Hing Yee Sy

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.

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

Aims/hypothesisMost 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.MethodsWe 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.ResultsWe 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 (pmeta = 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 (pmeta = 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/interpretationOur 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.

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 (FEV1) differed among patients with different control status (p < 0.001 for C-ACT and DSS; p = 0.014 for FEV1). Logistic regression confirmed that UA was associated with DSS (p < 0.001), PEF (p = 0.002), C-ACT (p = 0.011), and FEV1 (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 FEV1 (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.

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

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.

Differences in asthma genetics between Chinese and other populations

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.

Determinants of, and reference equation for, exhaled nitric oxide in the Chinese population

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 (r2 = 0.23), height (r2 = 0.20), IgE level (r2 = 0.18) and percentage eosinophil count (r2 = 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. Exhaled NO fraction in Chinese adults is higher than in Caucasians, and is affected by age, sex, height and atopy http://ow.ly/l5mNR

Asthma and bronchodilator responsiveness are associated with polymorphic markers of ARG1, CRHR2 and chromosome 17q21.

Objective Asthma is caused by complex interactions between multiple genes. &bgr;2-Agonist is the standard rescue treatment to relieve asthma symptoms and bronchoconstriction. A genetic study for spirometric parameters helps to predict the responses to this antiasthma treatment. This study investigated the relationship between asthma and bronchodilator responsiveness (BDR) and eight asthma genes. Methods Fifteen single-nucleotide polymorphisms in these genes were genotyped in 345 Chinese asthmatics and 464 controls. Gene–gene interactions were analysed by generalized multifactor dimensionality reduction (GMDR). Results The diagnosis of asthma was associated with rs7216389 in ORMDL3 [odds ratio (OR) 0.74 and 95% confidence interval (95% CI) 0.56–0.99] and rs3756780 in ARG1 (OR 0.67, 95% CI 0.51–0.89) and BDR with rs2749935 in ARG1. However, none of these associations remained significant at 5% when adjusted for multiple testing by the Bonferroni correction or a false discovery rate. GMDR analyses revealed that rs7216389 in ORMDL3 and rs3756780 in ARG1 might interact for a risk of asthma. Individuals with high-risk genotypes had OR 1.66 (95% CI 1.24–2.23) for asthma when compared with those with low-risk genotypes. GMDR suggested a two-locus model with rs2749935 in ARG1 and rs2190242 in CRHR2 to be associated with BDR. Specifically, reversibility of forced expiratory volume in 1 s was higher in high-risk than that in low-risk patients [mean (95% CI): 10.7 (8.6–12.9) vs. 6.8 (5.9–7.6)%]; with the latter group showing higher forced expiratory volume in 1 s reversibility compared with high-risk controls [2.8 (1.4–4.3)%]. Conclusion ARG1 and ORMDL3 may interact to determine the risk of asthma and ARG1 and CRHR2 to alter BDR in asthmatics. Nonetheless, this study is only hypothesis-generating as none of the single marker comparisons is significant when adjusted for multiple testing. These findings need to be confirmed in independent populations.

Interactions between Genetic Variants of FLG and Chromosome 11q13 Locus Determine Susceptibility for Eczema Phenotypes

Carmichael NM, Dostrovsky JO, Charlton MP (2010) Peptide-mediated transdermal delivery of botulinum neurotoxin type A reduces neurogenic inflammation in the skin. Pain 149:316–24 Chan J, Smoller BR, Raychauduri SP et al. (1997) Intraepidermal nerve fiber expression of calcitonin gene-related peptide, vasoactive intestinal peptide and substance P in psoriasis. Arch Dermatol Res 289:611–6 Dewing SB (1971) Remission of psoriasis associated with cutaneous nerve section. Arch Dermatol 104:220–1 Farber EM, Lanigan SW, Boer J (1990) The role of cutaneous sensory nerves in the maintenance of psoriasis. Int J Dermatol 29:418–20 Griffiths CE, Richards HL (2001) Psychological influences in psoriasis. Clin Exp Dermatol 26:338–42 Jiang W-Y, Raychaudhuri SP, Farber EM (1998) Double-labeled immunofluorescence study of cutaneous nerves in psoriasis. Int J Dermatol 37:572–4 Joachim RA, Kuhlmei A, Dinh QT et al. (2007) Neuronal plasticity of the ‘‘brain-skin connection’’: stress-triggered up-regulation of neuropeptides in dorsal root ganglia and skin via nerve growth factor-dependent pathways. J Mol Med 85:1369–78 Joseph T, Kurian J, Warwick DJ et al. (2005) Unilateral remission of psoriasis following traumatic nerve palsy. Br J Dermatol 152:185–6 Meng J, Wang J, Lawrence G et al. (2007) Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci 120:2864–74 Naukkarinen A, Nickoloff BJ, Farber EM (1989) Quantification of cutaneous sensory nerves and their substance P content in psoriasis. J Invest Dermatol 92:126–9 Ostrowski SM, Belkadi A, Loyd CM et al. (2011) Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptidedependent manner. J Invest Dermatol 131: 1530–8 Perlman HH (1972) Remission of psoriasis vulgaris from the use of nerve-blocking agents. Arch Dermatol 105:128–9 Remrod C, Lonne-Rahm S, Nordlind K (2007) Study of substance P and its receptor neurokinin-1 in psoriasis and their relation to chronic stress and pruritus. Arch Dermatol Res 299:85–91 Stratigos AJ, Katoulis AK, Stavrianeas NG (1998) Spontaneous clearing of psoriasis after stroke. J Am Acad Dermatol 38:768–70 Zanchi M, Favot F, Bizzarini M et al. (2008) Botulinum toxin type-A for the treatment of inverse psoriasis. J Eur Acad Dermatol Venereol 22:431–6

Genetic effects of multiple asthma loci identified by genomewide association studies on asthma and spirometric indices.

Genomewide association study (GWAS) published by GABRIEL consortium identified 10 asthma‐associated loci. However, their relationship with lung functions is unclear. This study investigated the association between asthma traits and single‐nucleotide polymorphisms (SNPs) of these GWAS loci.

Childhood asthma and spirometric indices are associated with polymorphic markers of two vitamin D 25‐hydroxylase genes

Polymorphic markers of vitamin D pathway genes have been associated with asthma traits in different White populations. This study investigated the relationship between asthma phenotypes and single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR), vitamin D binding protein (GC), two 25‐hydroxylases (CYP2R1 and CYP27A1), and 1α‐hydroxylase (CYP27B1) in Hong Kong Chinese children.