Impact of a variable number tandem repeat in the CYP2C9 promoter on warfarin sensitivity and responsiveness in Jordanians with cardiovascular disease

Figures & data

Table 1 Demographics and clinical characteristics of 211 cardiovascular patients treated with warfarin at the Queen Alia Heart Institute

Category	Subcategory	Poor metabolizer	Good metabolizers	Extensive metabolizers	P-value*
Demographics	Patients (N, %)	(32/211) 15.2%	(147/211) 69.6%	(32/211) 15.2%
	Agea, years [%]	57.2 [17.1]	54.7 [14.8]	47.2 [14.7]	0.019
	BMIa, kg/m^2 [%]	28.1 [6.2]	27.8 [4.9]	27.6 [3.5]	0.732
	Smoking (N, %)	(15/32) 46.9%	(42/147) 28.6%	(16/32) 50.0%	<0.0001
	Male	59.4%	51.0%	65.6%	0.27
	Female	40.6%	49.0%	34.4%
Concomitant disease	Comorbidity	65.6%	68.7%	53.1%	0.075
	Hypertension	40.6%	42.2%	18.8%	0.046
	Diabetes mellitus	21.9%	21.8%	21.9%	1.0
	CHD	31.3%	25.9%	28.1%	0.814
	Thyroid	0%	3.4%	3.1%	0.57
	Lipid	3.1%	6.8%	3.1%	0.55
Medication	Aspirin	59.4%	66%	75%	0.411
Indication of treatment	MVR	18.8%	12.9%	21.9%	0.163
	AVR	6.3%	23.8%	21.9%
	AF	37.5%	17.7%	18.8%
	DVR	18.7%	23.1%	25.0%
	Others	18.7%	22.5%	12.4%
Target INR	2–3	46.9%	38.8%	37.5%	0.69
	2.5–3.5	53.1%	61.2%	62.5%
Mean INRa		2.8 [0.73]	2.4 [0.75]	2.5 [0.85]	0.027

Notes:

* P-value <0.05 is considered significant.

a Mean SD in square brackets.

Abbreviations: AF, atrial fibrillation; AVR, aortic valve replacement; BMI, body mass index; CHD, chronic heart disease; DVR, double valve replacement; INR, international normalized ratio; MVR, mitral valve replacement.

Table 2 Allelic and genotypic frequencies for the p-VNTR polymorphism, in 205 controls and 211 Jordanian cardiovascular patients

Genotype and allele	Patients	Control	P-valuea	Overall P-valuea
SS	(5/211) 2.4%	(1/205) 0.5%	0.271	<0.0001
MM	(59/211) 28%	(54/205) 26.3%	0.841
LL	(7/211) 3.3%	(1/205) 0.5%	0.133
MS	(82/211) 38.8%	(119/205) 58.1%	0.045
ML	(58/211) 27.5%	(30/205) 14.6%	0.045
S	(92/422) 21.8%	(121/410) 29.5%	<0.0001	<0.0001
M	(258/422) 61.1%	(257/410) 62.7%	0.980
L	(72/422) 17.1%	(32/410) 7.8%	0.034

Note:

a Chi-squared test with P-value <0.05 is considered significant.

Abbreviation: p-VNTR, promoter variable number tandem repeat.

Table 3 Association of CYP2C9 p-VNTR polymorphism with variability on required warfarin

Polymorphism	Genotype	Initiation dose	95% CI		P-valuea	Overall P-valuea	Maintenance dose	95% CI		P-valuea	Overall P-valuea
			Lower bound	Upper bound
CYP2C9/p-VNTR	SS	33.8600	16.4615	51.2585	0.969	0.192	33.1500	28.4751	94.7751	0.982	0.966
	MM	36.4780	33.1357	39.8203	0.829		38.1206	32.2087	44.0325	0.979
	LL	40.6463	33.7602	47.5325	1		36.0167	17.6241	54.4092	0.981
	LM	35.8793	31.1840	40.5746	0.751		39.2184	32.3301	46.1068	0.998
	MS	41.0143	22.6276	59.4010	0.751		39.6346	34.8483	44.4209	0.998

Note:

a One-way ANOVA with P-value <0.05 is considered significant, mean doses.

Abbreviation: p-VNTR, promoter variable number tandem repeat.

Table 4 Association of CYP2C9 p-VNTR polymorphism with warfarin sensitivity during the initiation phase of therapy of 211 cardiovascular patients treated with warfarin

Polymorphism	Genotype	Sensitive	Moderate	Resistance	Overall P-valuea
p-VNTR	SS	(1/5) 20.0%	(3/5) 60.0%	(1/5) 20.0%	<0.001
	P-valuea	0.76	0.62	0.76
	MM	(8/59) 13.6%	(43/59) 72.9%	(8/59) 13.6%
	P-valuea	0.69	0.55	0.69
	LL	(0/0) 0.0%	(5/7) 71.4%	(2/7) 28.6%
	P-valuea	0.27	0.92	0.32
	LM	(13/58) 22.4%	(37/8) 63.8%	(8/58) 13.8%
	P-valuea	0.07	0.27	0.84
	MS	(10/82) 12.2%	(59/82) 71.9%	(13/82) 15.9%
	P-valuea	0.32	0.53	0.84

Note:

a Chi-squared test with P-value <0.05 is considered significant.

Abbreviation: p-VNTR, promoter variable number tandem repeat.

Table 5 Association of CYP2C9 p-VNTR polymorphism with warfarin sensitivity during the stabilization phase of therapy of 132 cardiovascular patients treated with warfarin

Polymorphism	Genotype	Sensitive	Moderate	Resistance	Overall P-valuea
p-VNTR	SS	(0/2) 0.0%	(2/0) 100.0%	(0/2) 0.0%	0.910
	P-valuea	0.55	0.27	0.42
	MM	(6/34) 17.6%	(20/34) 58.9%	(8/34) 23.5%
	P-valuea	0.42	0.62	0.92
	LL	(0/6) 0.0%	(5/6) 83.3%	(1/6) 16.7%
	P-valuea	0.32	0.27	0.69
	LM	(5/38) 13.2%	(23/38) 60.5%	(10/38) 26.3%
	P-valuea	0.92	0.84	0.69
	MS	(7/52) 11.8%	(32/52) 62.7%	(13/52) 25.4%
	P-valuea	1	0.92	0.84

Note:

a Chi-squared test with P-value <0.05 is considered significant.

Abbreviation: p-VNTR, promoter variable number tandem repeat.

Table 6 Association of CYP2C9 p-VNTR polymorphism with response to warfarin during the initiation phase of therapy of 211 cardiovascular patients treated with warfarin

Polymorphism	Genotype	Poor responder	Good responder	Ultra-responder	Overall P-valuea
p-VNTR	SS	(2/5) 40.0%	(3/5) 60.0%	(0/5) 0.0%	0.255
	P-valuea	0.92	0.55	0.37
	MM	(27/59) 45.8%	(27/59) 45.8%	(5/59) 8.5%
	P-valuea	0.42	1	0.23
	LL	(0/0) 0.0%	(5/7) 71.4%	(2/7) 28.6%
	P-valuea	0.02	0.16	0.19
	LM	(21/58) 36.2%	(30/8) 51.7%	(7/58) 12.1%
	P-valuea	0.27	0.23	0.84
	MS	(38/82) 46.3%	(31/82) 37.8%	(13/82) 15.9%
	P-valuea	0.23	0.07	0.32

Note:

a Chi-squared test with P-value <0.05 is considered significant.

Abbreviation: p-VNTR, promoter variable number tandem repeat.

Table 7 Association of CYP2C9 p-VNTR polymorphism with response to warfarin during the stabilization phase of therapy of 132 cardiovascular patients treated with warfarin

Polymorphism	Genotype	Poor responder	Good responder	Ultra-responder	Overall P-valuea
p-VNTR	SS	(0/2) 0.0%	(2/2) 100.0%	(0/2) 0.0%	0.350
	P-valuea	0.69	0.62	0.76
	MM	(4/34) 11.8%	(26/34) 76.5%	(4/34) 11.8%
	P-valuea	0.19	0.01	0.02
	LL	(1/6) 16.7%	(5/6) 83.3%	(0/6) 0.0%
	P-valuea	0.32	0.69	0.62
	LM	(2/38) 5.3%	(35/38) 92.1%	(1/38) 2.6%
	P-valuea	0.62	0.42	0.48
	MS	(2/52) 3.8%	(49/52) 94.2%	(1/52) 1.9%
	P-valuea	0.27	0.11	0.23

Note:

a Chi-squared test with P-value <0.05 is considered significant.

Abbreviation: p-VNTR, promoter variable number tandem repeat.

Table 8 Association of CYP2C9 p-VNTR polymorphism with INR treatment outcome

Polymorphism	Genotype	Initiation INR	95% CI		P-valuea	Overall P-valuea	Maintenance INR	95% CI		Upper bound	Overall P-valuea
			Lower bound	Upper bound				Lower bound	Upper bound
CYP2C9/p-VNTR	SS	2.32	1.2613	3.3787	0.477	0.598	2.85	−5.4090	11.1090	0.997	0.466
	MM	2.34	2.1444	2.5454	0.969		2.7	2.5625	2.8464	1
	LL	3.16	2.0133	4.3009	0.083		2.5	2.0450	2.9550	0.825
	LM	2.48	2.3006	2.6649	0.253		2.64	2.4986	2.7762	0.998
	MS	2.48	2.3138	2.6496	0.232		2.73	2.6447	2.8245	0.934

Note:

a One-way ANOVA with P-value <0.05 is considered significant, mean INR.

Abbreviations: p-VNTR, promoter variable number tandem repeat; INR, international normalized ratio.