an increased risk of asthma and recurrent wheeze beginning at the age of 6 years, but only for atopic children with asthmatic mothers.

Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families.

We previously described six families with Milroy congenital lymphedema, only one of which showed possible linkage to a candidate locus on chromosome 5 [Witte et al., 1998]. We have now performed a complex segregation analysis of these families, and performed linkage analyses with the other 387 markers used in our genome-wide search. Our results confirm that Milroy lymphedema is generally inherited as a dominant condition. However, this mode of inheritance, as elucidated from the segregation analyses, did not account for all observed familial correlations. The segregation analysis also suggested that shared environmental or additional genetic factors are important in explaining the observed familial aggregation. The finding of linkage to multiple locations in the largest family studied by multipoint parametric mapping (one of which was confirmed by sib-pair non-parametric mapping), suggests that Milroy congenital lymphedema may be oligogenic in this family.

Maternal asthma status alters relation of infant feeding to asthma in childhood.

The relation of infant feeding to childhood asthma is controversial. This study tested the hypothesis that maternal asthma alters the relation of breastfeeding to childhood asthma. Questionnaires were completed at age 6, 9 or 11 years by parents of 1043 children enrolled at birth. Active MD asthma was defined as a physician diagnosis of asthma plus asthma symptoms reported on one of the questionnaires. Duration of exclusive breastfeeding, categorized as never, < 4 months, or > or = 4 months, was based on prospective physician reports or questionnaires completed at 18 months. The relationship between breastfeeding and asthma differed by maternal asthma status. For children with maternal asthma, the percent developing active MD asthma increased significantly with longer duration of exclusive breastfeeding. Odds of developing asthma among these children were significantly elevated (OR: 5.7,CI: 2.8-11.5), after adjusting for confounders. This association of longer exclusive breastfeeding with increased risk of reported asthma among children with asthmatic mothers may be biologically based, or may reflect reporting biases.

A clinical index to define risk of asthma in young children with recurrent wheezing.

Because most cases of asthma begin during the first years of life, identification of young children at high risk of developing the disease is an important public health priority. We used data from the Tucson Children's Respiratory Study to develop two indices for the prediction of asthma. A stringent index included frequent wheezing during the first 3 yr of life and either one major risk factor (parental history of asthma or eczema) or two of three minor risk factors (eosinophilia, wheezing without colds, and allergic rhinitis). A loose index required any wheezing during the first 3 yr of life plus the same combination of risk factors described previously. Children with a positive loose index were 2.6 to 5.5 times more likely to have active asthma between ages 6 and 13 than children with a negative loose index. Risk of having subsequent asthma increased to 4.3 to 9.8 times when a stringent index was used. We found that 59% of children with a positive loose index and 76% of those with a positive stringent index had active asthma in at least one survey during the school years. Over 95% of children with a negative stringent index never had active asthma between ages 6 and 13. We conclude that the subsequent development of asthma can be predicted with reasonable accuracy using simple, clinically based parameters.

Siblings, day-care attendance, and the risk of asthma and wheezing during childhood.

BACKGROUND: Young children with older siblings and those who attend day care are at increased risk for infections, which in turn may protect against the development of allergic diseases, including asthma. However, the results of studies examining the relation between exposure to other children and the subsequent development of asthma have been conflicting. METHODS: In a study involving 1035 children followed since birth as part of the Tucson Children's Respiratory Study, we determined the incidence of asthma (defined as at least one episode of asthma diagnosed by a physician when the child was 6 to 13 years old) and the prevalence of frequent wheezing (more than three wheezing episodes during the preceding year) in relation to the number of siblings at home and in relation to attendance at day care during infancy. RESULTS: The presence of one or more older siblings at home protected against the development of asthma (adjusted relative risk for each additional older sibling, 0.8; 95 percent confidence interval, 0.7 to 1.0; P=0.04), as did attendance at day care during the first six months of life (adjusted relative risk, 0.4; 95 percent confidence interval, 0.2 to 1.0; P=0.04). Children with more exposure to other children at home or at day care were more likely to have frequent wheezing at the age of 2 years than children with little or no exposure (adjusted relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.8; P=0.01) but were less likely to have frequent wheezing from the age of 6 (adjusted relative risk, 0.8; 95 percent confidence interval, 0.6 to 1.0; P=0.03) through the age of 13 (adjusted relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001). CONCLUSIONS: Exposure of young children to older children at home or to other children at day care protects against the development of asthma and frequent wheezing later in childhood.

A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children.

BACKGROUND: Increased levels of total serum IgE are a strong risk factor for the development of asthma. IgE is also involved in host defenses against parasites and fungi. Linkage of total serum IgE with markers located close to the 3 Mb cluster of cytokine genes in chromosome 5q31 has been reported. IL-4 or IL-13 are regarded as essential for IgE synthesis. OBJECTIVE: We tested whether polymorphisms in the IL-13 gene might explain the linkage between chromosome 5q31 and total serum IgE levels. METHODS: We used denaturing HPLC to detect polymorphisms in overlapping PCR fragments of the IL-13 gene including promoter and 3' untranslated regions. After sequencing was performed to identify the locations of the polymorphisms, PCR and primer-induced restriction site assays were used to genotype subjects in 3 unselected populations. RESULTS: We report here 7 polymorphisms (6 novel) in IL-13. Four of these polymorphisms are tightly linked to a variant in the terminal portion of the coding region of the gene that results in a predicted amino acid change in residue 130 (Arg130Gln). The Gln form is strongly associated (P =.000002) with increased serum IgE levels in 3 different populations comprising a total of 1399 children. Two additional polymorphisms in the promoter region of IL-13 are more loosely linked to Arg130Gln and are also less significantly associated with total serum IgE levels. CONCLUSION: These data suggest that the Arg130Gln polymorphism in IL-13, or others in close linkage with it, is associated with the development of the elevated serum IgE phenotype.

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.