A polymorphism in the thyroid hormone receptor gene is associated with bronchodilator response in asthmatics.
A pro-asthmatic culture milieu and β2-agonist (isoproterenol) were previously shown to regulate the expression of select transcription factors (TFs) within human airway epithelial and smooth muscle cells. This study tests 1116 single-nucleotide polymorphisms (SNPs) across 98 of these TF genes for association with bronchodilator response (BDR) in asthma patients. Genotyping was conducted using the Illumina HumanHap550v3 Beadchip in 403 non-Hispanic White asthmatic children and their parents. SNPs were evaluated for association with BDR using family and population-based analyses. Forty-two SNPs providing P-values <0.1 in both analyses were then genotyped in three adult asthma trials. One SNP 5' of the thyroid hormone receptor-β gene was associated with BDR in the childhood population and two adult populations (P-value=0.0012). This investigation identified a novel locus for inter-individual variability in BDR and represents a translation of a cellular drug-response study to potential personalization of clinical asthma management.
Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. reqdu@channing.harvard.edu
Q L
QL
Duan
R
R
Du
J
J
Lasky-Su
B J
BJ
Klanderman
A B
AB
Partch
S P
SP
Peters
C G
CG
Irvin
J P
JP
Hanrahan
J J
JJ
Lima
K V
KV
Blake
S B
SB
Liggett
A A
AA
Litonjua
K G
KG
Tantisira
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001249:Asthma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D054316:Biomarkers, Pharmacological; D001993:Bronchodilator Agents; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors