Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.
Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.
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DOI：
10.3389/fphar.2017.00347
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发表时间：
2017
影响因子：
5.6
通讯作者：
Duconge-Soler J
中科院分区：
文献类型：
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作者：
Claudio-Campos K;Labastida A;Ramos A;Gaedigk A;Renta-Torres J;Padilla D;Rivera-Miranda G;Scott SA;Ruaño G;Cadilla CL;Duconge-Soler J
现有的算法解释了~50%的观察到的变异华法林剂量需求后，包括常见的多态性。然而，它们在高加索人以外的人群中表现不佳，部分原因是一些种族特异性遗传变异被忽视了。本研究的目的是确定遗传多态性，可以解释波多黎各加勒比海西班牙裔之间华法林剂量需求的变异性。对心血管患者的候选基因CYP 2C 9和VKORC 1进行了新一代测序，并通过DMET® Plus Assay进行了基因分型。我们还旨在表征该研究队列的基因组结构和混合模式。我们的研究使用极端不一致表型方法进行病例对照关联分析。CYP 2C 9变体rs 2860905存在于波多黎各人群的所有主要单倍型中，与常见变体CYP 2C 9 *2和CYP 2C 9 *3相比，与华法林敏感性（<4 mg/天）的相关性更强。尽管CYP 2C 9 *2和CYP 2C 9 *3分别包含在两种单倍型中，但10名具有敏感表型的受试者仅携带CYP 2C 9 rs 2860905变体。CES 2和ABCB 1的其他多态性与华法林耐药相关。将rs 2860905并入回归模型（R2 = 0.63，MSE = 0.37），该回归模型还包括另外的遗传学（即，VKORC 1 -1639 G>A; CYP 2C 9 rsl 856908; ABCB 1 c.IVS9- 44 A>G/rsl 0276036; CES 2 c.269- 965 A>G/rs 4783745）和非遗传因素（即，高血压、糖尿病和年龄）比CYP 2C 9 *2和CYP 2C 9 *3组合更好地预测华法林剂量需求（部分R2 = 0.132 vs. 0.023和0.007，p < 0.001）。研究队列中波多黎各人的遗传背景显示出三杂交混合模式，美洲土著血统的贡献略高于预期（25%）。波多黎各人的基因组多样性突出表现在CYP 2C 9基因座中存在四种不同的主要单倍型块。虽然，我们的研究结果需要进一步复制，这项研究有助于该领域确定新的遗传变异，增加稳定的华法林剂量加勒比西班牙裔之间的可预测性。
Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.