title: Genome-wide association identifies the T gene as a novel asthma pharmacogenetic locus.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  The lowest P value for the GWAS analysis was 2.09 × 10(-6). 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 × 10(-5) for rs3127412 and 6.13 × 10(-6) 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.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. kelan.tantisira@channing.harvard.edu
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
authors.forename: Amy
authors.initials: A
authors.lastname: Damask
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Szefler
authors.forename: Brooke
authors.initials: B
authors.lastname: Schuemann
authors.forename: Amy
authors.initials: A
authors.lastname: Markezich
authors.forename: Jessica
authors.initials: J
authors.lastname: Su
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.forename: Jody
authors.initials: J
authors.lastname: Sylvia
authors.forename: Rongling
authors.initials: R
authors.lastname: Wu
authors.forename: Fernando
authors.initials: F
authors.lastname: Martinez
authors.forename: Homer A
authors.initials: HA
authors.lastname: Boushey
authors.forename: Vernon M
authors.initials: VM
authors.lastname: Chinchilli
authors.forename: Dave
authors.initials: D
authors.lastname: Mauger
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000235:genetics / Q000627:therapeutic use*; D000328:Adult; D000483:Alleles; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005326:Fetal Proteins / Q000187:drug effects / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012129:Respiratory Function Tests; D018570:Risk Assessment; D012720:Severity of Illness Index; D020825:T-Box Domain Proteins / Q000187:drug effects / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult; D000098908:Brachyury Protein
chemical_list: D000305:Adrenal Cortex Hormones; D005326:Fetal Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein