Exome-wide pharmacogenomic analysis of response to thiopurines in inflammatory bowel disease patients / William Zabala, Raquel Cruz, Manuel Barreiro-de Acosta, María Chaparro, Julián Panes, Ana Echarri, Maria Esteve, Daniel Carpio, Montserrat Andreu, Esther Garcia-Planella, Eugeni Domenech, Angel Carracedo, Javier P. Gisbert, Francisco Barros, on behalf of EIGA and ENEIDA investigators
Background: The response to thiopurine treatment in inflammatory bowel disease patients differs greatly among individuals and nearly 50% of patients experience no benefit. Several factors have been implicated in determining this response, including individual genetic variation. Methods: Aiming to identify genes involved in the response to thiopurine drugs, a two-stage investigation of 20,000 coding single-nucleotide polymorphisms (cSNPs) in 10,000 genes was performed in a Spanish cohort of 257 individuals, 193 showing steroid free remission versus 64 non responder individuals 12 months after initial dose of the drug. The 20 top cSNPs with lower p-values for the association test identified at the first stage (133 responders / 34 non responders), were replicated in a second cohort (60 responders / 30 non responders). Results: Whereas not statistically significant in all of the two analyzed cohorts, the consistent across samples direction of the observed associations and the allelic joined analysis suggest a significant risk for lack of response related to two genes, PION and ZNF673. With a CMH p-value= 4.26x-06, the associated PION cSNP (rs17151692) minor A allele increases risk for treatment failure 4.5 times when all data is combined. Conclusion: These findings might help to understand the biological mechanisms behind thiopurine treatment failure and to tailor treatment for individual inflammatory bowel disease patients.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2015 |
|---|---|
| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Current pharmacogenomics and personalized medicine - 13(2015), 1, Seite 61- |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zabala, WilliamWilliam [VerfasserIn] |
|---|
| Links: |
FID Access [lizenzpflichtig] |
|---|
| Umfang: |
1 Online-Ressource (7 p) |
|---|
| doi: |
10.2174/1875692113666150813151413 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
KFL001009311 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | KFL001009311 | ||
| 003 | DE-627 | ||
| 005 | 20231129130323.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 210608s2015 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.2174/1875692113666150813151413 |2 doi | |
| 035 | |a (DE-627)KFL001009311 | ||
| 035 | |a (KFL)prod_DARH_10.2174/1875692113666150813151413 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 084 | |a PHARM |q DE-84 |2 fid | ||
| 100 | 1 | |a Zabala, WilliamWilliam |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Exome-wide pharmacogenomic analysis of response to thiopurines in inflammatory bowel disease patients |c William Zabala, Raquel Cruz, Manuel Barreiro-de Acosta, María Chaparro, Julián Panes, Ana Echarri, Maria Esteve, Daniel Carpio, Montserrat Andreu, Esther Garcia-Planella, Eugeni Domenech, Angel Carracedo, Javier P. Gisbert, Francisco Barros, on behalf of EIGA and ENEIDA investigators |
| 264 | 1 | |c 2015 | |
| 300 | |a 1 Online-Ressource (7 p) | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Background: The response to thiopurine treatment in inflammatory bowel disease patients differs greatly among individuals and nearly 50% of patients experience no benefit. Several factors have been implicated in determining this response, including individual genetic variation. Methods: Aiming to identify genes involved in the response to thiopurine drugs, a two-stage investigation of 20,000 coding single-nucleotide polymorphisms (cSNPs) in 10,000 genes was performed in a Spanish cohort of 257 individuals, 193 showing steroid free remission versus 64 non responder individuals 12 months after initial dose of the drug. The 20 top cSNPs with lower p-values for the association test identified at the first stage (133 responders / 34 non responders), were replicated in a second cohort (60 responders / 30 non responders). Results: Whereas not statistically significant in all of the two analyzed cohorts, the consistent across samples direction of the observed associations and the allelic joined analysis suggest a significant risk for lack of response related to two genes, PION and ZNF673. With a CMH p-value= 4.26x-06, the associated PION cSNP (rs17151692) minor A allele increases risk for treatment failure 4.5 times when all data is combined. Conclusion: These findings might help to understand the biological mechanisms behind thiopurine treatment failure and to tailor treatment for individual inflammatory bowel disease patients | ||
| 700 | 1 | |a Cruz, Raquel |e verfasserin |4 aut | |
| 700 | 1 | |a Barreiro-de Acosta, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Chaparro, María |e verfasserin |4 aut | |
| 700 | 1 | |a Panes, Julián |e verfasserin |4 aut | |
| 700 | 1 | |a Echarri, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Esteve, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Carpio, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Andreu, Montserrat |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia-Planella, Esther |e verfasserin |4 aut | |
| 700 | 1 | |a Domenech, Eugeni |e verfasserin |4 aut | |
| 700 | 1 | |a Carracedo, Angel |e verfasserin |4 aut | |
| 700 | 1 | |a Gisbert, Javier P. |e verfasserin |4 aut | |
| 700 | 1 | |a Barros, Francisco |e verfasserin |4 aut | |
| 700 | 0 | |a on behalf of EIGA and ENEIDA investigators |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Current pharmacogenomics and personalized medicine |d Sharjah : Bentham, 2008 |g 13(2015), 1, Seite 61- |h Online-Ressource |w (DE-627)KFL000006556 |w (DE-600)2424232-9 |w (DE-576)30683636X |x 1875-6913 |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2015 |g number:1 |g pages:61- |
| 856 | 4 | 0 | |u http://pharmazie.proxy.fid-lizenzen.de/fid/bentham-ejournals-pharmazie/www.eurekaselect.com/openurl/content.php?genre=article&issn=1875-6921&volume=13&issue=1&spage=61 |m X:KFL |x Verlag |y FID Access |z lizenzpflichtig |
| 912 | |a ZDB-1-BEJ | ||
| 912 | |a GBV_KFL | ||
| 912 | |a FID-PHARM | ||
| 912 | |a SSG-OLC-PHA | ||
| 935 | |i IMPORT_0628_prod_DARH_01 | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2015 |e 1 |h 61- | ||