Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids.
BACKGROUND
To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations.


OBJECTIVE
We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs.


METHODS
We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults).


RESULTS
The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10(-8) (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10(-5)), rs2388639 (combined P = 8.56 × 10(-9)), and rs10044254 (combined P = 9.16 × 10(-8)) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants.


CONCLUSIONS
We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Heung-Woo
HW
Park
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Amber
A
Dahlin
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Szeman
S
Tse
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Qing Ling
QL
Duan
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Brooke
B
Schuemann
Arizona Respiratory Center, University of Arizona, College of Medicine, Tucson, Ariz.
Fernando D
FD
Martinez
Center for Genomics and Personalized Medicine Research and the Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC.
Stephen P
SP
Peters
Department of Pediatric and Pharmacology, National Jewish Health and University of Colorado, Denver School of Medicine, Denver, Colo.
Stanley J
SJ
Szefler
Center for Pharmacogenomics and Translational Research, Nemours Children's Clinic, Jacksonville, Fla.
John J
JJ
Lima
Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan.
Michiaki
M
Kubo
Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan.
Mayumi
M
Tamari
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Mass. Electronic address: kelan.tantisira@channing.harvard.edu.
Kelan G
KG
Tantisira
D000280:Administration, Inhalation; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D044783:F-Box Proteins / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D000305:Adrenal Cortex Hormones; D044783:F-Box Proteins
Asthma; child; glucocorticoid; pharmacogenomics; polymorphism