<abstract xmlns="http://www.w3.org/1999/xhtml"><sec id="j_1905-7415.1101.542_s_005_w2aab3b7b9b1b6b1aab1c17b1Aa"><h3>Background</h3><p>Pharmacodynamics of warfarin are influenced by genetic polymorphisms of its metabolic enzymes.</p></sec><sec id="j_1905-7415.1101.542_s_006_w2aab3b7b9b1b6b1aab1c17b2Aa"><h3>Objectives</h3><p>To determine <italic>CYP2C9</italic> and <italic>VKORC1</italic> genotypes in a population in southern Thailand, and their association with warfarin maintenance doses.</p></sec><sec id="j_1905-7415.1101.542_s_007_w2aab3b7b9b1b6b1aab1c17b3Aa"><h3>Methods</h3><p>We genotyped <italic>CYP2C9</italic>*<italic>2</italic> (rs1799853), <italic>CYP2C9</italic>*<italic>3</italic> (rs1057910), <italic>VKORC1</italic> (rs9923231 and rs9934438) from the blood DNA of 210 healthy controls, and determined the association of 2 polymorphic markers (<italic>CYP2C9</italic>*<italic>3</italic> and rs9923231) in 154 patients with aortic valve protheses, with warfarin maintenance dose and coagulopathy.</p></sec><sec id="j_1905-7415.1101.542_s_008_w2aab3b7b9b1b6b1aab1c17b4Aa"><h3>Results</h3><p><italic>CYP2C9</italic>*<italic>3</italic> was detected in 17/210 controls; all were heterozygous variants (-*<italic>1</italic>*<italic>3</italic>). No <italic>CYP2C9</italic>*<italic>2</italic> polymorphisms were detected. The 2 <italic>VKORC1</italic> polymorphisms were in complete linkage disequilibrium. The genotype distribution of <italic>VKORC1</italic> (rs9923231) was 118:72:20 for AA:AG:GG. The warfarin maintenance dose in patients with <italic>CYP2C9</italic>*<italic>1</italic>*<italic>3</italic> (20.7 mg/week) was significantly less than in patients with <italic>CYP2C9</italic>*<italic>1</italic>*<italic>1</italic> (31.7 mg/week; <italic>P</italic> &lt; 0.01). In <italic>VKORC1</italic> patients, the warfarin maintenance dose increased significantly with minor variants (AA:AG:GG; 23.8:35.3:47.3 mg/week). The incidence of prolonged prothrombin time (INR > 5) was significantly higher in the <italic>VKORC1-AA</italic> group (45/76) than the AG (22/64) or GG (3/16) groups. The median time to achieve a stable INR was highest for patients with a GG genotype (342 days) compared with 20 days for those with AA, and 160 days for those with AG. Other factors associated with warfarin maintenance dose were body surface area, age (>45 years), and concomitant drug use.</p></sec><sec id="j_1905-7415.1101.542_s_009_w2aab3b7b9b1b6b1aab1c17b5Aa"><h3>Conclusion</h3><p>Polymorphisms of <italic>CYP2C9</italic>*<italic>3</italic> and <italic>VKORC1</italic> are present in southern Thais. We recommend pharmacogenetic studies of these markers as a component of warfarin therapy.</p></sec></abstract>

BackgroundPharmacodynamics of warfarin are influenced by genetic polymorphisms of its metabolic enzymes.ObjectivesTo determine CYP2C9 and VKORC1 genotypes in a population in southern Thailand, and their association with warfarin maintenance doses.MethodsWe genotyped CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231 and rs9934438) from the blood DNA of 210 healthy controls, and determined the association of 2 polymorphic markers (CYP2C9*3 and rs9923231) in 154 patients with aortic valve protheses, with warfarin maintenance dose and coagulopathy.ResultsCYP2C9*3 was detected in 17/210 controls; all were heterozygous variants (-*1*3). No CYP2C9*2 polymorphisms were detected. The 2 VKORC1 polymorphisms were in complete linkage disequilibrium. The genotype distribution of VKORC1 (rs9923231) was 118:72:20 for AA:AG:GG. The warfarin maintenance dose in patients with CYP2C9*1*3 (20.7 mg/week) was significantly less than in patients with CYP2C9*1*1 (31.7 mg/week; P < 0.01). In VKORC1 patients, the warfarin maintenance dose increased significantly with minor variants (AA:AG:GG; 23.8:35.3:47.3 mg/week). The incidence of prolonged prothrombin time (INR > 5) was significantly higher in the VKORC1-AA group (45/76) than the AG (22/64) or GG (3/16) groups. The median time to achieve a stable INR was highest for patients with a GG genotype (342 days) compared with 20 days for those with AA, and 160 days for those with AG. Other factors associated with warfarin maintenance dose were body surface area, age (>45 years), and concomitant drug use.ConclusionPolymorphisms of CYP2C9*3 and VKORC1 are present in southern Thais. We recommend pharmacogenetic studies of these markers as a component of warfarin therapy.

Genotype distributions of <italic>CYP2C9</italic> and <italic>VKORC1</italic> in southern Thais and their association with warfarin maintenance dose in patients with cardiac surgery

Department of Surgery, Faculty of Medicine

Songklanagarind Hospital, Prince of Songkla University

Asian Biomedicine

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Genotype distributions of  and  in southern Thais and their association with warfarin maintenance dose in patients with cardiac surgery

BackgroundPharmacodynamics of warfarin are influenced by genetic polymorphisms of its metabolic enzymes.ObjectivesTo determine CYP2C9 and VKORC1 genotypes in a population in southern Thailand, and their association with warfarin maintenance doses.MethodsWe genotyped CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231 and rs9934438) from the blood DNA of 210 healthy controls, and determined the association of 2 polymorphic markers (CYP2C9*3 and rs9923231) in 154 patients with aortic valve protheses, with warfarin maintenance dose and coagulopathy.ResultsCYP2C9*3 was detected in 17/210 controls; all were heterozygous variants (-*1*3). No CYP2C9*2 polymorphisms were detected. The 2 VKORC1 polymorphisms were in complete linkage disequilibrium. The genotype distribution of VKORC1 (rs9923231) was 118:72:20 for AA:AG:GG. The warfarin maintenance dose in patients with CYP2C9*1*3 (20.7 mg/week) was significantly less than in patients with CYP2C9*1*1 (31.7 mg/week; P  5) was significantly higher in the VKORC1-AA group (45/76) than the AG (22/64) or GG (3/16) groups. The median time to achieve a stable INR was highest for patients with a GG genotype (342 days) compared with 20 days for those with AA, and 160 days for those with AG. Other factors associated with warfarin maintenance dose were body surface area, age (>45 years), and concomitant drug use.ConclusionPolymorphisms of CYP2C9*3 and VKORC1 are present in southern Thais. We recommend pharmacogenetic studies of these markers as a component of warfarin therapy.

BackgroundPharmacodynamics of warfarin are influenced by genetic polymorphisms of its metabolic enzymes.ObjectivesTo determine CYP2C9 and VKORC1 genotypes in a...

Gene symbol and variants	dbSNP rs No.	MAF in Asians*	Remarks
CYP2C9
CYP2C9*2 (c.430 C>T, p.Arg144Cys)	rs1799853	EAS 0.00	Variants detected in Indian-Malaysians [11]
		SAS 0.03
CYP2C9*3 (c.1075 A>C, p.Ile359Leu)	rs1057910	EAS 0.03
		SAS 0.11
VKORC1
–1639G>A	rs9923231	EAS 0.88
		SAS 0.15
1173C>T	rs9934438	EAS 0.88	Complete linkage disequilibrium with
		SAS 0.15	rs9923231 in a recent study from Bangkok [8]

	Number (cases)	Average warfarin dose (mg/week)	P
All	154	31	–
Sex			0.46
Male	59 (38.3%)	31.9
Female	95 (61.7%)	30.4
Age			< 0.01
<45 years	81 (52.6%)	35
≥45 years	73 (47.4%)	26.5
Body mass index			0.31
<23.4 kg/m²	90 (58.4%)	30.2
≥23.4 kg/m²	64 (41.6%)	32.2
Body surface area			0.02
<1.7 m²	103 (66.8%)	29.4
≥1.7 m²	51 (33.1%)	34.3
Uric acid food consumption			0.74
Never/seldom	144 (93.5%)	30.9
Usually	10 (6.5%)	32.3
Green vegetable food consumption		0.77
Never/seldom	57 (37.3%)	31.5
Usually	96 (62.7%)	30.9
Medication used			0.01* (List-1)
None	102 (66.2%)	32.7
List-1	50 (32.5%)	27.6
List-2	2 (1.3%)	29.8
rs9923231 (VKORC1)			<0.01**
AA	74 (48.1%)	23.8
AG	64 (41.6%)	35.3
GG	16 (10.4%)	47.3
rs1057910 (CYP2C9)			<0.01
AA (11)	144 (93.5%)	31.7
AC (13)	10 (6.5%)	20.7

Genotype distributions of CYP2C9 and VKORC1 in southern Thais and their association with warfarin maintenance dose in patients with cardiac surgery

Article Category: Brief communication (Original)

Published Online: Aug 31, 2017

Page range: 81 - 87

DOI: https://doi.org/10.5372/1905-7415.1101.542

Keywords
Pharmacogenetics, Thai patients, warfarin

© 2017 Wanwisa Maneechay, Voravit Chittithavorn, Laorrat Lertlam, Thassanan Sirisathienrooch, Pongsanae Duangpakdee, Surasak Sangkhathat

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

Studied single nucleotide polymorphisms (SNPs) of CYP2C9 and VKORC1

Association between genetic polymorphisms and other factors and warfarin dose

Median (95% confidence interval) of maintenance warfarin dose (mg/week) according to combined genotypes of CYP2C9 and VKORC1

VKORC1	CYP2C911	CYP2C913
AA	21.8 (21.0-24.5)	15.8 (7.0-24.5)
AG	35.0 (31.6-39.9)	24.0 (14.7-32.5)
GG	49.0 (35.0-56.0)	(no observation)

Genotype distributions of CYP2C9 and VKORC1 in southern Thais and their association with warfarin maintenance dose in patients with cardiac surgery

Article Category: Brief communication (Original)

Published Online: Aug 31, 2017

Page range: 81 - 87

DOI: https://doi.org/10.5372/1905-7415.1101.542

KeywordsPharmacogenetics, Thai patients, warfarin

© 2017 Wanwisa Maneechay, Voravit Chittithavorn, Laorrat Lertlam, Thassanan Sirisathienrooch, Pongsanae Duangpakdee, Surasak Sangkhathat

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

Studied single nucleotide polymorphisms (SNPs) of CYP2C9 and VKORC1

Association between genetic polymorphisms and other factors and warfarin dose

Median (95% confidence interval) of maintenance warfarin dose (mg/week) according to combined genotypes of CYP2C9 and VKORC1

Keywords
Pharmacogenetics, Thai patients, warfarin