Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci. Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma. Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV 1 in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma. Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 3 10 26. Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 3 10 25 for rs3127412 and 6.13 3 10 26 for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV 1 response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP. Conclusions: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma.Keywords: polymorphism; genome; pharmacogenomics; glucocorticoid Approximately 300 million individuals worldwide carry a diagnosis of asthma (1). Asthma is a genetic disease, known for more than three centuries to cluster in families. Based on twin studies, the broad sense heritability estimates (proportion of the total variance of a trait due to genetic causes) of an asthma diagnosis range from approximately 36-75%. For asthma control, the most widely prescribed medications are inhaled corticosteroids (ICS). Endogenous corticosteroid level and exogenous therapeutic Supported by NIH U01 HL65899 and R01 HL092197. SHARP was funded by NIH U10 HL74231, U01 HL65899, U54LM8748, U01 HL75232, U01 HL75408, U01 HL75409, U01 HL75415, U01 HL75416, U01 HL75417, U01 HL75419, U01 HL75420, U10 HL64287, U10 HL64288, U10 HL64295, U10 HL64305, U10 HL64307, U01 HL64313, U10 HL51831, U10 HL51834, U10 HL51843, U10 HL51810, U10 HL51823, U10 HL51845, and U10 HL56443. The full SHARP acknowledgment can be found in the online supplement. The NHLBI SHARe (SNP Health Association Resource) genotyping services were provided by Affymetrix, Inc. under US Federal Government contract number N02-HL-6-4278 from the NHLBI. The NIH GWAS Repository of ...

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.

Rationale: b 2 -Agonists are the most common form of treatment of asthma, but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable.Objectives: To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma.Methods: We performed a GWAS of acute bronchodilator response (BDR) to inhaled b 2 -agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. Measurements and Main Results:The combined P value for four SNPs reached statistical genome-wide significance after correcting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2.21 3 10 210 , 5.75 3 10 28 , 9.3 3 10 28 , and 3.95 3 10 28 , respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20% in the original population and by a similar percentage in the confirmatory population.Conclusions: These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma. Supported by National Institutes of Health (NIH) U01 HL65899, R01 NR013391, and R01 HL092197. SHARP was funded by NIH U10 HL74231, U01 HL65899, U54LM8748, U01 HL75232, U01 HL75408, U01 HL75409, U01 HL75415, U01 HL75416, U01 HL75417, U01 HL75419, U01 HL75420, U10 HL64287, U10 HL64288, U10 HL64295, U10 HL64305, U10 HL64307, U01 HL64313, U10 HL51831, U10 HL51834, U10 HL51843, U10 HL51810, U10 HL51823, U10 HL51845, and U10 HL56443. The full SHARP acknowledgment can be found in the online supplement. The NHLBI SHARe (SNP Health Association Resource) genotyping services were provided by Affymetrix, Inc. under U.S. Federal Government contract number N02-HL-6-4278 from the NHLBI, the NIH GWAS Repository of Genotype and Phenotype data (termed dbGaP) (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) was developed by the NIH National Center for Biotechnology Information to archive and distribute the results of studies that have investigated the interaction of genotype and phenotype in genome-wide association studies. The dbGaP project accession number for SHARP (SHARe Asthma Resource Project) is phs000166.v2.p1.

Introduction Atopic dermatitis (AD) in children significantly impacts families due to medical costs, “lost” hours, and secondary characteristics like asthma and ancillary infections. We investigate whether children delivered vaginally to women receiving intrapartum antibiotics have a greater risk of AD under the age of 2 years than their counterparts. Methods We conducted a retrospective analysis of women who delivered child(ren) vaginally between 1996 and 2008. Women were identified as those who received intrapartum antibiotics and those who did not. Pediatric records were used to determine incidence of AD. Results We collected data for 492 mother-child pairs. Intrapartum antibiotics were administered during 128 births; 28.9% of those children were diagnosed with AD by 2 years (RR 1.03 [0.75-1.41], p=0.854). Factors with greatest risks of diagnosis with AD by 2 years were intrapartum antibiotic exposure for >24hrs (RR 1.99 [1.13-3.49], p=0.0173), first born (RR 1.78 [1.33-2.38], p<0.0001) and higher maternal education (RR 1.43[0.99-2.06], p=0.039). No statistical difference in prevalence of AD related to parental eczema, maternal Group B Streptococcus status, or gestational age existed. Conclusions Exposure to antibiotics for <24hrs during a vaginal delivery does not increase the risk of AD. Studies are needed to understand if exposures >24hrs during the intrapartum period increase the risk of AD.