Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study

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Fältnamn	Indikatorer	Metadata
000		04818naa a2200745 4500
001		oai:DiVA.org:uu-209174
003		SwePub
008		131015s2013 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2091742 URI
024	7	a https://doi.org/10.1016/S0140-6736(13)60681-92 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Perera, Minoli A.4 aut
245	1 0	a Genetic variants associated with warfarin dose in African-American individuals :b a genome-wide association study
264	1	c 2013
338		a print2 rdacarrier
520		a Background VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. Methods We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged >= 18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G -> A, followed by the composite genotype of CYP2C92 and CYP2C93. We prespecified a genome-wide significance threshold of p<5x10(-8) in the discovery cohort and p<0.0038 in the replication cohort. Findings The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1.51x10(-8)). This association was confirmed in the replication cohort (p=5.04x10(-5)); analysis of the two cohorts together produced a p value of 4.5x10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6.92 mg/week and those homozygous 9.34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). Interpretation A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C92 and CYP2C93. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population.
700	1	a Cavallari, Larisa H.4 aut
700	1	a Limdi, Nita A.4 aut
700	1	a Gamazon, Eric R.4 aut
700	1	a Konkashbaev, Anuar4 aut
700	1	a Daneshjou, Roxana4 aut
700	1	a Pluzhnikov, Anna4 aut
700	1	a Crawford, Dana C.4 aut
700	1	a Wang, Jelai4 aut
700	1	a Liu, Nianjun4 aut
700	1	a Tatonetti, Nicholas4 aut
700	1	a Bourgeois, Stephane4 aut
700	1	a Takahashi, Harumi4 aut
700	1	a Bradford, Yukiko4 aut
700	1	a Burkley, Benjamin M.4 aut
700	1	a Desnick, Robert J.4 aut
700	1	a Halperin, Jonathan L.4 aut
700	1	a Khalifa, Sherief I.4 aut
700	1	a Langaee, Taimour Y.4 aut
700	1	a Lubitz, Steven A.4 aut
700	1	a Nutescu, Edith A.4 aut
700	1	a Oetjens, Matthew4 aut
700	1	a Shahin, Mohamed H.4 aut
700	1	a Patel, Shitalben R.4 aut
700	1	a Sagreiya, Hersh4 aut
700	1	a Tector, Matthew4 aut
700	1	a Weck, Karen E.4 aut
700	1	a Rieder, Mark J.4 aut
700	1	a Scott, Stuart A.4 aut
700	1	a Wu, Alan H. B.4 aut
700	1	a Burmester, James K.4 aut
700	1	a Wadelius, Miau Uppsala universitet,Klinisk farmakogenomik och osteoporos4 aut0 (Swepub:uu)miawadel
700	1	a Deloukas, Panos4 aut
700	1	a Wagner, Michael J.4 aut
700	1	a Mushiroda, Taisei4 aut
700	1	a Kubo, Michiaki4 aut
700	1	a Roden, Dan M.4 aut
700	1	a Cox, Nancy J.4 aut
700	1	a Altman, Russ B.4 aut
700	1	a Klein, Teri E.4 aut
700	1	a Nakamura, Yusuke4 aut
700	1	a Johnson, Julie A.4 aut
710	2	a Uppsala universitetb Klinisk farmakogenomik och osteoporos4 org
773	0	t The Lancetg 382:9894, s. 790-796q 382:9894<790-796x 0140-6736x 1474-547X
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-209174
856	4 8	u https://doi.org/10.1016/S0140-6736(13)60681-9

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Av författaren/redakt...: Perera, Minoli A ...; Cavallari, Laris ...; Limdi, Nita A.; Gamazon, Eric R.; Konkashbaev, Anu ...; Daneshjou, Roxan ...; visa fler...; Pluzhnikov, Anna; Crawford, Dana C ...; Wang, Jelai; Liu, Nianjun; Tatonetti, Nicho ...; Bourgeois, Steph ...; Takahashi, Harum ...; Bradford, Yukiko; Burkley, Benjami ...; Desnick, Robert ...; Halperin, Jonath ...; Khalifa, Sherief ...; Langaee, Taimour ...; Lubitz, Steven A ...; Nutescu, Edith A ...; Oetjens, Matthew; Shahin, Mohamed ...; Patel, Shitalben ...; Sagreiya, Hersh; Tector, Matthew; Weck, Karen E.; Rieder, Mark J.; Scott, Stuart A.; Wu, Alan H. B.; Burmester, James ...; Wadelius, Mia; Deloukas, Panos; Wagner, Michael ...; Mushiroda, Taise ...; Kubo, Michiaki; Roden, Dan M.; Cox, Nancy J.; Altman, Russ B.; Klein, Teri E.; Nakamura, Yusuke; Johnson, Julie A ...; visa färre...

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Av lärosätet: Uppsala universitet

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