ABSTRACT
BACKGROUND: The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study (GWAS) on the slope of BHR in adult asthmatics. METHODS: We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n = 650), adjusting for smoking and inhaled corticosteroid use, and verified results in three other cohorts. Furthermore, we performed eQTL and co-expression analyses in lung tissue. RESULTS: In the discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D) and 26 SNPs with P-values < 1*10-5 were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumour-transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind-like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co-expression with pituitary tumour-transforming 1, the binding factor of PTTG1lP, and with vimentin and E-cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 (MAML2), both involved in Notch signalling. CONCLUSIONS: PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co-expression of PTTG1lP with vimentin and E-cadherin1, and MAML3 with MAML2.
Subject(s)
Asthma/genetics , Bronchial Hyperreactivity/genetics , DNA-Binding Proteins/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Membrane Proteins/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Adult , Asthma/diagnosis , Bronchial Hyperreactivity/diagnosis , Cohort Studies , Female , Gene Expression , Genotype , Humans , Intracellular Signaling Peptides and Proteins , Male , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Respiratory Function Tests , Severity of Illness Index , Trans-ActivatorsABSTRACT
Reversibility of airway obstruction in response to ß2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215 and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P=1.98 × 10(-7)) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P=8.51 × 10(-6)). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.
Subject(s)
Adrenergic beta-2 Receptor Agonists/therapeutic use , Asthma/drug therapy , Bronchodilator Agents/therapeutic use , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Adolescent , Adrenergic beta-2 Receptor Agonists/administration & dosage , Adult , Aged , Aged, 80 and over , Asthma/genetics , Bronchodilator Agents/administration & dosage , Child , Child, Preschool , Clinical Trials as Topic , Female , Genome-Wide Association Study , Humans , Male , Middle Aged , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Asthma is a common chronic respiratory disease in children and adults. An important genetic component to asthma susceptibility has long been recognized, most recently through the identification of several genes (e.g., ORMDL3, PDE4D, HLA-DQ, and TLE4) via genome-wide association studies. OBJECTIVE: To identify genetic variants associated with asthma affection status using genome-wide association data. METHODS: We describe results from a genome-wide association study on asthma performed in 3855 subjects using a panel of 455 089 single nucleotide polymorphisms (SNPs). RESULT: The genome-wide association study resulted in the prioritization of 33 variants for immediate follow-up in a multi-staged replication effort. Of these, a common polymorphism (rs9272346) localizing to within 1 Kb of HLA-DQA1 (chromosome 6p21.3) was associated with asthma in adults (P-value = 2.2E-08) with consistent evidence in the more heterogeneous group of adults and children (P-value = 1.0E-04). Moreover, some genes identified in prior asthma GWAS were nominally associated with asthma in our populations. CONCLUSION: Overall, our findings further replicate the HLA-DQ region in the pathogenesis of asthma. HLA-DQA1 is the fourth member of the HLA family found to be associated with asthma, in addition to the previously identified HLA-DRA, HLA-DQB1 and HLA-DQA2.
Subject(s)
Asthma/genetics , Genetic Predisposition to Disease , HLA-DQ Antigens/genetics , HLA-DQ alpha-Chains/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Asthma/epidemiology , Asthma/physiopathology , Child , Child, Preschool , Clinical Trials as Topic , Female , Genome-Wide Association Study , Humans , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) have been associated with IgE (in girls) and asthma (in general). We sought to determine whether TSLP SNPs are associated with asthma in a sex-specific fashion. METHODS: We conducted regular and sex-stratified analyses of association between SNPs in TSLP and asthma in families of children with asthma in Costa Rica. Significant findings were replicated in whites and African-American participants in the Childhood Asthma Management Program, in African-Americans in the Genomic Research on Asthma in the African Diaspora study, in whites and Hispanics in the Children's Health Study, and in whites in the Framingham Heart Study (FHS). MAIN RESULTS: Two SNPs in TSLP (rs1837253 and rs2289276) were significantly associated with a reduced risk of asthma in combined analyses of all cohorts (P values of 2 × 10(-5) and 1 × 10(-5) , respectively). In a sex-stratified analysis, the T allele of rs1837253 was significantly associated with a reduced risk of asthma in males only (P = 3 × 10(-6) ). Alternately, the T allele of rs2289276 was significantly associated with a reduced risk of asthma in females only (P = 2 × 10(-4) ). Findings for rs2289276 were consistent in all cohorts except the FHS. CONCLUSIONS: TSLP variants are associated with asthma in a sex-specific fashion.
Subject(s)
Asthma/genetics , Cytokines/genetics , Genetic Predisposition to Disease/genetics , Sex Characteristics , Black People/genetics , Child , Cohort Studies , Costa Rica , Female , Genetic Predisposition to Disease/ethnology , Genome-Wide Association Study , Genotype , Hispanic or Latino/genetics , Humans , Male , Polymorphism, Single Nucleotide , Risk Factors , White People/genetics , Thymic Stromal LymphopoietinABSTRACT
The effect of S/N from +20 to -10 db on loudness levels of connected discourse with or without background cafeteria noise was investigated for one set of instructions sampling the most comfortable loudness level (MCLL) and a second set sampling the upper limit of CLL. Normal young adults (N:16) showed no significant differences for either set of instructions in quiet or from 20 to 0 db S/N but mn MCLL was about 5 db lower at -10 db. Elderly hearing-aid wearers (N:10, mn age: 77 yrs) yielded mn differences across S/N of less than 5 db for either set of instructions. No data indicate that the speech CLL accurately predicts optimal hearing-aid gain, while the literature indicates that occasionally the desired maximum intelligibility frequently is not obtained at the MCLL. We question whether MCLL for speech justifies its measurement. A discussion is presented of the Comfort Level Method of adjusting gain in hearing-aid evaluations and a perhaps preferable Threshold Level Method in which the test stimulus is presented at a level corresponding to the predicted threshold and the aid's volume control is adjusted until S just perceives the signal.
