Eczema phenotypes are associated with multiple vitamin D pathway genes in Chinese children.

BACKGROUND: Vitamin D is increasingly recognized to play crucial roles in cutaneous immunity, and vitamin D treatment improved eczema control in small clinical trials. Several vitamin D-related genes were associated with asthma, but there are no data for eczema. METHODS: Twenty-three single-nucleotide polymorphisms (SNPs) of five vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, GC and VDR) were genotyped in 1442 Chinese children with eczema and 1231 non-allergic controls. SNPs that followed Hardy-Weinberg equilibrium and yielded ≥ 95% genotyping call-rate were included. Haplotypic associations and SNP-SNP interactions for eczema diagnosis and subphenotypes were analysed. RESULTS: Atopic eczema was associated with rs4674343 of CYP27A1 (odds ratio 0.66, 95% confidence interval 0.53-0.83, P = 0.0004). Increased eosinophil percentage was associated with CYP2R1 rs2060793A (P = 0.001) and rs1933064A (P = 0.001). Two CYP2R1 haplotypes increased eczema risk whereas one VDR haplotype lowered eczema risk. GC rs7041 and CYP2R1 rs7935792 interacted to modulate total IgE (cross-validation consistency 10/10, P = 0.047). Specifically, high-risk eczema patients had higher log-transformed total IgE than low-risk patients (2.76 ± 0.76 vs 2.60 ± 0.80, P = 0.002). CONCLUSION: A vitamin D-related SNP rs4674343 on CYP27A1 was found to be protective against atopic eczema. CYP2R1 and VDR haplotypes altered eczema susceptibility and eosinophil percentage, and GC and CYP2R1 interacted to determine total IgE among eczema patients.

Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4.

AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.

Asthma and atopy are associated with chromosome 17q21 markers in Chinese children.

BACKGROUND: Single-nucleotide polymorphism (SNP)-based genome-wide association study revealed that markers on chromosome 17q21 were linked to childhood asthma but not atopy in Caucasians, with the strongest signal being detected for the SNP rs7216389 in the ORMDL3 gene. Such association was unknown in Chinese. This study delineated the allele and genotype frequencies of 10 SNPs at chromosome 17q21, and investigated the relationship between these SNPs and asthma and plasma IgE in southern Chinese children. METHODS: Asthmatic children and non-allergic controls were recruited from pediatric clinics. Their plasma total and aeroallergen-specific IgE concentrations were measured by immunoassay. Ten SNPs on 17q21 region were genotyped by multiplex SNaPshot, and their genotype associations with asthma traits analyzed using multivariate regression. RESULTS: 315 patients and 192 controls were enrolled. The allele frequency for C allele of rs7216389 varied significantly from 0.232 in our controls, 0.389 in Han Chinese to 0.536 in Caucasians. Asthma diagnosis was associated with rs11650680 and five other SNPs including rs7216389 (P = 0.019-0.034), whereas atopy was associated only with rs11650680 (P = 0.0004). Linear regression revealed the covariates for plasma total IgE to be significant for rs11650680 (P = 0.008-0.0002). Haplotypic associations were found with atopy and increased plasma total IgE, with the respective odds ratios and 95% confidence intervals for TTTCCGTT haplotype to be 0.21 and 0.09-0.52 (P = 0.0002) and 0.41 and 0.18-0.90 (P = 0.025). CONCLUSION: Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region.

Identifying uncontrolled asthma in young children: clinical scores or objective variables?

OBJECTIVE: Several international asthma guidelines emphasize the importance of assessing asthma control. However, there is limited data on the usefulness of available assessment tools in indicating disease control in young asthmatics. This study investigated the ability of Chinese version of Childhood Asthma Control Test (C-ACT) and other disease-related factors in identifying uncontrolled asthma (UA) in young children. METHODS: During the same clinic visit, asthma patients 4 to 11 years of age completed C-ACT and underwent exhaled nitric oxide and spirometric measurements. Blinded to these results, the same investigator assigned Disease Severity Score (DSS) and rated asthma control according to Global Initiative for Asthma. RESULTS: The mean (SD) age of 113 recruited patients was 9.1 (2.0) years, and 35% of them had UA. C-ACT, DSS and forced expiratory volume in 1 second (FEV(1)) differed among patients with different control status (p < 0.001 for C-ACT and DSS; p = 0.014 for FEV(1)). Logistic regression confirmed that UA was associated with DSS (p < 0.001), PEF (p = 0.002), C-ACT (p = 0.011), and FEV(1) (p = 0.012). By ROC analysis, C-ACT and DSS were the best predictors for UA (p < 0.001), followed by PEF (p = 0.006) and FEV(1) (p = 0.007). When analyzed by the Classification and Regression Tree (CART) approach, the sequential use of DSS and C-ACT had 77% sensitivity and 84% specificity in identifying UA. CONCLUSIONS: C-ACT is better than objective parameters in identifying young Chinese children with UA.

Airway inflammatory and spirometric measurements in obese children.

OBJECTIVES: To investigate the association between obesity and airway inflammation and spirometric parameters in local children. DESIGN: Cross-sectional and observational study. SETTING: Paediatric clinics of a university-affiliated teaching hospital in Hong Kong. PATIENTS: Chinese subjects aged 6 to 18 years were recruited from the paediatric clinics. Obesity was defined as being 120% or more of the median weight-for-height. MAIN OUTCOME MEASURES: Airway inflammation assessed by exhaled nitric oxide concentration; lung function evaluated by measuring forced expiratory flow in 1-second and forced vital capacity using spirometry; and peak expiratory flow rate measured by using a mini-Wright peak flow meter. RESULTS: Fifty-five subjects were recruited into four groups as follows: 13 non-obese controls, 16 obese non-asthmatics, 15 non-obese asthmatics, and 11 obese asthmatics. The median (interquartile range) exhaled nitric oxide concentrations of these groups were 17.6 (14.4-20.9), 33.3 (26.1-75.4), 65.7 (32.0-110.0) and 49.2 (41.1-82.6) parts per billion, respectively (P=0.001 for trend). Post-hoc analysis revealed higher exhaled nitric oxide concentration in the latter three groups (obese and/or asthmatic subjects) than controls (P< or =0.002). Exhaled nitric oxide concentration did not differ among obese non-asthmatics, non-obese asthmatics, and obese asthmatics (P>0.1 for all). In non-asthmatics, exhaled nitric oxide concentration correlated positively with age (P=0.048), weight-for-height z-score (P=0.001), and forced vital capacity (P=0.009). Weight-for-height z-score correlated positively with forced vital capacity (P=0.041), but inversely with the forced expiratory flow in 1-second/forced vital capacity ratio (P=0.049). Such correlations were not observed in asthmatic children. CONCLUSION: Increased airway inflammation as revealed by exhaled nitric oxide concentration was found in obese non-asthmatic children. Weight-for-height z-score as an indicator of childhood obesity correlated with exhaled nitric oxide concentration and spirometric parameters in children without asthma. Nonetheless, concomitant obesity does not influence exhaled nitric oxide concentration in asthmatic children. Further studies are needed to identify the pathophysiologic mechanisms for such associations.