title: Chromosome 17: association of a large inversion polymorphism with corticosteroid response in asthma.
abstract: A 900-kb inversion exists within a large region of conserved linkage disequilibrium (LD) on chromosome 17. CRHR1 is located within the inversion region and associated with inhaled corticosteroid response in asthma. We hypothesized that CRHR1 variants are in LD with the inversion, supporting a potential role for natural selection in the genetic response to corticosteroids. We genotyped six single nucleotide polymorphisms (SNPs) spanning chromosome 17: 40,410,565-42,372,240, including four SNPs defining inversion status. Similar allele frequencies and strong LD were noted between the inversion and a CRHR1 SNP previously associated with lung function response to inhaled corticosteroids. Each inversion-defining SNP was strongly associated with inhaled corticosteroid response in adult asthma (P values 0.002-0.005). The CRHR1 response to inhaled corticosteroids may thus be explained by natural selection resulting from inversion status or by long-range LD with another gene. Additional pharmacogenetic investigations into regions of chromosomal diversity, including copy number variation and inversions, are warranted.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. kelan.tantisira@channing.harvard.edu
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D007446:Chromosome Inversion / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D011110:Polymorphism, Genetic / Q000187:drug effects
chemical_list: D000305:Adrenal Cortex Hormones