Screening study for genetic polymorphisms affecting pharmacokinetics of simvastatin

Sohee Im; Bo-Hyung Kim; Kidong Lee; KyuBum Kwack; Sung-Vin Yim

doi:10.12793/tcp.2016.24.1.43

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Im, Kim, Lee, Kwack, and Yim: Screening study for genetic polymorphisms affecting pharmacokinetics of simvastatin

Original Article

Translational and Clinical Pharmacology 2016;24(1):43-54.

Published online: 15 March 2016

DOI: https://doi.org/10.12793/tcp.2016.24.1.43

Screening study for genetic polymorphisms affecting pharmacokinetics of simvastatin

Sohee Im¹, Bo-Hyung Kim¹, Kidong Lee², KyuBum Kwack^2,^∗, Sung-Vin Yim^1,^∗

¹Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul 02447, Korea

²Department of BioMedical Science, College of Life Science, CHA University, Pangyo-ro, Bundang-gu, SeongNam 13488, Korea

^∗Correspondence: S. V. Yim; Tel: +82-2-958-9567, Fax: +82-2-958-9559, E-mail: ysvin@khu.ac.kr; K. B. Kwack; Tel: +82-10-4416-3704, E-mail: kbkwack@cha.ac.kr

Received 4 November 20155 February 2016 Accepted 6 February 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Simvastatin reduces plasma cholesterol by inhibiting HMG-CoA reductase (HMGR) and is widely used in the treatment of hypercholesterolemia. To screening the possible genetic factors affecting the pharmacokinetics (PK) of simvastatin, 35 male Korean volunteers were enrolled from two separate bioequivalence studies. Each subject was administered 20 mg simvastatin and reference drug PK parameters were used. We used Illumina Human610Quad v1.0 DNA Analysis BeadChip for whole genome SNPs analysis and whole genome genotyping data was processed by linear regression analysis for PK parameters of drug metabolizing enzymes and transporters. We found 145 significant SNPs (P < 0.01) in C_max, 135 significant SNPs (P < 0.01) in T_max and 85 significant SNPs (P < 0.01) in AUC_inf from whole genome analysis. In particular, we found that the ABCC2 gene had a significant effect on C_max and AUC_inf. These results could provide information of possible candidate genes for personalized simvastatin therapy.

Keywords: Pharmacogenomics, Simvastatin, Pharmacokinetics, Single nucleotide polymorphism

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Table 1.

Demographic characteristics and reference simvastatin pharmacokinetics parameters of volunteers

Subject No.	*Age (year)*	*Sex (M/F)*	*Weight (kg)*	*Height (cm)*	Zocor 40 mg (two tablets of 20 mg simvastatin, MSD Co., Ltd., Seoul, Korea)
Subject No.	*Age (year)*	*Sex (M/F)*	*Weight (kg)*	*Height (cm)*	C_max (ng/ml)	T_max (h)	AUC_t (ng·h/ml)	AUC_inf (ng·h/ml)
1	27	M	84.0	176.0	4.80	3.50	17.983	19.700
2	26	M	76.4	180.6	0.97	1.00	13.499	18.390
3	26	M	55.0	163.0	4.49	5.00	42.589	46.237
4	33	M	67.6	176.9	8.20	0.67	38.992	46.317
5	30	M	75.8	180.2	2.68	1.33	7.561	8.224
6	31	M	64.0	180.0	9.96	0.67	30.355	32.879
7	31	M	77.7	181.7	12.61	2.00	43.494	45.780
8	20	M	63.0	167.8	7.30	1.67	26.874	27.686
9	27	M	57.0	167.5	9.98	0.67	28.825	32.290
10	21	M	68.0	177.0	16.34	3.00	61.885	63.780
11	24	M	93.0	188.0	6.61	1.00	15.617	18.476
12	25	M	69.5	172.2	4.97	0.67	11.166	15.134
13	25	M	68.3	183.0	3.93	2.50	17.679	18.479
14	23	M	87.0	181.6	17.25	1.67	21.184	21.635
15	25	M	68.0	175.4	4.68	1.67	43.160	45.254
16	26	M	65.0	177.4	6.81	1.33	35.282	90.582
17	24	M	66.0	170.0	4.63	3.00	48.621	54.339
18	20	M	75.2	173.8	2.14	1.00	6.787	9.535
19	27	M	79.0	184.0	5.42	1.67	15.221	15.958
20	27	M	61.0	174.0	9.12	1.67	40.288	48.106
21	28	M	60.0	173.0	5.06	0.67	13.200	19.015
22	28	M	85.2	179.9	9.19	1.67	32.320	34.484
23	23	M	68.8	169.4	9.53	0.67	31.386	37.412
24	22	M	65.0	169.7	6.52	3.00	31.262	33.912
25	20	M	55.0	176.3	3.65	3.50	9.345	10.303
26	25	M	66.2	174.4	17.66	1.00	39.767	42.814
27	24	M	75.2	185.1	1.25	0.67	8.561	23.638
28	25	M	59.8	170.2	2.40	3.00	27.549	31.360
29	20	M	56.0	170.0	5.95	5.00	33.259	39.373
30	24	M	59.3	169.1	3.91	2.00	19.060	20.786
31	27	M	83.0	171.6	21.33	1.67	76.230	77.471
32	26	M	70.0	176.0	6.27	1.33	29.589	31.321
33	27	M	75.4	177.4	10.12	1.67	31.061	32.953
34	25	M	70.6	177.6	7.21	1.00	21.359	23.410
35	40	M	71.0	177.0	10.29	3.50	67.206	80.128
Mean ± SD	26 ± 4.0		69.7 ± 9.6	175.6 ± 5.6	7.5 ± 4.8	1.9 ± 1.2	29.7 ± 16.8	34.8 ± 20.0

Abbreviation; M: male, F: female, C_max: maximum measured plasma concentration, T_max: time of the maximum measured plasma concentration, AUC_t: area under the plasma concentration-time curve from time zero to time of last measurable concentration, AUC_inf: area under the plasma concentration-time curve from zero to infinity, SD: standard deviation.

Table 2.

Summary of linear regression analysis

*PK parameters*	*P-value*	SNP number	Model number
*PK parameters*	*P-value*	Drug metabolizing enzyme	ADD	DOM	REC
^C_max	P < 0.00001	7		7
	< 0.0001	7		7
	< 0.001	33	10	9	23
	< 0.01	145	91	75	63
	< 0.05		100	89	69
^T_max	P < 0.00001	2			2
	< 0.0001	4			4
	< 0.001	25	3	3	20
	< 0.01	135	63	37	73
	< 0.05		67	49	92
^AUC_inf	P < 0.00001
	< 0.0001	3			3
	< 0.001	12	2	1	9
	< 0.01	85	32	20	56
	< 0.05		32	20	56

Abbreviation; ADD: additive model, DOM: dominant model, REC: recessive model.

Table 3.

Highly significant SNPs of drug metabolizing enzymes in C_max group from linear regression analysis

*Gene*	*SNP*	*Chr*	*Location*	*Genotype*	n	*Mean*	SD	*Model*	β	95% CI		*P-value Sig*
*Gene*	*SNP*	*Chr*	*Location*	*Genotype*	n	*Mean*	SD	*Model*	β	LCL	UCL	*P-value Sig*
SLC44A3	rs696620	1	intron	CC	13	7.22	4.06	Additive	1.61	–1.30	4.52	0.287
				CT	20	6.52	3.80	Dominant	–0.71	–4.15	2.74	0.689
				TT	2	19.49	2.60	Recessive	11.80	6.19	17.41	2.580x10⁻⁴ ∗∗∗
SLC4A5	rs10182348	2	intron	CC	15	8.01	3.82	Additive
				CT	16	5.02	2.44	Dominant
				TT	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
	rs10211612	2	intron	GG	15	8.01	3.82	Additive
				GA	16	5.02	2.44	Dominant
				AA	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
	rs2421844	2	intron	GG	15	8.01	3.82	Additive
				GA	16	5.02	2.44	Dominant
				AA	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
	rs3755441	2	intron	TT	14	8.41	3.63	Additive
				TC	17	4.87	2.44	Dominant
				CC	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
	rs3771740	2	intron	AA	15	8.01	3.82	Additive
				AT	16	5.02	2.44	Dominant
				TT	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
	rs3821303	2	intron	GG	15	8.01	3.82	Additive
				GA	16	5.02	2.44	Dominant
				AA	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
	rs7567768	2	intron	TT	15	8.01	3.82	Additive
				TC	16	5.02	2.44	Dominant
				CC	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
	rs7592599	2	intron	TT	14	8.41	3.63	Additive
				TC	17	4.87	2.44	Dominant
				CC	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
	rs9789404	2	intron	CC	15	8.01	3.82	Additive	1.63	–0.73	3.98	0.185
				CT	16	5.02	2.44	Dominant	–0.52	–3.73	2.70	0.755
				TT	4	15.69	6.38	Recessive	9.20	5.00	13.41	1.604x10⁻⁴ ∗∗∗
SLC2A12	rs2811675	6	intron	AA	17	5.24	2.80	Additive	4.23	2.16	6.30	3.621x10⁻⁴ ∗∗∗
				AG	15	8.37	4.39	Dominant	4.23	1.45	7.00	0.006 ∗∗
				GG	3	16.23	5.67	Recessive	9.11	3.61	14.62	0.003 ∗∗
ALDH3B1	rs15518	11	3UTR	TT	25	5.51	2.71	Additive	3.84	1.91	5.77	4.881x10⁻⁴ ∗∗∗
				TC	6	13.39	5.86	Dominant	6.93	4.36	9.51	9.759x10⁻⁴ ∗∗∗∗∗
				CC	4	11.31	4.95	Recessive	3.57	–1.32	8.46	0.162
	rs2286164	11	intron	TT	25	5.51	2.71	Additive	4.16	2.10	6.22	4.120x10⁻⁴ ∗∗∗
				TC	7	12.90	5.51	Dominant	6.93	4.36	9.51	9.759x10⁻⁶ ∗∗∗∗∗
				CC	3	11.76	5.96	Recessive	3.35	–2.31	9.02	0.255
ALDH3B1	rs2286168	11	missense	GG	25	5.51	2.71	Additive	4.16	2.10	6.22	4.120x10⁻⁴ ∗∗∗
				GA	7	12.90	5.51	Dominant	6.93	4.36	9.51	9.759x10⁻⁶ ∗∗∗∗∗
				AA	3	11.76	5.96	Recessive	3.35	–2.31	9.02	0.255
	rs3133268	11	3flanking	GG	25	5.51	2.71	Additive	3.84	1.91	5.77	4.881x10⁻⁴ ∗∗∗
				GC	6	13.39	5.86	Dominant	6.93	4.36	9.51	9.759x10⁻⁶ ∗∗∗∗∗
				CC	4	11.31	4.95	Recessive	3.57	–1.32	8.46	0.162
	rs886701	11	intron	GG	25	5.51	2.71	Additive	4.16	2.10	6.22	4.881x10⁻⁴ ∗∗∗
				GA	7	12.90	5.51	Dominant	6.93	4.36	9.51	9.759x10⁻⁶ ∗∗∗∗∗
				AA	3	11.76	5.96	Recessive	3.35	–2.31	9.02	0.255
SLC38A1	rs11183395	12	intron	AA	14	6.00	3.85	Additive	3.40	0.95	5.85	0.011 ∗∗
				AG	19	7.64	4.60	Dominant	2.37	–0.85	5.59	0.159
				GG	2	17.00	0.93	Recessive	11.45	5.90	17.01	3.280x10⁻⁴ ∗∗∗
ABCC4	rs1729741	13	intron	AA	24	6.79	4.23	Additive	2.90	0.68	5.13	0.016 ∗∗
				AG	8	6.43	2.77	Dominant	2.27	–1.02	5.55	0.186
				GG	3	16.32	5.79	Recessive	9.06	4.41	13.70	5.973x10⁻⁴ ∗∗∗
	rs2892716	13	intron	CC	17	5.20	3.70	Additive	3.97	2.06	5.87	2.941x10⁻⁴ ∗∗∗
				CT	14	8.19	2.30	Dominant	4.18	1.32	7.05	0.008 ∗∗
				TT	4	15.04	7.63	Recessive	8.02	3.77	12.28	8.436x10⁻⁴ ∗∗∗
	rs4148436	13	intron	TT	17	5.20	3.70	Additive	3.97	5.06	5.87	2.941x10⁻⁴ ∗∗∗
				TC	14	8.19	2.30	Dominant	4.18	1.32	7.05	0.008 ∗∗
				CC	4	15.04	7.63	Recessive	8.02	3.77	12.28	8.436x10⁻⁴ ∗∗∗
	rs4148440	13	intron	AA	10	5.77	4.52	Additive	2.99	0.98	4.99	0.007 ∗∗
				AG	18	6.68	2.94	Dominant	2.19	–1.20	5.58	0.215
				GG	7	12.17	6.59	Recessive	6.23	2.95	9.50	7.833x10⁻⁴ ∗∗∗
SLC25A21	rs10483482	14	intron	CC	20	6.35	3.87	Additive	3.36	1.00	5.73	0.009 ∗∗
				CT	13	7.49	3.88	Dominant	2.46	–0.64	5.55	0.130
				TT	2	19.49	2.60	Recessive	11.80	6.19	17.41	2.580x10⁻⁴ ∗∗∗
	rs1884777	14	intron	CC	22	6.63	4.42	Additive	3.01	0.78	5.24	0.013 ∗∗
				CT	10	6.83	2.45	Dominant	2.34	–0.91	2.59	0.169
				TT	3	16.32	5.79	Recessive	9.06	4.41	13.70	5.973x10⁻⁴ ∗∗∗
	rs1955761	14	intron	AA	22	6.63	4.42	Additive	3.01	0.78	5.24	0.013 ∗∗
				AT	10	6.83	2.45	Dominant	2.34	–0.91	5.59	0.169
				TT	3	16.32	5.79	Recessive	9.06	4.41	13.70	5.973x10⁻⁴ ∗∗∗
	rs1956424	14	intron	CC	22	6.51	4.37	Additive	3.06	0.85	5.28	0.011 ∗∗
				CT	10	7.11	2.60	Dominant	2.42	–0.79	5.62	0.149
				TT	3	16.32	5.79	Recessive	9.06	4.41	13.70	5.973x10⁻⁴ ∗∗∗
	rs2078246	14	intron	GG	21	6.89	4.36	Additive	2.58	0.30	4.86	0.034 ∗∗
				GA	11	6.33	2.87	Dominant	1.54	–1.71	4.78	0.360
				AA	3	16.32	5.79	Recessive	9.06	4.41	13.70	5.973x10⁻⁴ ∗∗∗
SLC25A21	rs2415388	14	intron	GG	21	6.89	4.36	Additive	2.58	0.30	4.86	0.034 ∗∗
				GA	11	6.33	2.87	Dominant	1.54	–1.71	4.78	0.360
				AA	3	16.32	5.79	Recessive	9.06	4.41	13.70	5.973x10⁻⁴ ∗∗∗
	rs8008478	14	intron	AA	22	6.63	4.42	Additive	3.01	0.78	5.24	0.013 ∗∗
				AG	10	6.83	2.45	Dominant	2.34	–0.91	5.59	0.169
				GG	3	16.32	5.79	Recessive	9.06	4.41	13.70	5.973x10⁻⁴ ∗∗∗
	rs8019489	14	intron	CC	23	6.64	4.32	Additive	3.01	0.76	5.25	0.013 ∗∗
				CT	9	6.84	2.60	Dominant	2.35	–0.96	5.66	0.173
				TT	3	16.32	5.79	Recessive	9.06	4.41	13.70	5.973x10⁻⁴ ∗∗∗

Abbreviation; Chr: chromosome, n: number, SD: standard deviation, CI: confidence intervals, LCL: lower confidence limit, UCL: upper confidence limit, Sig: significant. ∗P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001, ∗∗∗∗ P < 0.0001.

Table 4.

Highly significant SNPs of drug-metabolizing enzymes in T_max group from linear regression analysis

*Gene*	*SNP*	*Chr*	*Location*	*Genotype*	n	*Mean*	SD	*Model*	β	95% CI		*P-value*	*Sig*
*Gene*	*SNP*	*Chr*	*Location*	*Genotype*	n	*Mean*	SD	*Model*	β	LCL	UCL	*P-value*	*Sig*
DPYD	rs12725266	1	intron	CC	23	1.80	1.11	Additive	0.80	0.13	1.47	0.026 ∗
				CT	10	1.62	0.95	Dominant	0.49	–0.39	1.36	0.283
				TT	2	4.25	1.06	Recessive	3.43	1.89	4.97	1.317x10⁻⁴ ∗∗∗
ABCA4	rs1889404	1	intron	GG	24	1.84	1.13	Additive	0.52	–0.14	1.18	0.135
				GA	9	1.48	0.80	Dominant	0.16	–0.71	1.02	0.721
				AA	2	4.25	1.06	Recessive	2.73	1.27	4.19	9.115x10⁻⁴ ∗∗∗
	rs1889405	1	intron	GG	24	1.84	1.13	Additive	0.52	–0.14	1.18	0.135
				GA	9	1.48	0.80	Dominant	0.16	–0.71	1.02	0.721
				AA	2	4.25	1.06	Recessive	2.73	1.27	4.19	9.115x10⁻⁴ ∗∗∗
	rs3789439	1	intron	GG	25	1.71	1.08	Additive	0.82	0.17	1.47	0.019 ∗
				GA	8	1.86	1.00	Dominant	0.64	–0.26	1.54	0.176
				AA	2	4.25	1.06	Recessive	2.73	1.27	4.19	9.115x10⁻⁴ ∗∗∗
	rs3789442	1	intron	TT	25	1.71	1.08	Additive	0.82	0.17	1.47	0.019 ∗
				TC	8	1.86	1.00	Dominant	0.64	–0.26	1.54	0.176
				CC	2	4.25	1.06	Recessive	2.73	1.27	4.19	9.115x10⁻⁴ ∗∗∗
	rs3789443	1	intron	AA	25	1.71	1.08	Additive	0.82	0.17	1.47	0.019 ∗
				AT	8	1.86	1.00	Dominant	0.64	–0.26	1.54	0.176
				TT	2	4.25	1.06	Recessive	2.73	1.27	4.19	9.115x10⁻⁴ ∗∗∗
	rs3789444	1	intron	CC	25	1.71	1.08	Additive	0.82	0.17	1.47	0.019 ∗
				CT	8	1.86	1.00	Dominant	0.64	–0.26	1.54	0.176
				TT	2	4.25	1.06	Recessive	2.73	1.27	4.19	9.115x10⁻⁴ ∗∗∗
	rs4147807	1	intron	TT	27	1.75	1.11	Additive	0.85	0.19	1.51	0.017 ∗
				TC	6	1.72	0.83	Dominant	0.69	–0.26	1.63	0.164
				CC	2	4.25	1.06	Recessive	2.73	1.27	4.19	9.115x10⁻⁴ ∗∗∗
	rs4147808	1	intron	CC	27	1.75	1.11	Additive	0.85	0.19	1.51	0.017 ∗
				CT	6	1.72	0.83	Dominant	0.69	–0.26	1.63	0.164
				TT	2	4.25	1.06	Recessive	2.73	1.27	4.19	9.115x10⁻⁴ ∗∗∗
ALDH1L1	rs11923466	3	intron	TT	15	1.54	1.01	Additive	0.83	0.26	1.40	0.008 ∗∗
				TC	17	1.80	0.87	Dominant	0.63	–0.15	1.41	0.122
				CC	3	4.17	1.44	Recessive	2.45	1.19	3.71	6.221x10⁻⁴ ∗∗∗
	rs2166766	3	intron	TT	15	1.54	2.80	Additive	0.83	0.26	1.40	0.008 ∗∗
				TC	17	1.80	4.39	Dominant	0.63	–0.15	1.41	0.122
				CC	3	4.17	5.67	Recessive	2.45	1.19	3.71	6.221x10⁻⁴ ∗∗∗
	rs4646715	3	intron	GG	15	0.91	2.71	Additive	0.91	0.30	1.51	0.006 ∗∗
				GC	18	0.63	5.86	Dominant	0.63	–0.15	1.41	0.122
				CC	2	3.25	4.95	Recessive	3.25	1.83	4.66	8.905x10⁻⁵ ∗∗∗∗
	rs4646717	3	intron	TT	15	0.91	2.71	Additive	0.91	0.30	1.51	0.006 ∗∗
				TC	18	0.63	5.51	Dominant	0.63	–0.15	1.41	0.122
				CC	2	3.25	5.96	Recessive	3.25	1.83	4.66	8.905x10⁻⁵ ∗∗∗∗
SLC10A7	rs6537420	4	intron	GG	11	2.82	1.34	Additive	-0.68	-1.16	-0.19	0.011 ∗
				GT	15	1.29	0.70	Dominant	-1.49	-2.19	-0.78	2.416x10⁻⁴ ∗∗∗
				TT	9	1.74	1.01	Recessive	–0.31	–1.24	0.62	0.516
SLC2A12	rs2811675	6	intron	AA	17	1.22	0.63	Additive	0.92	0.35	1.49	0.003 ∗∗
				AG	15	2.69	1.32	Dominant	1.36	0.70	2.01	2.952x10⁻⁴ ∗∗∗
				GG	3	1.67	0.00	Recessive	0.19	–1.44	1.82	0.822
SLCO1B1	rs4149032	12	intron	TT	13	1.31	0.69	Additive	1.13	0.57	1.70	4.342x10⁻⁴ ∗∗∗
				TC	19	2.00	1.18	Dominant	1.01	0.24	1.78	0.015 ∗
				CC	3	3.67	1.26	Recessive	2.37	1.04	3.70	0.001 ∗∗
	rs4149034	12	intron	AA	13	1.31	0.69	Additive	1.13	0.57	1.70	4.342x10⁻⁴ ∗∗∗
				AG	19	2.00	1.18	Dominant	1.01	0.24	1.78	0.015 ∗
				GG	3	3.67	1.26	Recessive	2.37	1.04	3.70	0.001 ∗∗
ABCC4	rs1059751	13	3UTR	TT	10	1.34	0.75	Additive	0.88	0.39	1.38	0.001 ∗∗
				TC	17	1.69	0.88	Dominant	0.84	–0.04	1.72	0.070
				CC	8	3.00	1.56	Recessive	1.51	0.70	2.32	9.468x10⁻⁴ ∗∗∗
	rs3742106	13	3UTR	CC	10	1.34	0.75	Additive	0.88	0.39	1.38	0.001 ∗
				CA	17	1.39	0.88	Dominant	0.84	–0.04	1.72	0.070
				AA	8	3.00	1.56	Recessive	1.51	0.70	2.32	9.468x10⁻⁴ ∗∗∗
	rs4148549	13	intron	AA	10	1.34	0.75	Additive	0.88	0.39	1.38	0.001 ∗
				AG	17	1.39	0.88	Dominant	0.84	–0.04	1.72	0.070
				GG	18	3.00	1.56	Recessive	1.51	0.70	2.32	9.468x10⁻⁴ ∗∗∗
	rs4148553	13	3UTR	GG	10	1.34	0.75	Additive	0.88	0.39	1.38	0.001 ∗
				GA	17	1.39	0.88	Dominant	0.84	–0.04	1.72	0.070
				AA	8	3.00	1.56	Recessive	1.51	0.70	2.32	9.468x10⁻⁴ ∗∗∗
	rs7330196	13	intron	TT	10	1.34	0.75	Additive	0.88	0.39	1.38	0.001 ∗
				TC	17	1.39	0.88	Dominant	0.84	–0.04	1.72	0.070
				CC	8	3.00	1.56	Recessive	1.51	0.70	2.32	9.468x10⁻⁴ ∗∗∗
SLC39A11	rs2859523	17	intron	CC	14	1.81	0.86	Additive	0.62	0.00	1.24	0.058
				CT	18	1.51	0.91	Dominant	0.06	–0.76	0.89	0.880
				TT	3	4.50	0.87	Recessive	2.82	1.78	3.87	9.471x10⁻⁶ ∗∗∗∗∗
	rs2915446	17	intron	AA	12	1.75	0.85	Additive	0.71	0.08	1.34	0.035 ∗
				AC	20	1.58	0.92	Dominant	0.14	–0.72	0.99	0.754
				CC	3	4.50	0.87	Recessive	2.82	1.78	3.87	9.471x10⁻⁶ ∗∗∗∗∗
CYP2F1	rs305968	19	synonymous	GG	12	2.79	1.14	Additive	-0.86	-1.30	-0.42	5.876x10⁻⁴ ∗∗∗
				GA	14	1.61	1.11	Dominant	-1.38	-2.07	-0.68	5.239x10⁻⁴ ∗∗∗
				AA	9	1.11	0.44	Recessive	-1.01	-1.89	-0.13	0.032 ∗

Table 5.

Highly significant SNPs of drug-metabolizing enzymes in AUC_inf group from linear regression analysis

*Gene*	*SNP*	*Chr*	*Location*	*Genotype*	n	*Mean*	SD	*Model*	β	95% CI		*P-value*	*Sig*
*Gene*	*SNP*	*Chr*	*Location*	*Genotype*	n	*Mean*	SD	*Model*	β	LCL	UCL	*P-value*	*Sig*
ARNT	rs2134688	1	intron	AA	19	34.71	19.36	Additive	7.32	–2.34	16.98	0.148
				AG	13	25.94	10.67	Dominant	0.41	–12.57	13.40	0.951
				GG	3	67.01	21.57	Recessive	39.44	20.35	58.54	3.188x10⁻⁴ ∗∗∗
	rs3738483	1	intron	GG	19	34.71	19.36	Additive	7.32	–2.34	16.98	0.148
				GA	13	25.94	10.67	Dominant	0.41	–12.57	13.40	0.951
				AA	3	67.01	21.57	Recessive	39.44	20.35	58.54	3.188x10⁻⁴ ∗∗∗
SLC45A2	rs35390	5	intron	CC	10	29.18	14.40	Additive	12.22	3.93	20.51	0.007 ∗∗
				CA	18	27.68	10.09	Dominant	6.09	–8.09	20.28	0.406
				AA	7	58.24	27.42	Recessive	28.88	16.31	41.45	8.877x10⁻⁵ ∗∗∗∗
	rs35391	5	intron	TT	10	29.18	14.40	Additive	12.22	3.93	20.51	0.007 ∗∗
				TC	18	27.68	10.09	Dominant	6.09	–8.09	20.28	0.406
				CC	7	58.24	27.42	Recessive	28.88	16.31	41.45	8.877x10⁻⁵ ∗∗∗∗
	rs35408	5	intron	CC	11	32.59	12.59	Additive	10.69	2.41	18.97	0.017 ∗
				CT	17	25.57	10.63	Dominant	3.91	–10.14	17.97	0.589
				TT	7	57.80	27.63	Recessive	28.64	16.01	41.27	1.047x10⁻⁴ ∗∗∗
	rs35412	5	intron	CC	11	32.59	12.59	Additive	10.69	2.41	18.97	0.017 ∗
				CG	17	25.57	10.63	Dominant	3.91	–10.14	17.97	0.589
				GG	7	57.80	27.63	Recessive	28.64	16.01	41.27	1.047x10⁻⁴ ∗∗∗
SLC25A46	rs6892259	5	intron	AA	15	25.20	12.14	Additive	17.21	7.95	26.47	0.001 ∗∗∗
				AC	18	39.00	19.22	Dominant	17.16	5.57	28.75	0.007 ∗∗
				CC	2	58.90	44.42	Recessive	31.96	6.07	57.85	0.022 ∗
SLC2A12	rs2811675	6	intron	AA	17	24.25	10.40	Additive	15.58	6.67	24.49	0.002 ∗∗
				AG	15	43.71	21.53	Dominant	20.14	9.34	30.95	0.001 ∗∗∗
				GG	3	43.27	28.79	Recessive	14.85	–10.77	40.47	0.265
SLC25A37	rs2928686	8	intron	CC	25	31.48	14.10	Additive	11.91	1.11	22.70	0.038 ∗
				CT	8	30.21	20.54	Dominant	7.57	–6.63	21.77	0.304
				TT	2	84.51	8.20	Recessive	51.49	25.97	77.01	4.141x10⁻⁴ ∗∗∗
	rs2942194	8	missense	TT	23	31.48	14.72	Additive	11.19	1.56	20.83	0.030 ∗
				TC	9	26.86	14.94	Dominant	4.96	–8.87	18.79	0.487
				CC	3	77.33	13.72	Recessive	44.53	26.45	62.60	3.513x10⁻⁵ ∗∗∗∗
	rs7830129	8	intron	AA	23	31.41	14.73	Additive	10.68	–0.4422	21.8	0.069
				AG	10	30.63	18.14	Dominant	4.912	–9.013	18.84	0.495
				GG	2	84.51	8.20	Recessive	51.49	25.97	77.01	4.141x10⁻⁴ ∗∗∗
SLC18A1	rs4922132	8	intron	CC	21	29.47	16.26	Additive	19.92	10.22	29.62	3.414x10⁻⁴ ∗∗∗
				CT	12	37.57	21.78	Dominant	20.33	7.635	33.02	0.004 ∗∗
				TT	2	64.00	16.75	Recessive	36.81	10.68	62.94	0.010 ∗∗

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