The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans.
The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans.
复制标题
DOI：
10.1038/clpt.2010.322
复制
发表时间：
2011-03
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
众所周知，遗传变异体VKORC 1 -1639、CYP 2C 9 *2和CYP 2C 9 *3有助于华法林剂量反应。这导致华法林剂量算法包括这些多态性，并解释了高加索人剂量变异性的47%至56%。然而，这些多态性对非裔美国人剂量差异的解释明显较少。为了确定影响非洲裔美国人华法林剂量的新变异，我们使用了一种有针对性的重测序策略，该策略检查了进化上保守的序列和推定的转录结合区域。通过在330名非洲裔美国人中建立种族特异性华法林剂量模型，我们确定了两种与较高华法林剂量相关的新遗传学，即CYP 2C 9中的VKORC 1 -8191（rs61162043，P = 0.0041）和18786（rs7089580，P = 0.035）。这些新的发现独立于先前与这些基因的关联。我们的回归模型，包括遗传和临床变量，解释了40%的非洲裔美国人受试者华法林剂量的变异性，显著高于迄今为止的任何模型。
it is well recognized that the genetic variants VKORC1-1639, CYP2C9*2, and CYP2C9*3 contribute to warfarin dose response. This has led to warfarin dosing algorithms that include these polymorphisms and explains between 47% and 56% of variability in dose in Caucasians. however, these polymorphisms explain significantly less of the variance in dose among African Americans. In order to identify novel variations that affect warfarin dose in African Americans, we used a targeted resequencing strategy that examined evolutionarily conserved sequences and regions of putative transcriptional binding. Through ethnicity-specific warfarin dose model building in 330 African Americans, we identified two novel genetic associations with higher warfarin dose, namely, VKORC1-8191 (rs61162043, P = 0.0041) and 18786 in CYP2C9 (rs7089580, P = 0.035). These novel finds are independent of the previous associations with these genes. Our regression model, encompassing both genetic and clinical variables, explained 40% of the variability in warfarin dose in African-American subjects, significantly more than any model thus far.
登录
查看更多内容
影响因子：
56.9
作者：
Gabriel, SB;Schaffner, SF;Altshuler, D
通讯作者：
Altshuler, D
DOI：
10.1038/tpj.2008.13
发表时间：
2009-02
期刊：
The pharmacogenomics journal
影响因子：
--
作者：
Perera MA;Thirumaran RK;Cox NJ;Hanauer S;Das S;Brimer-Cline C;Lamba V;Schuetz EG;Ratain MJ;Di Rienzo A
通讯作者：
Di Rienzo A
影响因子：
2.3
作者：
Limdi, Nita A.;Goldstein, J. A.;Acton, R. T.
通讯作者：
Acton, R. T.
DOI：
10.1111/j.1538-7836.2009.03677.x
发表时间：
2010-01
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Ferder NS;Eby CS;Deych E;Harris JK;Ridker PM;Milligan PE;Goldhaber SZ;King CR;Giri T;McLeod HL;Glynn RJ;Gage BF
通讯作者：
Gage BF
影响因子：
2.1
作者：
Momary, Kathryn M.;Shapiro, Nancy L.;Cavallari, Larisa H.
通讯作者：
Cavallari, Larisa H.