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BACKGROUND: Lung function growth occurs in most asthmatic children. A subgroup has subnormal lung function trajectory, but such data are limited in children. This prospective study characterized longitudinal changes of spirometric indices and fractional exhaled nitric oxide level (FeNO) among asthmatic children and identified their genetic and environmental determinants. METHODS: Chinese asthmatic children recruited from pediatric clinics underwent 5-year follow-up for pre-bronchodilator spirometric indices and FeNO. Fourteen asthma-associated single nucleotide polymorphisms (SNPs) were genotyped. Generalized estimating equation was used to analyze longitudinal changes of spirometric indices and FeNO. RESULTS: One hundred and ninety-three asthmatic children, aged 9.7 (1.9) years, had significant annual decline of 1.3% for forced vital capacity (FVC) and annual increase of 1.2% and 3.6% for FEV1 /FVC and FEF25-75 , respectively. Patients who received inhaled corticosteroid (ICS) had 2.4% lower baseline FEV1 /FVC but 0.81% higher annual increase in FEV1 . Body mass index (BMI) was associated inversely with FEV1 /FVC but positively with FEV1 % and FVC% changes. Asthma exacerbation was associated with lower FEV1 % and FVC% but not their longitudinal changes. When classified by FEV1 curve, one-quarter of patients had reduced lung function growth which was associated with female gender and lower spirometric and higher FeNO values at baseline. IL33_rs1342326 was associated with spirometric indices and FeNO, whereas GSDMB_rs2305480 was significantly associated with FEV1 /FVC change. CONCLUSION: Asthmatic children have annual decline in FVC and increase in FEV1 /FVC and FEF25-75 . Their lung function trajectory is influenced by gender, ICS treatment, BMI, and asthma exacerbations. IL33 and GSDMB may be candidate genes for their lung function growth.
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Asma/fisiopatología , Pulmón/fisiopatología , Óxido Nítrico/análisis , Espirometría/métodos , Pueblo Asiatico , Asma/genética , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Polimorfismo de Nucleótido Simple , Estudios ProspectivosRESUMEN
Asthma is caused by complex gene-gene and gene-environment interactions. Most asthma genes are not replicable across populations, which is possibly because of differences in the epidemiology of these genes. Our case-control association and next-generation sequencing studies revealed substantial discrepancies in the frequencies of single nucleotide polymorphisms (SNPs) and haplotype blocks for asthma genes between Chinese and other populations. The minor allele frequencies for nearly half of our studied SNPs differed by 0.2 or greater between southern Chinese subjects in Hong Kong and European white populations, African populations, or both. Because genome-wide association studies for asthma have not been performed in Chinese subjects, we cannot tell whether the genomic findings of recent consortium-based genome-wide association studies are applicable to our population. In addition, our group performed Roche 454 pyrosequencing on a 100-kb area spanning each of 10 asthma loci in 24 healthy Hong Kong children. For the 17q21 locus, there was substantial variation in the haplotype structures that were constructed from 224 common SNPs among Hong Kong subjects and 6 ethnic groups under the 1000 Genomes Project. Sixteen mostly small haplotype blocks were formed in Hong Kong, whereas 6 haplotype blocks were identified in Han Chinese in Beijing and central European subjects and 11 and 19 blocks were identified in Puerto Rican and Yoruba African subjects. In conclusion, differences in allele frequencies of asthma genes and haplotype structures of asthma loci are found between Chinese subjects and other ethnic groups. These sequence variations must be considered during the selection of tagging SNPs for replicating genetic associations between populations.
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Asma/epidemiología , Asma/genética , Pueblo Asiatico/genética , Niño , Cromosomas Humanos Par 17/genética , Frecuencia de los Genes , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Haplotipos , Hong Kong/etnología , Humanos , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
Spirometric testing is traditionally achievable in children of school-age and beyond. Incorporation of interactive incentives motivates preschool children to facilitate measurement of forced expiratory indices. Validated spirometric reference standards are available for Caucasian preschoolers but lacking in Asians. We established spirometric references in Chinese children aged 2-7 years, who were recruited from 19 randomly selected nurseries and kindergartens in Hong Kong. Parents completed International Study of Asthma and Allergies in Childhood questionnaire, and children concurrently performed incentive spirometry on-site according to international guideline. Prediction equations for spirometric indices were formulated by linear regression. One thousand four hundred two (72.9%) of 1,922 consented children, with mean (SD) age 4.4 (1.0) years, successfully performed spirometry. Following exclusions due to medical and technical reasons, 895 (63.8%) children contributed spirometric data to our references. Girls had lower FEV0.5 , FEV0.75 , FEV1 , FVC, and PEF but similar FEF25-75 than boys, adjusted for age, weight, and standing height as covariates. Standing height was the most important predictor for FEV0.5 , FEV0.75 , FEV1 , FVC, and PEF in both boys (adjusted R(2) 0.525-0.734) and girls (adjusted R(2) 0.583-0.721), whereas the best prediction model for both gender is formed by standing height, weight, and age. At various standing heights, our preschoolers had FEV1 Z-scores 0.13-1.00 higher than those of collaborative Caucasian reference. This study justifies the need for ethnic-specific reference equations and presents spirometry references in young Chinese children. Their forced expiratory indices are determined by gender, age, weight and standing height, and standing height is the best anthropometric index to predict all spirometric indices.
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Volumen Espiratorio Forzado , Espirometría , Pueblo Asiatico , Niño , Preescolar , Femenino , Humanos , Masculino , Estándares de ReferenciaRESUMEN
Measurement of fractional exhaled nitric oxide concentration (FeNO) has been proposed as a useful biomarker for monitoring and management of airway diseases. Limited information is available regarding reference levels of FeNO levels in Chinese adults. This study aimed to investigate the reference equation and determinants of FeNO in Chinese adults. 1093 (577 males) healthy nonsmoking subjects aged 18-90 years were recruited. FeNO was measured online using a chemiluminescence analyser. Other assessments included spirometry, skin prick tests, total serum IgE levels and eosinophil count in peripheral blood. The geometric mean FeNO was 32.6 (95% reference interval (RI) 31.4-33.7) ppb for all subjects. FeNO values were higher in males than females (geometric mean (95% RI) 38.3 (36.5-40.2) ppb versus 27.1 (25.8-28.5) ppb, p<0.0001), and in atopic than nonatopic subjects (34.6 (33.0-36.3) ppb versus 29.8 (28.3-31.4) ppb, p<0.0001). FeNO correlated with age (r(2) = 0.23), height (r(2) = 0.20), IgE level (r(2) = 0.18) and percentage eosinophil count (r(2) = 0.18) (all p<0.0001), but not with spirometric parameters. Based on multiple regression modelling, the reference equation of FeNO value was: log(FeNO) = 0.781 + 0.104(sex) + 0.004(age) + 0.084(atopy) + 0.003(height in cm), where for sex 1 = male and 0 = female, age is measured in years, for atopy 1 = atopic and 0 = nonatopic, and height is measured in cm. The FeNO of Chinese adults is higher than that of the Caucasian population, and is affected by age, sex, height and atopic status. This study provides useful references for the interpretation of FeNO.
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Pueblo Asiatico , Óxido Nítrico/metabolismo , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Estatura , Pruebas Respiratorias , Eosinófilos , Femenino , Volumen Espiratorio Forzado , Humanos , Hipersensibilidad Inmediata/etnología , Inmunoglobulina E/sangre , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Valores de Referencia , Factores Sexuales , Pruebas Cutáneas , Espirometría , Adulto JovenRESUMEN
Indoor aeroallergen exposures increased asthma symptoms in Caucasians, but their determinants and relationship to asthma and allergy in Asians are unclear. This study investigated exposures to cat, cockroach, and Blomia tropicalis allergens in 115 Hong Kong families with asthmatic children. Patients underwent exhaled nitric oxide and spirometric measurements. Home visits were made within 2 weeks during which parents completed a standardized questionnaire. Fel d 1, Bla g 2, and Blo t 5 in dust samples collected from patients' mattresses, bedroom floors, and living room floors were measured by immunoassays. These aeroallergens were only detectable in some homes (38-55% for Fel d 1; 9-21% for Bla g 2, and 7-14% for Blo t 5). The presence of cat and/or dog was a strong determinant for Fel d 1 in all indoor sites. The timing and frequency of bedding change was associated with Bla g 2 levels, whereas the timing of bedroom floor cleaning was a consistent factor for Blo t 5 levels. Asthmatic children in families with high allergen exposure were more likely to have ≥4 wheezing attacks in preceding 12 months and exercise-induced wheezing than those with normal allergen exposure (P = 0.051 and 0.030, respectively). Mattress levels of all three allergens were also associated with severity of several allergy symptoms (P = 0.025-0.005). None of these aeroallergens correlated with exhaled nitric oxide and spirometric parameters. This study identifies determinants for cat, cockroach, and B. tropicalis levels in Hong Kong families with asthmatic children. These exposures are associated with severity of allergy symptoms.
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Contaminación del Aire Interior/efectos adversos , Alérgenos/análisis , Asma/etiología , Exposición a Riesgos Ambientales/análisis , Adolescente , Animales , Asma/inmunología , Pruebas Respiratorias , Gatos , Niño , Cucarachas , Perros , Femenino , Hong Kong , Humanos , Mediciones Luminiscentes , Masculino , Ácaros , Óxido Nítrico/análisis , EspirometríaRESUMEN
SUMMARY: Positional cloning and candidate gene studies in different Caucasian populations identified the gene encoding plant homeodomain zinc finger protein 11 (PHF11) to be associated with asthma and eczema. Microarray analysis also confirmed increased PHF11 expression in type 1 T-helper lymphocytes. However, such disease associations are unclear in Asian subjects. This case-control genetic association study investigated the relationship between asthma and eczema phenotypes and tagging single-nucleotide polymorphisms (SNPs) of PHF11 in Hong Kong Chinese children. Three hundred and nineteen asthmatic children and 236 children with eczema were recruited from hospital clinics and 445 children without any history of allergic disease were recruited as controls from local schools and hospitals. Atopy was defined by the presence of allergen-specific IgE in plasma or positive skin prick tests with wheal >or=3 mm larger than negative control. Lung function of asthmatics was evaluated by pre-bronchodilator spirometry. Ten PHF11 SNPs were genotyped by multiplex SNaPshot assay. Genotyping call rates were 100% for all SNPs, which also followed Hardy-Weinberg equilibrium. These SNPs were tightly linked in one haplotype block (D' >or= 0.95 for nearly all SNP pairs). Physician-diagnosed asthma was weakly associated with PHF11 +20860 and +22818 (P = 0.032 for both). Atopy was also associated with PHF11 +22398 (P = 0.029). However, none of the PHF11 SNPs was associated with eczema diagnosis and plasma total IgE and spirometric parameters in our patients. Our findings do not support PHF11 to be a major candidate gene for asthma, eczema and aeroallergen sensitization in Chinese children.