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Hum Mol Genet DOI:10.1093/hmg/ddh149

Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids.

Publication TypeJournal Article
Year of Publication2004
AuthorsTantisira, KG, Lake, S, Silverman, ES, Palmer, LJ, Lazarus, R, Silverman, EK, Liggett, SB, Gelfand, EW, Rosenwasser, LJ, Richter, B, Israel, E, Wechsler, M, Gabriel, S, Altshuler, D, Lander, E, Drazen, J, Weiss, ST
JournalHum Mol Genet
Volume13
Issue13
Pages1353-9
Date Published2004 Jul 01
ISSN0964-6906
KeywordsAdministration, Inhalation, Adolescent, Adrenal Cortex Hormones, Adult, Anti-Asthmatic Agents, Asthma, Child, Female, Genetic Variation, Humans, Lung, Male, Middle Aged, Pharmacogenetics, Receptors, Corticotropin-Releasing Hormone
Abstract

Corticosteroids mediate a variety of immunological actions and are commonly utilized in the treatment of a wide range of diseases. Unfortunately, therapy with this class of medications is associated with a large proportion of non-responders and significant side effects. Inhaled corticosteroids are the most commonly used asthma controller therapy. However, asthmatic response to corticosteroids also varies widely between individuals. We investigated the genetic contribution to the variation in response to inhaled corticosteroid therapy in asthma. The association of longitudinal change in lung function and single nucleotide polymorphisms from candidate genes crucial to the biologic actions of corticosteroids were evaluated in three independent asthmatic clinical trial populations utilizing inhaled corticosteroids as the primary therapy in at least one treatment arm. Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to therapy in each of our three populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to corticosteroids compared with lack of the variants (P-values ranging from 0.006 to 0.025 for our three asthmatic populations). As the primary receptor mediating the release of adrenocorticotropic hormone, which regulates endogenous cortisol levels, CRHR1 plays a pivotal, pleiotropic role in steroid biology. These data indicate that genetic variants in CRHR1 have pharmacogenetic effects influencing asthmatic response to corticosteroids, provide a rationale for predicting therapeutic response in asthma and other corticosteroid-treated diseases, and suggests this gene pathway as a potential novel therapeutic target.

URLhttp://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=15128701
DOI10.1093/hmg/ddh149
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/15128701?dopt=Abstract

Alternate JournalHum. Mol. Genet.
PubMed ID15128701
Grant ListHR16045 / HR / NHLBI NIH HHS / United States
HR16046 / HR / NHLBI NIH HHS / United States
HR16047 / HR / NHLBI NIH HHS / United States
HR16048 / HR / NHLBI NIH HHS / United States
HR16049 / HR / NHLBI NIH HHS / United States
HR16050 / HR / NHLBI NIH HHS / United States
HR16051 / HR / NHLBI NIH HHS / United States
HR16052 / HR / NHLBI NIH HHS / United States
M01 RR00079 / RR / NCRR NIH HHS / United States
M01 RR03186 / RR / NCRR NIH HHS / United States
N01 HR16044 / HR / NHLBI NIH HHS / United States
P01 HL67664 / HL / NHLBI NIH HHS / United States
U01 HL 51843 / HL / NHLBI NIH HHS / United States
U01 HL51510 / HL / NHLBI NIH HHS / United States
U01 HL51831 / HL / NHLBI NIH HHS / United States
U01 HL51834 / HL / NHLBI NIH HHS / United States
U01 HL51845 / HL / NHLBI NIH HHS / United States