Relationship between the 17q21 locus and adult asthma in a Czech population

Several whole-genome association studies have shown a significant link between childhood asthma and the 17q12 chromosome region. We selected tagging single nucleotide polymorphisms (SNPs) in the ORMDL3 gene (17q12) to investigate gene variability in relation to adult allergic asthma and asthma/atopy traits in a Czech Caucasian population of adults. We conducted a case-control association study comprising 668 unrelated subjects (337 asthmatic and 331 control subjects). Four selected SNPs (rs17608925, rs12603332, rs8076131, and rs3169572) were genotyped using the TaqMan SNP Genotyping Assays. The single locus analysis showed only a borderline association between rs3169572 variant and asthma (p = 0.030, p(corr) > 0.05). However, seven different haplotypes were identified; among them, the TTAA haplotype was marginally associated with asthma (p = 0.045, p(corr) > 0.05) and TCAG haplotype was significantly associated with asthma in males (p = 0.009, p(corr) < 0.05, odds ratio = 1.48, 95% confidence interval = 1.10-2.00). In addition, associations between the ORMDL3 genotypes and the total IgE level (p = 0.05, p(corr) > 0.05) and hypersensitivity to the pollen (p = 0.007, p(corr) < 0.05) were established. However, no relationship between ORMDL3 SNPs and the pulmonary functions was found (p > 0.05). These findings suggest that the genetic variability in the 17q21 region may be one of the risk factors also for adult asthma, especially in male individuals.     

17q12-21 and asthma: interactions with early-life environmental exposures

Background17q12-21 polymorphisms are associated with asthma presence and severity across different populations.ObjectiveTo extensively investigate the genes in this region among Croatian schoolchildren in a case-control study, taking account of early-life environmental exposures.MethodsWe included 423 children with asthma and 414 controls aged 5 to 18 years. Fifty-one haplotype tagging single-nucleotide polymorphisms (SNPs) were genotyped (GSDMA, GSDMB, ORMDL3, IKZF3, ZPBP2, and TOP2). Data on exposure to smoking and furry pet ownership were collected using a validated questionnaire. Information on severe asthma exacerbations with hospital admission were retrieved from hospital notes. All patients underwent spirometry.ResultsWe found 2 SNPs (1 novel rs9635726 in IKZF3) to be associated with asthma. Among children with asthma, 4 SNPs (in ZPBP2, GSDMB, and GSDMA) were associated with hospital admissions and 8 SNPs with lung function. One SNP (rs9635726) remained significantly associated with a predicted forced expiratory volume in 1 second after false discovery rate correction. Nine markers across 5 genes showed interaction with early-life environmental tobacco smoke (ETS) exposure in relation to asthma and 2 with furry pet ownership. Among children with asthma, we observed significant interactions between early-life ETS exposure and 3 SNPs for lung function and among early-life ETS exposure, 3 SNPs (in ORMDL3 and GSDMA), and hospital admission with asthma exacerbation. Three SNPs (in ORMDL3) interacted with current furry pet ownership in relation to hospital admissions for asthma exacerbation.ConclusionOur results indicate that several genes in the 17q12-21 region may be associated with asthma. This study confirms that environmental exposures may need to be included into the genetic association studies.     

17q12-21 variants are associated with asthma and interact with active smoking in an adult population from the United Kingdom

BackgroundAlthough an association between 17q12-21 and asthma has been replicated across different populations, some inconsistencies have been found between different studies.ObjectiveWe investigated the association between genetic variation in this region with asthma, lung function, airway inflammation, hyperresponsiveness (AHR), and atopy in a case-control study of United Kingdom adults. The interaction between genotype and smoking was also evaluated.MethodsStudy subjects (n = 983) were carefully phenotyped using questionnaires, measurement of lung function, AHR (methacholine challenge), exhaled nitric oxide (eNO), and assessment of atopic status. Blood/saliva/buccal swabs were collected, and 47 single nucleotide polymorphisms (SNPs) in 17q12-21 were genotyped using MALDI-TOF (Matrix-assisted LASER desorption/ionisation-time of flight) mass spectrometry. We conducted a comprehensive investigation of 28 common SNPs within 6 genes of interest (IKZF3, ZPBP2, ORMDL3, GSDMA, GSDMB, TOP2A).ResultsSixteen SNPs were significantly associated with asthma after multiple testing correction (P ≤ .01), of which 5 (rs2290400, rs8079416, rs3894194, rs7212938, and rs3859192) were strongly associated (FDR P ≤ .0002), and one was novel (IKZF3-rs1453559). For 3 of these SNPs, we found significant interaction with smoking and asthma (rs12936231, rs2290400, and rs8079416). Smoking modified the associations between 8 SNPs and lung function (rs9911688, rs9900538, rs1054609, rs8076131, rs3902025, rs3859192, rs11540720, and rs11650680). We observed significant interaction between 5 SNPs and smoking on AHR, and 3 interacted with smoking in relation to asthma with AHR (rs4795404, rs4795408, rs3859192).ConclusionWe found 1 novel association and replicated several previously reported associations between 17q12-21 polymorphisms and asthma. We demonstrated significant interactions between active smoking and polymorphisms in 17q12-21 with asthma, lung function, and AHR in adults. Our data confirm that 17q12-21 is an important asthma susceptibility locus.     

Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia

Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P=4.8 × 10⁻⁷). Five other loci were associated with P<10⁻⁵, most notably the chemokine CXC motif ligand 14 (CXCL14) gene (rs31263, P=7.8 × 10⁻⁶). We found no evidence for association with the specific risk variants reported recently for PDE4D, DENND1B and ILR1L1. However, a variant in IL1RL1 that is in low linkage disequilibrium with that reported previously was associated with asthma risk after accounting for all variants tested (rs10197862, gene wide P=0.01). This association replicated convincingly in an independent cohort (P=2.4 × 10⁻⁴). A 300-kb deletion on chromosome 17q21 was associated with asthma risk, but this did not reach experiment-wide significance. Asthma cases and controls had comparable CNV rates, length and number of genes affected by deletions or duplications. In conclusion, we confirm the association between asthma risk and variants in ORMDL3 and identify a novel risk variant in IL1RL1. Follow-up of the 17q21 deletion in larger cohorts is warranted.     

Interleukin-17A and -17F single nucleotide polymorphisms associate with susceptibility of asthma in Chinese Han population

Interleukin 17 (IL-17) plays important roles in the progression of asthma. Genetic variants in the Il-17 may influence the immunopathogenesis of many diseases. Many studies have investigated the relevance of IL-17 polymorphism with cancers or immune diseases, including asthma. In this study, single nucleotide polymorphisms (SNPs) of IL-17 were explored by PCR-RFLP and verified by sequencing method. The frequencies of genotypes and alleles were analyzed. Haplotypes were analyzed with the SHEsis online program. The relationship between the genotypes of SNPs and IgE level was also investigated. The False Discovery Rate (FDR) correction was performed (P-adjusted?<?0.05). The frequencies of A allele, GA and (GA?+?AA) genotype of rs3748067 were significantly higher in asthma patients. As for rs763780, the C allele in patients was more frequent than healthy controls. In addition, we found C carriers (CT?+?CC) were significantly higher in asthma patients. We further found that the haplotype CT for IL-17F (rs763780/rs2397084) was associated with an increased susceptibility of asthma, but this association did not survive after FDR correction. The level of serum total IgE in mutant group (GA?+?AA) of rs3748067 was significantly higher than the wild genotype (GG) group and control group. These results suggested that IL-17 SNPs, but not haplotypes may be associated with the susceptibility of asthma in Chinese Han population from central China.     

A sequence variant on 17q21 is associated with age at onset and severity of asthma

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0–5 years OR=1.51, P=6.89·10⁻⁹) and adolescence (age: 14–17 years OR=1.71, P=5.47·10⁻⁹). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.     

Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze

The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure.     

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.     

支气管哮喘易感区域5q31-33内Tim-3基因单体型分析

目的： 探讨染色体上支气管哮喘易感区域5q31-33内Tim-3基因多态性与支气管哮喘的关系。方法：应用限制性片段长度多态性技术方法,分析了118个儿童变应性哮喘核心家系Tim-3基因4个SNPs(rs10053538、rs10515746、rs13170556和rs9313441)的基因型;采用基于家系传递不平衡检验（TDT）,分析基因分型数据;应用TRANSMIT软件构建单体型并进行单体型关联分析。结果：①基于家系的TDT分析显示,Tim-3基因的4个SNPs由杂合子父母传递给患病子代的等位基因频率不比预期值高,与哮喘无关（P>0.05）。②Transmit多个位点单体型分析结果显示由Tim-3基因rs10053538、 rs13170556、 rs9313441构建的单体型与支气管哮喘有关联（Global 2=10.83,P<0.05）。父母传递给患病子女GGG单体型的观察值小于期望值,差异显著（2=8.24,P<0.01）。结论：中国汉族人群中,位于染色体5q31-33区域的Tim-3基因本身或其附近的基因可能与儿童变应性哮喘的易感性相关。     

Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma

Background:  A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3 ) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans.
Objective:  We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like ( GSDML ) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population.
Methods:  We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4–17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens.
Results:  Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19–2.53, P  = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12–2.38, P  = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high ( r ² = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35–1.54, P  < 0.00001).
Conclusions:  Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma.     

The Association of GSDMB and ORMDL3 Gene Polymorphisms With Asthma: A Meta-Analysis

PurposeORM1-like 3 (ORMDL3) belongs to a highly conserved protein family which is anchored as transmembrane protein in the endoplasmic reticulum. Gasdermin B (GSDMB) is adjacent to ORMDL3 on chromosome 17q21.2 and belongs to the gasdermin-domain containing the protein family (GSDM family). Recent reports suggest that GSDMB and ORMDL3 are associated with asthma in several populations. However, genetic association studies that examined the association of GSDMB and ORMDL3 gene variants with asthma showed conflicting results. To assess whether combined evidence shows the association between GSDMB/ORMDL3 polymorphism and asthma.MethodsA bibliographic search from MEDLINE identified 13 original articles using the search keywords ''GSDMB'', ''ORMDL3'', and ''asthma''. An updated literature-based meta-analysis involving 6,691 subjects with asthma, 9,281 control individuals, and 1,360 families were conducted. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on the fixed effects model or the random effects model depended on Cochran''s Q-statistic and I² values. Data from case-control and TDT studies were analyzed in an allelic model using the Catmap software.ResultsWe selected and identified 3 SNPs of ORMDL3 associated with asthma (rs8076131: OR=1.10; 95% CI, 1.02-1.20; P=0.012. rs12603332: OR=1.15; 95% CI, 1.05-1.25; P=0.002. rs3744246: OR=1.10; 95% CI, 1.02-1.17; P=0.008) and 1 SNP of GSDMB associated with asthma (rs7216389: OR=1.37; 95% CI, 1.27-1.47; P<0.01). Publication bias was estimated using modified Egger''s linear regression test proposed by Harbordetal and revealed no evidence of biases. Furthermore, cumulative meta-analysis in chronological order showed the inclination toward significant association for rs7216389 and rs12603332 with continually adding studies, and the inclination toward null-significant association for rs3744246 and rs8076131.ConclusionsModerate evidence exists for associations of the ORMDL3 rs8076131, rs12603332, and rs3744246 and GSDMB rs7216389 variants with asthma. Large sample size and representative population-based studies and TDT studies with homogeneous asthmatic patients and well-matched controls are warranted to confirm this finding.     

Genetic variation in ORMDL3 gene may contribute to the risk of asthma: A meta-analysis

Background

Since the first genome-wide association study report of an association between the ORMDL3 rs7216389 polymorphism and asthma, many studies have been carried out to establish its role in asthma susceptibility among different ethnic groups. However, results have not been consistent across all studies, compelling us to conduct the present meta-analysis.

Methods

A literature search for eligible studies published before January 20, 2014 was conducted in the MEDLINE, EMBASE, and CNKI databases. The association was assessed using pooled crude odds ratios (ORs) with their corresponding 95% confidence intervals (CIs).

Results

A total of 18 individual studies in 15 publications (total 7904 asthma patients and 10,874 healthy controls) were included in the meta-analysis. A meta-analysis of all included studies suggested that there was a highly significant risk effect conferred by the rs7216389*T allele on asthma susceptibility. In addition, we performed stratified analyses to evaluate ethnicity-specific and age-specific effects. Our subgroup analyses based on ethnicity and age-of-onset confirmed the role of the ORMDL3 rs7216389 polymorphism in conferring susceptibility to both childhood- and adult-onset asthma, especially in Caucasians and Asians.

Conclusions

The results of this meta-analysis firmly established that genetic variation at the rs7216389 locus, which controls the expression of the ORMDL3, may be a major, independent predisposing factor for asthma in ethnically diverse populations. However, further systematic studies are needed to determine the underlying mechanisms of this association.     

Clinical and molecular description of a 17q21.33 microduplication in a girl with severe kyphoscoliosis and developmental delay

High proportion of disease-associated copy number variant maps to chromosome 17. Genomic studies have provided an insight into its complex genomic structure such as relative abundance of segmental duplication and intercepted repetitive elements. 17q21.31, 17q11.2 and 17q12 loci are well known on this chromosome and are associated with microdeletion and microduplication syndrome. No syndrome associated with 17q21.33 locus have been described.We report clinical, cytogenetic and molecular investigations of a 13 years-old girl admitted for evaluation of microcephaly, scoliosis, skeletal defects and learning difficulties. We carried out detailed analysis of the clinical phenotype of this patient and investigated the genetic basis using Agilent 180K Array Comparative Genomic Hybridization.We identified a ∼0.9 Mb de novo microduplication on chromosome 17q21.33. Four genes, COL1A1, SGCA, PPP1R9B and CHAD located within the duplicated region are possible candidates for clinical features present in our patients. Gene expression studies by real-time RT-PCR assay only showed an overexpression of SGCA (P < 0.01), a component of the dystrophin glycoprotein complex. Defect of SGCA was previously shown to lead to severe childhood autosomal recessive muscular dystrophy (LGMD2D) which result in progressive muscle weakness and can also be associated with hyperlordosis or scoliosis. Further cases with similar duplications are expected to be diagnosed. This will contribute to the delineation of this potential new microduplication syndrome and to improve genetic counseling.     

Association of single nucleotide polymorphisms on Interleukin 17 receptor A (IL17RA) gene with aspirin hypersensitivity in asthmatics

Aim

To investigate the association of single nucleotide polymorphisms (SNP) on IL17RA gene with Aspirin Exacerbated Respiratory Disease (AERD) and the functional effect of these variants on expression of IL17RA gene products.

Material & methods

15 SNPs of IL17RA gene were analyzed in 825 normal controls and 143 subjects with AERD and 411 with aspirin-tolerant asthma (ATA) and functionally characterized using measurement of protein and m-RNA expression.

Result

Minor alleles frequencies of the three SNPs (−1075 A > G, −947 A > G, −50 C > T) and one haplotype (BL1_ht1) were significantly lower in AERD compared to those in ATA (p^corr = 0.002–0.03). IL17RA protein expression and mRNA amount in CD14⁺ peripheral blood monocytes and mononuclear cells were significantly increased in subjects carrying the common alleles homozygote compared with those carrying the minor alleles.

Conclusions

The minor alleles of the three SNPs may decrease the risk of AERD via attenuation of IL17RA gene expression.     

Associations between interleukin 17A and 17F polymorphisms and asthma susceptibility: A meta-analysis

Owing to their role in inflammatory reactions and immunological responses as well as their chromosomal location, interleukin (IL) 17A and 17F are regarded as candidate causal genes associated with asthma. The aim of this study was to determine whether IL17 polymorphisms are associated with susceptibility to asthma. We used the PubMed/Medline and Embase databases to search for studies reporting IL17 polymorphisms in patients with asthma and healthy controls. Meta-analyses were conducted to determine the associations between IL17A rs8193036 (−737C/T), rs2275913 (−197G/A), rs3819024 (A/G), rs3748067 (C/T), and rs4711998 (A/G) and IL17F rs763780 (7488A/G), rs2397084 (T/C), rs1889570 (C/T), rs11465553 (G/A), and rs1266828 (T/C) polymorphisms and asthma susceptibility. A total of 20 studies were included in this meta-analysis. Our results revealed the IL17A rs8193036 CC genotype was associated with asthma susceptibility (odds ratio [OR] = 1.490, 95% confidence interval [CI] = 1.027–2.161, p = .036). However, stratification by ethnicity indicated no association between this polymorphism and asthma in European and Asian subjects. Furthermore, no association was found between this polymorphism and asthma using the allele contrast, dominant or homozygous contrast models. No evidence of an association was found between any of the other IL17A and IL17F polymorphisms and asthma susceptibility in this meta-analysis. This meta-analysis showed that, among the studied polymorphisms, only the CC genotype of IL17A rs8193036 is associated with asthma susceptibility.     

GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness

In 2007, a genome-wide association study identified associations between variants involved in the regulation of ORMDL3 expression and asthma. These observations were subsequently replicated in case-control studies in several ethnic groups. We investigated the possible contribution of GSDMB/ORMDL3 variants to asthma susceptibility and intermediate asthma phenotypes in Korean children. The polymorphisms rs7216389, rs4794820, rs4065275, and rs11650680 were genotyped using the TaqMan assay in 931 asthmatics and 480 normal controls in a case-control study, and in 1907 elementary school children in a general population study. Each subject also underwent peripheral blood analysis of immunoglobulin E levels, eosinophil cationic protein (ECP) levels, and eosinophil percentage. Pulmonary function testing (FEV₁ and MMEF) and a methacholine provocation test (PC₂₀) were also performed. The case-control study revealed a significant association between a linkage disequilibrium block, including rs7216389, rs4794820, and rs4065275, and susceptibility to asthma and atopic asthma. The CT and TT genotypes of rs11650680 were associated with lower log ECP levels than the CC genotype in asthmatics, while the GA and AA genotypes of rs4794820 were associated with higher log PC₂₀ values than the GG genotype in atopic asthmatics. The haplotype (CAA) of rs7216389, rs4794820 and rs4065275 was associated with a lower risk of asthma susceptibility and a higher log PC₂₀. In the general population study, rs11650680 was significantly associated with a diagnosis of asthma. Moreover, the GA and AA genotypes of rs4794820 were associated with higher log PC₂₀ values and lower eosinophil percentages than the GG genotype in subjects who had been diagnosed with asthma, or showed bronchial hyperresponsiveness (PC₂₀ ? 16). The GSDMB/ORMDL3 gene block, which includes rs7216389, rs4065275, rs4794820, and rs11650680, may be associated with asthma susceptibility in Korean children because it promotes eosinophilic inflammation, which induces bronchial hyperresponsiveness.     

Expansive marker analysis replicating the association of glaucoma susceptibility with human chromosome loci 1q43 and 10p12.31

Three human chromosome loci (1q43, 10p12.31, and 12q21.31) were recently associated with the susceptibility to primary open-angle glaucoma (POAG) in a Japanese population; however, this was not replicated in three subsequent studies using South Indian, Afro-Caribbean, and Chinese populations. To identify genetic markers that are robustly associated across ethnic populations, numerous markers in addition to the six in the three reported loci were examined in this study. A total of 31 single-nucleotide polymorphism (SNP) markers were genotyped for 1115 Korean participants, and many neighboring SNPs were imputed using the Korean HapMap Project genotype data. Each SNP was statistically tested for association with POAG susceptibility by comparisons among 211 POAG patients with 904 unaffected controls. A strong and statistically significant association was found with a previously unreported SNP, rs7098387 (odds ratio, OR=2.0 (1.4–3.0), P=0.00038) at the 10p12.31 locus (where 11 SNPs were typed and 38 imputed) in contrast to the reported rs7081455, which was too poorly correlated with newly associated rs7098387 (r²=0.003, D′=0.40) to show association. Additionally, a modest association was observed with the reported rs693421 (OR=1.4 (1.1–1.7), P=0.0082) and several other SNPs located within and around ZP4 at the 1q43 locus (10 SNPs typed and 14 imputed). However, no association was observed with the reported rs7961953 SNP or any other SNPs at the 12q21.31 locus, upstream of TMTC2 (10 SNPs typed and 29 imputed). Accordingly, POAG susceptibility association was replicated using rs7098387 (C) rather than rs7081455 (T) at the 10p12.31 locus and additionally with rs693421 (T) at the 1q43 locus.     

Molecular and clinical delineation of the 17q22 microdeletion phenotype

Deletions involving 17q21–q24 have been identified previously to result in two clinically recognizable contiguous gene deletion syndromes: 17q21.31 and 17q23.1–q23.2 microdeletion syndromes. Although deletions involving 17q22 have been reported in the literature, only four of the eight patients reported were identified by array-comparative genomic hybridization (array-CGH) or flourescent in situ hybridization. Here, we describe five new patients with 1.8–2.5-Mb microdeletions involving 17q22 identified by array-CGH. We also present one patient with a large karyotypically visible deletion involving 17q22, fine-mapped to ∼8.2 Mb using array-CGH. We show that the commonly deleted region in our patients spans 0.24 Mb and two genes; NOG and C17ORF67. The function of C17ORF67 is not known, whereas Noggin, the product of NOG, is essential for correct joint development. In common with the 17q22 patients reported previously, the disease phenotype of our patients includes intellectual disability, attention deficit hyperactivity disorder, conductive hearing loss, visual impairment, low set ears, facial dysmorphology and limb anomalies. All patients displayed NOG-related bone and joint features, including symphalangism and facial dysmorphology. We conclude that these common clinical features indicate a novel clinically recognizable, 17q22 contiguous microdeletion syndrome.     

Genetic variants at 10q 23.33 are associated with plasma lipid levels in a Chinese population

Plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes.The IDE-KIF11-HHEX gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes.We hypothesized that genetic variants at 10q23.33 may be associated with plasma lipid concentrations.Seven tagging single nucleotide polymorphisms(SNPs:rs7923837,rs2488075,rs947591,rs11187146,rs5015480,rs4646957 and rs1111875) at 10q23.33 were genotyped in 3,281 subjects from a Han Chinese population,using the TaqMan OpenArray and Sequenom MassARRAY platforms.Multiple linear regression analyses showed that SNP rs7923837 in the 3’-flanking region of HHEX was significantly associated with triglyceride levels(P = 0.019,0.031 mmol/L average decrease per minor G allele) and that rs2488075 and rs947591 in the downstream region of HHEX were significantly associated with total cholesterol levels(P = 0.041,0.058 mmol/L average decrease per minor C allele and P = 0.018,0.063 mmol/L average decrease per minor A allele,respectively).However,the other four SNPs(rs11187146,rs5015480,rs4646957 and rs1111875) were not significantly associated with any plasma lipid concentrations in this Chinese population.Our data suggest that genetic variants in the IDE-KIF11-HHEX gene cluster at 10q23.33 may partially explain the variation of plasma lipid levels in the Han Chinese population.Further studies are required to confirm these findings in other populations.     

Role of gene polymorphisms/haplotypes and serum levels of interleukin-17A in susceptibility to viral myocarditis

Interleukin-17A (IL-17A) has been implicated in the pathogenesis of viral myocarditis (VMC). However, the role of IL-17A polymorphisms in susceptibility to VMC has not been reported to date. The aim of this study was to explore the association between IL-17A variants as well as serum IL-17 levels with VMC. Three single-nucleotide polymorphisms (SNPs) (rs2275913, rs3819025, and rs3748067) were analyzed by the polymerase chain reaction-restriction fragment length polymorphism method in 236 VMC patients and 259 controls from China. Serum IL-17A levels were measured by enzyme-linked immunosorbent assay kits. Multivariable logistic regression analysis that the rs2275913 AA genotype and the haplotype -197A/+45G/+1249G (AGG) were associated with an increased risk of VMC (all P?<?0.05). Consistent with these findings, the rs2275913 AA genotype was linked to higher serum IL-17A compared to GG/AG genotype (all P?<?0.001). We observed no associations between the other two SNPs and risk of VMC. Serum IL-17A levels were significantly higher in the VMC group than controls (P?<?0.001) and gradually increased with the increase of New York Heart Association grade in VMC patients (P?<?0.05). Spearman correlation test revealed that the serum IL-17A level was correlated with the cardiac damage and left ventricular systolic functions among VMC patients (all P?<?0.05). Our study reveals that IL-17A expression may contribute to the development and severity of VMC. The SNP rs2275913 in the IL-17A gene might exert influence on susceptibility to VMC via linking with the serum IL-17A level.