Genetic polymorphisms of pharmacogenomic VIP variants in the Dai population from Yunnan province.

BACKGROUND: Pharmacogenomics plays a crucial role in individualized therapy, but the variant information of pharmacogenomics in the Dai population is limited. We therefore aimed to screen very important pharmacogenetic (VIP) in the Dai population and compared differences between Dai and other 25 populations.
METHODS: In this study, we genotyped 73 VIP variants from the PharmGKB and compared genotype distribution of variants in Dai with other 25 populations by χ2 test. To assess the genetic relationship among 26 populations, we performed the structure analysis. In addition, pair-wise F-statistics (Fst) was calculated to measure the population differentiation.
RESULTS: We found 12, 10, 13, 17, 11, 39, 46, 46, 45, 43, 49, 46, 46, 46, 49, 45, 41, 42, 48, 53, 45, 50, 50, 51, 47, and 50 significantly different variants in Dai compared with other 25 populations. Genetic structure analysis showed Dai had close relationships with CDX (Chinese Dai in Xishuangbanna), CHB (Han Chinese in Beijing), JPT (Japanese in Tokyo), and KHV (Kinh in Ho Chi Minh City, Vietnam). Moreover, Dai is the most similar to KHV according to Fst analysis.
CONCLUSIONS: Our study complement the pharmacogenomics information of Dai population from Yunnan province and provide a theoretical basis for personalized medicine.

INTRODUCTION

It is well known that people respond differently to the same medications due to the complex interplay of multiple factors, including age, sex, race, diseases, genetic factors, and environmental factors. It is reported that genetics could account for 20%–95% of the variability in drug response (Kalow, Tang, & Endrenyi, 1998). Pharmacogenomics is a study to elucidate the effects of genomic variations on drug disposition and effects, thereby providing information for personalized medicine (Jin et al., 2016). The pharmacogenomics knowledge database (PharmGKB: http://www.pharmgkb.org) is a useful resource for describing the associations between genes, medications, and diseases. At present, it includes the information of more than 3,000 diseases, 3,000 drugs, and 26,000 genes with genotyped variants (Evans & Relling, 1999).

Very important pharmacogenetic (VIP) variants are certain important genes and genetic variations that play an important role in the process of drug reaction. The main goal of VIP gene research is to assess the relationship of VIP gene variants and specific medications, and to provide the right medicine at right dose for an individual. Cytochrome P450 (CYP450) genes are responsible for over 75% of phase I drug metabolism. Previous study compared the allele and genotype frequencies of CYP450 among different populations, and found the effects of CYP450 variants on drug response are ethnicity dependent. For instance, CYP2C9 has effects on metabolic clearance of drug and the allele frequency of CYP2C9 is varied in different populations, which proved that frequencies of gene variants and drug reaction are significantly different among the populations (Van Booven et al., 2010; Hong et al., 2005). In this study, we explored the pharmacogenomics of CYP450 genes, including CYP2J2, CYP3A4, CYP2C19, CYP2C9, CYP2C8, CYP2E1, CYP1A2, CYP4F2, CYP2A6, CYP2B6, and CYP2D6. In addition, combined previous studies and database, we selected 28 genes related to drug metabolism (MTHFR, DPYD, F5, PTGS2, UGT1A5, UGT1A1, SCN5A, NR1I2, P2RY12, P2RY1, ADH1A, ADH1B, HMGCR, ADRB2, TPMT, AHR, ABCB1, NAT2, GSTP1, ANKK1, DRD2, SLCO1B1, VDR, SULT1A1, NQO1, PTGIS, SLC19A1, and COMT) and performed the genotyping studies among 26 populations.

Different ethnicities have different effects on the same drug, and ethnicity has been identified as a factor for many diseases, such as oral diseases, cancer (Zhang, Lo, Liu, & Chu, 2015). The study of pharmacogenomics among different populations could be helpful for precision medication. China is the most populous country with 56 ethnic groups, Han ethnic group is the majority at 93% of the Chinese population (Corpman, 2013). Dai is one of the major Chinese ethnic minorities with 1.2 million population in 2010 (3% population in Yunnan), primarily living in the southwestern region of mainland China(Yang et al., 2016a). Dai population is the descendants of the ancient Yue people, and their social customs are close to the Thais in Thailand, Shan in Burma, and Lao in Laos (Shen et al., 2015). It is reported that many diseases afflict them, including visual impairment (Yang et al., 2016b), recurrent spontaneous abortion (Tang et al., 2017), hepatitis B virus(Gao, Liu, Wang, Zuo, & Yan, 2015), and cancers (Zha, Gan, Liu, & Tan, 2015). However, little is known about the pharmacogenomics of Dai population in Yunnan province.

In this study, we aimed to extend our understanding of ethnic diversity and pharmacogenomics of Dai. Hence, we genotyped 73 VIP variants in 200 Dai population from Yunnan province, China. And, we compared the frequency differences and identified the relationships between Dai population and 25 other populations. We hope that our results will provide new strategies for personalized medicine among the Dai population in the future.

MATERIALS AND METHODS

Study subjects

A total of 200 unrelated Dai individuals from Yunnan province were recruited in this study. All subjects were healthy identified by physical examination or medical history, and they had Dai ancestry for more than three generations. We obtained written informed consents from all participants before study. This study was in accordance with the 1964 Helsinki Declaration, and the Ethics Committees of the People's Hospital of Yunnan Province approved it.

Variant selection and genotyping

According to the database of Pharmacogenetics and Pharmacogenomic Knowledge, International HapMap Project and previous studies, we selected 73 genetic variant loci for our investigation. The blood DNA kit (GoldMag Co. Ltd.) was used to extract genomic DNA from peripheral blood samples, and we measured DNA concentration using Nanodrop 2000 (Thermo Scientific). SNP genotyping was conducted by the MassARRAY iPLEX platform (Agena Bioscience) according to the manufacturer's protocol. Agena Bioscience TYPER version 4.0 software was used to manage and analyze the data in this study.

Statistical analyses

We performed statistical analyses using Microsoft Excel and SPSS 20.0 (IBM®). All p values were two‐sided, and p < .05/ (73 × 26) was set as statistical significant via Bonferroni's correction. We compared the genotype frequencies of the selected variants in the Dai population with the other 25 populations from the HapMap database (CDX: Chinese Dai in Xishuangbanna, China; CHB: Han Chinese in Beijing, China; JPT: Japanese in Tokyo, Japan; KHV: Kinh in Ho Chi Minh City, Vietnam; BEB: Bengali from Bangladesh; GIH: Gujarati Indian from Houston, Texas; ITU: Indian Telugu from the United Kingdom; PJL: Punjabi from Lahore, Pakistan; STU: Sri Lankan Tamil from the United Kingdom; CEU: Utah Residents with Northern and Western European Ancestry; FIN: Finnish in Finland; GBR: British in England and Scotland; IBS: Iberian Population in Spain; TSI: Toscani in Italia; CLM; Colombians from Medellin, Colombia; MXL: Mexican Ancestry from Los Angeles, United States; PEL: Peruvians from Lima, Peru; PUR: Puerto Ricans from Puerto Rico; ACB: African Caribbean in Barbados; ASW: Americans of African Ancestry in southwest United States; ESN: Esan in Nigeria; GWD: Gambian in Western Divisions in the Gambia; LWK: Luhya in Webuye, Kenya; MSL: Mende in Sierra Leone; YRI: Yoruba in Ibadan, Nigeria) by χ2 test (Jin et al., 2016; Zhang et al., 2018). Subsequently, we investigated the population structure using the Bayesian clustering algorithm STRUCTURE v2.3.1 (Pritchard Lab, Stanford University, USA, http://pritchardlab.stanford.edu/structure.html) and we calculated pair‐wise F‐statistic (Fst) using Arlequin v3.5(Ding et al., 2016; Yunus et al., 2013).

RESULTS

Basic information of the selected variants in the Dai population is presented in Table 1, including chromosome, position, allele, genotype, Hardy–Weinberg equilibrium (HWE), and functional consequence. The 73 variant loci belong to 39 genes (MTHFR, CYP2J2, DPYD, F5, PTGS2, UGT1A5, UGT1A1, SCN5A, NR1I2, P2RY12, P2RY1, ADH1A, ADH1B, HMGCR, ADRB2, TPMT, AHR, ABCB1, CYP3A4, NAT2, CYP2C19, CYP2C9, CYP2C8, CYP2E1, GSTP1, ANKK1, DRD2, SLCO1B1, VDR, CYP1A2, SULT1A1, NQO1, CYP4F2, CYP2A6, CYP2B6, PTGIS, SLC19A1, COMT, and CYP2D6). Then, we compared the genotype frequencies differences between the Dai and 25 other populations from the 1,000 genomes project database (Table 2). In CDX population, 12 loci (DPYD rs1801265, PTGS2 rs20417, PTGS2 rs689466, UGT1A5 rs4124874, TPMT rs1142345, NAT2 rs4646244, NAT2 rs4271002, NAT2 rs1799931, CYP2C19 rs4244285, NQO1 rs1800566, CYP2A6 rs28399433, and PTGIS rs5629) were different with Dai population. Ten significant variants were observed in CHB population, including MTHFR rs1801131, DPYD rs1801265, PTGS2 rs5275, PTGS2 rs20417, UGT1A1 rs4148323, TPMT rs1142345, ABCB1 rs1045642, NAT2 rs4646244, CYP1A2 rs762551, and CYP2A6 rs28399433. When we compared Dai with JPT, KHV, BEB, GIH, ITU, PJL, STU, CEU, FIN, GBR, IBS, TSI, CLM, MXL, PEL, PUR, ACB, ASW, ESN, GWD, LWK, MSL, and YRI, there were 17, 11, 39, 46, 46, 45, 43, 49, 46, 46, 46, 49, 45, 41, 42, 48, 53, 45, 50, 50, 51, 47, and 50 different SNPs in the frequency distribution. Specially, the genotype frequency of PTGS2 rs20417, TPMT rs1142345, and CYP2A6 rs28399433 in the Dai population was significantly different from the other 25 populations. In Table 3, we presented the allele frequencies of PTGS2 (rs5275, rs20417, rs689466), TPMT (rs1142345), and CYP2A6 (rs8192726, rs1801272, rs28399433) in 26 populations. It showed TPMT (rs1142345) is remarkably varied between Dai population and the other populations. Meanwhile, we showed the allele frequencies of PTGS2 (rs20417), CYP2A6 (rs28399433), and TPMT (rs1142345) in Figure 1. There were close allele frequencies of PTGS2 (rs20417) and CYP2A6 (rs28399433), but not TPMT (rs1142345).

Table 1

Basic characteristic of the selected variants

SNP	Gene	Chromosome		Position	Alleles	Dai population			HWE‐P	Functional consequence
					A/B	AA	AB	BB
rs1801131	MTHFR	1		11,794,419	G/T	25	87	88	0.631	missense
rs890293	CYP2J2	1		59,926,822	A/C	0	6	194	/	upstream variant 2KB
rs3918290	DPYD	1		97,450,058	T/C	0	0	200	/	splice donor variant
rs1801159	DPYD	1		97,515,839	C/T	10	71	119	0.887	intron variant, missense
rs1801265	DPYD	1		97,883,329	G/A	9	84	107	0.101	intron variant, missense, nc transcript variant, utr variant 5 prime
rs6025	F5	1		169,549,811	T/C	0	0	200	/	Missense
rs5275	PTGS2	1		186,673,926	G/A	15	83	102	0.734	utr variant 3 prime
rs20417	PTGS2	1		186,681,189	G/C	3	0	197	/	nc transcript variant, upstream variant 2KB
rs689466	PTGS2	1		186,681,619	C/T	28	96	76	0.791	downstream variant 500B,upstream variant 2KB
rs4124874	UGT1A5	2		233,757,013	G/T	21	93	86	0.569	intron variant, upstream variant 2KB
rs10929302	UGT1A5	2		233,757,136	A/G	2	44	154	0.496	intron variant, upstream variant 2KB
rs4148323	UGT1A1	2		233,760,498	A/G	2	49	149	0.246	intron variant, missense
rs1805124	SCN5A	3		38,603,929	C/T	3	31	166	0.378	missense
rs6791924	SCN5A	3		38,633,208	A/G	0	0	200	/	missense
rs3814055	NR1I2	3		119,781,188	T/C	7	64	129	0.780	upstream variant 2KB, utr variant 5 prime
rs2046934	P2RY12	3		151,339,854	G/A	8	47	145	0.157	intron variant
rs1065776	P2RY1		3	152,835,839	T/C	1	14	185	0.440	synonymous codon
rs701265	P2RY1		3	152,836,568	G/A	14	77	109	0.937	synonymous codon
rs975833	ADH1A		4	99,280,582	G/C	13	66	121	0.355	intron variant
rs2066702	ADH1B		4	99,307,860	A/G	0	0	200	/	missense
rs17244841	HMGCR		5	75,347,030	A/T	200	0	0	/	intron variant
rs3846662	HMGCR		5	75,355,259	G/A	40	104	56	0.508	intron variant
rs1042713	ADRB2		5	148,826,877	G/A	35	99	66	0.839	missense
rs1042714	ADRB2		5	148,826,910	G/C	2	28	170	0.562	missense
rs1142345	TPMT		6	18,130,687	T/C	192	8	0	/	missense
rs2066853	AHR		7	17,339,486	A/G	23	88	87	0.917	missense
rs1045642	ABCB1		7	87,509,329	A/G	58	92	50	0.265	synonymous codon
rs1128503	ABCB1		7	87,550,285	G/A	27	86	87	0.441	synonymous codon
rs2740574	CYP3A4		7	99,784,473	C/T	0	1	199	/	upstream variant 2KB
rs4646244	NAT2		8	18,390,208	A/T	27	95	78	0.820	intron variant, upstream variant 2KB
rs4271002	NAT2		8	18,390,758	C/G	7	59	134	0.874	intron variant, upstream variant 2KB
rs1801280	NAT2		8	18,400,344	C/T	1	20	179	0.665	missense
rs1799929	NAT2		8	18,400,484	T/C	1	25	174	0.924	synonymous codon
rs1208	NAT2		8	18,400,806	G/A	1	27	172	0.956	missense
rs1799931	NAT2		8	18,400,860	A/G	6	55	139	0.847	missense
rs12248560	CYP2C19		10	94,761,900	T/C	0	4	196	/	upstream variant 2KB
rs4986893	CYP2C19		10	94,780,653	A/G	0	19	181	/	stop gained
rs4244285	CYP2C19		10	94,781,859	A/G	23	99	78	0.308	synonymous codon
rs1057910	CYP2C9		10	94,981,296	C/A	0	14	186	/	missense
rs7909236	CYP2C8		10	95,069,673	T/G	1	39	160	0.246	upstream variant 2KB
rs17110453	CYP2C8		10	95,069,772	C/A	18	92	90	0.410	upstream variant 2KB
rs2070676	CYP2E1		10	133,537,633	G/C	13	77	110	0.923	intron variant
rs1695	GSTP1		11	67,585,218	G/A	3	58	139	0.175	missense
rs1138272	GSTP1		11	67,586,108	T/C	0	0	200	/	missense
rs1800497	ANKK1		11	113,400,106	A/G	33	107	60	0.200	missense
rs6277	DRD2		11	113,412,737	A/G	2	20	178	0.282	synonymous codon
rs1801028	DRD2		11	113,412,762	C/G	0	8	192	/	missense
rs4149056	SLCO1B1		12	21,178,615	C/T	3	51	146	0.492	missense
rs731236	VDR		12	47,844,974	G/A	0	15	185	/	synonymous codon
rs7975232	VDR		12	47,845,054	A/C	20	75	105	0.244	intron variant
rs1544410	VDR		12	47,846,052	T/C	0	14	186	/	intron variant
rs2239185	VDR		12	47,850,776	A/G	18	71	111	0.200	intron variant
rs1540339	VDR		12	47,863,543	C/T	12	81	107	0.502	intron variant
rs2239179	VDR		12	47,863,983	C/T	8	74	118	0.357	intron variant
rs3782905	VDR		12	47,872,384	C/G	4	57	139	0.464	intron variant
rs4516035	VDR		12	47,906,043	C/T	0	10	190	/	upstream variant 2KB
rs11568820	VDR		12	47,908,762	T/C	41	94	65	0.513	None
rs762551	CYP1A2		15	74,749,576	C/A	9	83	108	0.124	intron variant
rs3760091	SULT1A1		16	28,609,479	G/C	20	101	79	0.121	intron variant, upstream variant 2KB
rs1800566	NQO1		16	69,711,242	A/G	49	94	57	0.407	missense
rs2108622	CYP4F2		19	15,879,621	T/C	3	59	138	0.145	missense
rs8192726	CYP2A6		19	40,848,591	A/C	7	43	149	0.151	intron variant
rs1801272	CYP2A6		19	40,848,628	T/A	2	0	198	/	missense
rs28399433	CYP2A6		19	40,850,474	C/A	0	63	137	/	upstream variant 2KB
rs3211371	CYP2B6		19	41,016,810	T/C	0	199	1	/	downstream variant 500B,missense,utr variant 3 prime
rs5629	PTGIS		20	49,513,169	T/G	9	63	128	0.733	stop gained, synonymous codon
rs1051298	SLC19A1		21	45,514,912	A/G	74	91	34	0.509	intron variant, utr variant 3 prime
rs1051296	SLC19A1		21	45,514,947	C/A	72	94	34	0.726	intron variant, utr variant 3 prime
rs1051266	SLC19A1		21	45,537,880	T/C	55	99	46	0.910	missense, utr variant 5 prime
rs4680	COMT		22	19,963,748	A/G	14	78	108	0.987	missense, upstream variant 2KB
rs59421388	CYP2D6		22	42,127,608	T/C	0	0	200	/	missense, synonymous codon, upstream variant 2KB
rs28371725	CYP2D6		22	42,127,803	T/C	0	15	185	/	intron variant, upstream variant 2KB
rs61736512	CYP2D6		22	42,129,132	T/C	0	0	200	/	intron variant, missense, upstream variant 2KB

‘/’ means no data.

Abbreviations: HWE, Hardy–Weinberg equilibrium; SNP, single‐nucleotide polymorphism.

Table 2

VIP variants in Dai compared with the 25 other populations after Bonferroni's multiple adjustment

Gene	SNP	CDX	CHB	JPT	KHV	BEB	GIH	ITU	PJL	STU	CEU	FIN	GBR	IBS	TSI	CLM	MXL	PEL	PUR	ACB	ASW	ESN	GWD	LWK	MSL	YRI
MTHFR	rs1801131	8.79E‐05	5.1E‐06	8.78E‐08	1.39E‐05	0.000129	9.99E‐05	8.59E‐06	9.84E‐05	0.000392	0.000467	0.000346	0.000487	6.52E‐05	0.000376	8.11E‐10	4.33E‐07	6.96E‐13	3.48E‐06	3.72E‐07	9.23E‐06	6.95E‐10	1.36E‐12	2.3E‐07	2.88E‐09	2.49E‐11
CYP2J2	rs890293	‐	5.66E‐05	‐	‐	‐	‐	4.78E‐06	‐	‐	‐	1.32E‐06	3.24E‐05	‐	‐	‐	0	0	4.44E‐06	3.24E‐09	4.06E‐12	9.22E‐16	4.42E‐13	3.37E‐12	1.56E‐17	9.49E‐13
DPYD	rs3918290	‐	‐	‐	‐	‐	‐		‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐
DPYD	rs1801159	0.000179	0.000253	0.000232	0.000102	6.95E‐07	3.77E‐07	1.9E‐10	1.06E‐07	3.92E‐09	4.78E‐05	1.75E‐05	0.00014	0.000406	0.000148	0.000215	0.000382	5.19E‐11	0.000348	1.48E‐05	8.17E‐05	0.00018	9.6E‐09	6.38E‐05	2.57E‐08	3.15E‐05
DPYD	rs1801265	6.32E‐07	3.5E‐11	1.53E‐12	7.11E‐09	0.000117	7.15E‐05	0.000155	0.000183	0.000117	5.25E‐06	0.000244	6.17E‐05	0.000241	7.38E‐05	0.000415	5.63E‐05	1.34E‐05	0.000502	2.23E‐07	1.43E‐09	1.82E‐08	1.13E‐10	1.84E‐12	4.93E‐07	5.74E‐09
F5	rs6025	‐	‐	‐	‐	‐	‐	‐	‐	‐	8.44E‐06	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐
PTGS2	rs5275	6.22E‐05	2.21E‐06	0.000209	7.72E‐05	1.28E‐05	2.42E‐05	5.91E‐05	1.41E‐08	7.19E‐06	1.83E‐05	0.000115	0.000396	0.000222	0.000358	1.2E‐05	0.000106	9.34E‐06	0.000298	5.75E‐17	1.66E‐11	7.48E‐21	1.32E‐16	3.08E‐17	1.45E‐19	6.11E‐21
PTGS2	rs20417	3.93E‐08	3.99E‐09	3.38E‐08	4.16E‐06	1.3E‐18	4.16E‐19	2.29E‐17	6.15E‐22	2.49E‐20	6.49E‐18	6.3E‐13	6.11E‐16	1.36E‐16	3.92E‐19	‐	8.51E‐23	2.36E‐19	4.53E‐21	5.5E‐31	1.07E‐28	1.32E‐39	4.28E‐29	2.1E‐26	6.06E‐38	7.83E‐35
PTGS2	rs689466	2.71E‐06	4.8E‐05	2.42E‐05	4.46E‐05	2.34E‐10	4.77E‐13	2.39E‐12	1.32E‐12	2.53E‐14	1.91E‐09	3.26E‐08	3.83E‐08	1.03E‐11	8.24E‐09	6.41E‐07	2.01E‐05	1.26E‐05	1.74E‐06	3.06E‐14	5.75E‐10	9.66E‐15	1.45E‐20	2.09E‐22	4.92E‐16	3.93E‐18
UGT1A5	rs4124874	7.84E‐06	6.07E‐05	0.00034	0.000325	3.52E‐12	9.72E‐13	4.05E‐12	1.84E‐15	1.86E‐16	2.92E‐05	6.96E‐05	0.000308	0.00016	1.56E‐05	1.38E‐07	4.06E‐07	9.4E‐12	4.22E‐07	1.9E‐31	1.08E‐19	6.98E‐39	1.96E‐45	6.27E‐36	3.81E‐41	2.25E‐39
UGT1A5	rs10929302	0.000276	0.000302	2.01E‐05	0.000145	5.99E‐17	2.31E‐18	1.32E‐15	3.5E‐18	1.39E‐20	7.72E‐11	2.16E‐12	9.98E‐07	4.18E‐08	3.23E‐07	1.25E‐11	2.29E‐11	1.94E‐19	2.82E‐12	1.91E‐10	7.97E‐12	2.16E‐12	3.55E‐13	2.85E‐14	2.25E‐12	4.08E‐14
UGT1A1	rs4148323	0.000229	2.79E‐06	0.000371	1.24E‐05	2.98E‐07	1.12E‐08	2.74E‐09	2.95E‐10	3.71E‐08	1.24E‐10	3.56E‐07	3.94E‐10	3.98E‐11	3.98E‐11	1.05E‐07	7.84E‐07	9.4E‐10	6.1E‐11	1.92E‐10	1.21E‐07	1.24E‐10	1.7E‐11	1.24E‐10	9.4E‐10	3.45E‐11
SCN5A	rs1805124	0.000338	3.16E‐05	6.42E‐05	0.000237	2.73E‐11	6.16E‐08	1.94E‐11	1.54E‐10	1.05E‐13	1.55E‐06	2.84E‐06	3.66E‐08	4.65E‐10	5.09E‐09	4.33E‐10	4.34E‐05	1.75E‐07	5.47E‐10	1.05E‐10	1.32E‐08	2.92E‐08	1.48E‐16	9.5E‐13	6.71E‐17	9.41E‐16
SCN5A	rs6791924	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	2.65E‐15	‐	‐	1.01E‐17	4.14E‐18	1.62E‐20	1.04E‐11
NR1I2	rs3814055	0.000129	3.85E‐05	6.79E‐05	9.92E‐05	8.2E‐07	3.94E‐11	6.32E‐08	3.01E‐06	4.09E‐08	3.15E‐07	4.17E‐07	7.42E‐10	3.68E‐10	2.64E‐08	1.69E‐11	1.43E‐06	4.58E‐09	6.19E‐11	9.12E‐10	2.76E‐05	2.13E‐05	9.07E‐08	4.78E‐06	5.98E‐05	2.09E‐05
P2RY12	rs2046934	0.000158	0.000199	0.000133	0.000321	0.000184	8.88E‐05	5.39E‐06	0.000353	1.14E‐06	6.95E‐05	0.000372	8.97E‐05	9.02E‐05	0.000242	7.21E‐05	0.00022	1.3E‐05	6.44E‐05	0.000193	0.000342	0.000463	9E‐05	9.11E‐05	6.29E‐05	0.000365
P2RY1	rs1065776	0.000173	0.000391	4.52E‐05	0.000318	4.74E‐07	1.06E‐06	4.27E‐10	1.75E‐08	2.53E‐05	0.000361	1.07E‐05	0.000277	0.000454	0.000334	0.000114	0.000357	0.000112	8.55E‐06	1.72E‐12	1.76E‐11	1.17E‐11	1.79E‐20	1.83E‐13	2.44E‐15	1.06E‐13
P2RY1	rs701265	5.91E‐05	0.000412	0.000443	0.000303	9.95E‐05	0.000133	0.000178	0.000431	1.91E‐06	1.69E‐05	6.74E‐05	8.42E‐07	3.5E‐06	9.08E‐06	0.000436	0.000199	0.000239	0.000378	7.26E‐25	7.73E‐18	1.7E‐25	3.2E‐37	1.14E‐32	2.04E‐38	4.85E‐34
ADH1A	rs975833	0.000189	9.65E‐05	0.000205	0.000347	7.03E‐10	4.85E‐14	7.77E‐09	1.41E‐17	1.09E‐15	3.99E‐30	3.38E‐36	2.69E‐29	9.43E‐24	3.07E‐29	4.27E‐30	1.25E‐33	6.14E‐40	2.1E‐32	5.34E‐27	7.45E‐24	4.23E‐25	6.67E‐32	1.34E‐34	8.51E‐36	4.77E‐27
ADH1B	rs2066702	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	4.01E‐19	3.98E‐21	4.18E‐29	7.7E‐16	‐	1.52E‐11	6.04E‐31
HMGCR	rs17244841	‐	‐	4.93E‐70	‐	‐	‐	‐	‐	1.34E‐69	6E‐69	6E‐69	3.27E‐67	1.1E‐70	9.83E‐70	7.2E‐67	2.39E‐61	6.58E‐66	4.93E‐70	2.46E‐66	1.07E‐60	5.25E‐67	2.69E‐68	5.67E‐68	7.46E‐64	5.93E‐70
HMGCR	rs3846662	0.000152	0.00014	0.000109	4.32E‐05	2.03E‐06	7.38E‐09	1.11E‐05	1.36E‐05	3.28E‐06	0.000323	0.000338	0.000344	7.69E‐05	0.000385	0.000173	0.000368	3.83E‐05	0.000262	7.5E‐25	4.14E‐19	9.28E‐37	1.41E‐35	5.8E‐36	1.8E‐32	7.81E‐36
ADRB2	rs1042713	0.000506	0.000201	3.18E‐06	0.000443	2.61E‐06	1.28E‐06	4.84E‐07	2.84E‐06	8.55E‐06	5.39E‐10	3.02E‐07	7.4E‐07	1.14E‐08	2.42E‐09	0.000124	5.98E‐05	1.14E‐06	2.02E‐07	0.000113	0.000404	7.74E‐05	0.000152	5.59E‐05	0.000135	0.000142
ADRB2	rs1042714	0.000125	8.41E‐05	0.000277	0.000236	1.63E‐06	3.63E‐10	9.3E‐07	6.37E‐09	1.6E‐05	4.46E‐25	3.18E‐20	1.33E‐21	4.02E‐24	4.24E‐22	2.96E‐10	7.13E‐05	6.66E‐05	5.33E‐23	6.87E‐06	0.000176	0.000101	0.00013	9.59E‐10	0.000201	0.000139
TPMT	rs1142345	3.3E‐64	5.89E‐69	1.84E‐67	6.24E‐66	6E‐63	7.71E‐67	1.1E‐67	4.84E‐66	9.76E‐69	1.38E‐65	6.24E‐66	9.54E‐64	1.23E‐66	1.34E‐68	3.36E‐65	2.71E‐57	4.21E‐61	4.33E‐63	2.4E‐63	7.08E‐55	5.02E‐65	5.3E‐68	1.02E‐60	4.53E‐60	1.55E‐65
AHR	rs2066853	5.84E‐05	0.000315	6.79E‐06	0.000459	3.15E‐07	1.1E‐11	2.33E‐09	4.74E‐09	2.87E‐09	6.36E‐13	9.13E‐10	6.19E‐12	1.39E‐11	7.52E‐13	1.85E‐07	2.93E‐08	8.77E‐06	2.62E‐09	2.88E‐06	0.000254	7.08E‐08	4.85E‐06	9.48E‐07	5.07E‐06	1.05E‐05
ABCB1	rs1045642	5.96E‐05	3.04E‐06	9.31E‐05	1.9E‐05	5.22E‐05	0.000263	0.00014	0.000385	0.000121	0.000211	3.87E‐05	0.000383	0.000206	0.000245	0.00011	0.000175	2.53E‐06	5.66E‐05	3.57E‐18	1.59E‐12	1.69E‐21	1.49E‐16	3.54E‐19	3.24E‐17	5.5E‐22
ABCB1	rs1128503	0.000195	0.000247	0.00026	0.000113	0.000415	3.88E‐05	7.76E‐05	1.55E‐05	0.000321	8.36E‐10	1.82E‐09	2.37E‐09	2.24E‐12	5.97E‐10	2.7E‐09	7.87E‐07	4.53E‐14	5.57E‐11	2.43E‐29	6.85E‐21	5.97E‐34	7.22E‐29	2.1E‐32	4.94E‐28	3.77E‐30
CYP3A4	rs2740574	‐	‐	‐	‐	‐		‐	‐	1.63E‐05	‐	5.46E‐06	‐	‐	‐	1.69E‐11	‐	‐	1.29E‐18	5.34E‐57	1.31E‐53	2.76E‐62	1.76E‐66	2.66E‐62	7.53E‐62	2.03E‐64
NAT2	rs4646244	1.15E‐07	2.12E‐08	6.58E‐06	0.000355	9.2E‐06	0.000478	0.000186	0.000357	0.000394	9.93E‐05	4.59E‐05	1.89E‐06	1.28E‐05	3.55E‐05	5.28E‐06	5.04E‐10	3.43E‐14	3.76E‐07	1.2E‐05	3.26E‐05	1.12E‐05	3.36E‐08	3.07E‐06	7.26E‐06	2.85E‐08
NAT2	rs4271002	5.76E‐06	0.000132	0.00033	0.000486	0.00031	0.000178	2.24E‐05	0.000224	0.000205	7.33E‐07	5.84E‐05	0.000432	0.000133	0.000419	3.68E‐05	0.000487	6.24E‐05	0.000415	1.99E‐05	0.000108	8.8E‐10	1.61E‐09	3.93E‐06	2.45E‐05	2.22E‐06
NAT2	rs1801280	0.000399	0.000181	6.42E‐05	0.000434	3.16E‐20	7.11E‐20	1.15E‐20	3.01E‐26	2.23E‐16	2.46E‐26	1.95E‐28	3.36E‐28	2.62E‐31	1.91E‐27	2E‐22	7.76E‐20	4.56E‐16	3.18E‐23	2.47E‐15	2.96E‐15	1.64E‐15	4.69E‐20	1E‐22	1.62E‐12	7.82E‐13
NAT2	rs1799929	0.000311	7.33E‐05	1.94E‐05	0.000234	2.17E‐17	1.33E‐15	1.91E‐16	1.18E‐21	1.15E‐13	5.1E‐24	8.08E‐25	1.05E‐24	9.01E‐29	2.63E‐25	2.13E‐19	1.46E‐17	1.5E‐13	7.25E‐19	3.71E‐11	5.18E‐11	8.26E‐09	6.01E‐15	7.25E‐18	3.73E‐08	2.94E‐07
NAT2	rs1208	0.000257	4.83E‐05	1.15E‐05	0.000317	4.29E‐20	1.98E‐17	2.51E‐18	4.8E‐24	1.14E‐15	5.04E‐22	1.23E‐23	3.76E‐24	2.44E‐28	4.47E‐25	2E‐20	1.39E‐21	1.68E‐13	1.51E‐20	3.12E‐19	3.68E‐16	1.36E‐20	1.39E‐25	1.04E‐25	1.59E‐17	1.75E‐20
NAT2	rs1799931	5.64E‐06	7.38E‐05	1.79E‐05	0.000399	4.25E‐05	2.27E‐07	3.54E‐07	9.11E‐07	5.49E‐06	1.24E‐11	1.4E‐08	2.22E‐09	3.98E‐09	1.53E‐10	2.3E‐06	0.00019	3.26E‐05	7.57E‐06	2.23E‐08	2.34E‐06	1.74E‐10	5.69E‐11	4.85E‐11	2.98E‐07	8.9E‐09
CYP2C19	rs12248560	‐	‐	‐	‐	‐	5.35E‐13	2.77E‐13	3.96E‐13	1.14E‐12	1.62E‐21	2.17E‐20	4.5E‐22	1.53E‐20	1.46E‐20	1.9E‐12	4.97E‐10	‐	7.49E‐17	7.81E‐26	5.31E‐18	1.05E‐22	1.33E‐22	1.52E‐16	1.53E‐23	5.41E‐22
CYP2C19	rs4986893	‐	‐	0.000136		‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐
CYP2C19	rs4244285	2.52E‐05	0.000213	0.000245	6.71E‐05	0.000232	5.73E‐05	0.000294	3.86E‐05	0.000169	5.24E‐12	4.25E‐07	1.32E‐10	2.7E‐11	1.17E‐15	2.44E‐13	3.95E‐10	8.16E‐17	2.2E‐12	2.51E‐10	3.86E‐09	1.32E‐07	8.36E‐13	2.42E‐07	1.34E‐08	2.15E‐10
CYP2C9	rs1057910	‐	‐	‐	‐	‐!	1.98E‐08	2.22E‐06	2.21E‐06	‐	‐	‐	‐	‐	1.54E‐05	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐
CYP2C8	rs7909236	0.000374	0.000443	0.000209	1.79E‐05	6.71E‐07	2.01E‐08	4.83E‐07	9.86E‐07	3.81E‐05	7.97E‐10	7.53E‐10	2.51E‐07	5.02E‐06	1.14E‐05	1.76E‐11	2.19E‐10	6.26E‐15	6.27E‐06	9.54E‐06	0.000372	5.51E‐09	1.2E‐09	2.17E‐07	2.57E‐08	2.06E‐09
CYP2C8	rs17110453	9.3E‐05	0.000439	0.000132	0.000112	0.000202	0.000168	0.000397	0.000102	0.000162	8.23E‐13	4.29E‐06	2.82E‐11	1.94E‐06	2.93E‐12	4.15E‐12	3.46E‐09	3.23E‐15	3.15E‐11	8.51E‐21	7.57E‐16	2.95E‐21	7.88E‐25	1E‐22	1.49E‐20	2.43E‐23
CYP2E1	rs2070676	0.000342	7.38E‐05	0.000135	9.17E‐06	4.78E‐05	3.58E‐06	5.16E‐05	1.78E‐05	3.63E‐05	1.64E‐06	2.4E‐09	3.43E‐08	1.82E‐06	5.85E‐06	1.09E‐06	6.06E‐06	3.74E‐07	0.000355	7.19E‐25	2.71E‐13	4.69E‐23	4.26E‐24	1.94E‐29	1.06E‐25	3.81E‐22
GSTP1	rs1695	9.07E‐05	0.000368	2.65E‐05	0.00013	7.39E‐05	2.62E‐08	5.56E‐09	2.39E‐08	1.01E‐08	4.98E‐13	5.13E‐07	1.28E‐08	3.25E‐11	1.41E‐07	1.5E‐10	7.35E‐21	4.08E‐31	1.86E‐11	6.52E‐16	1.91E‐14	9.27E‐23	2.37E‐22	4.96E‐21	1.18E‐16	2.3E‐13
GSTP1	rs1138272	‐		‐	‐	2.4E‐10	‐	‐	6.34E‐12	‐	‐	‐	‐	‐	‐	‐	3.46E‐08	‐	‐	‐	‐	‐	‐	‐	‐	‐
ANKK1	rs1800497	0.000323	4.95E‐05	0.000257	0.000458	2.06E‐06	4.73E‐07	0.000226	6.07E‐08	2.34E‐06	2.35E‐11	6.64E‐14	2.12E‐10	4.62E‐16	9.04E‐11	1.06E‐11	0.000472	5.18E‐05	3.88E‐09	6.22E‐05	0.000356	5.88E‐05	4.89E‐05	0.000214	0.000163	0.000224
DRD2	rs6277	0.000313	0.000243	0.000121	9.84E‐05	7.21E‐18	6.05E‐19	1.54E‐20	3.48E‐18	1.81E‐12	3.17E‐34	3.02E‐32	2.85E‐33	1.22E‐38	3.06E‐42	2.71E‐20	4.13E‐14	3.22E‐06	3.62E‐31	0.000163	6.01E‐06	0.000103	0.000497	3.04E‐05	0.000328	0.000117
DRD2	rs1801028	‐	7.11E‐05	‐	‐	‐	4.99E‐13	‐	‐	9.53E‐09	0.000168	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐
SLCO1B1	rs4149015	0.000113	9.95E‐05	8.78E‐05	0.000477	3.58E‐07	1.22E‐06	2.05E‐07	2.64E‐09	1.95E‐07	1.35E‐07	2.43E‐05	1.07E‐08	1.14E‐05	7.57E‐06	5.48E‐06	2.35E‐07	7.53E‐10	1.51E‐07	3.21E‐11	3.71E‐08	8.18E‐11	2.17E‐12	2.43E‐08	7.53E‐10	4.78E‐12
VDR	rs731236	‐	‐	‐	‐	3.96E‐20	1.53E‐22	1.13E‐34	1.48E‐19	2.56E‐31	5.17E‐32	3.42E‐23	2.37E‐21	2.1E‐31	4.11E‐30	2.43E‐16	6.47E‐12	7.63E‐07	1.54E‐28	1.7E‐22	3.3E‐15	3.96E‐20	7.15E‐18	2.21E‐18	2.43E‐15	2.06E‐22
VDR	rs7975232	0.000195	0.000502	0.000148	0.00035	1.93E‐13	2.93E‐11	1.29E‐16	9.21E‐12	5.59E‐18	5.47E‐14	2.51E‐11	2.52E‐07	7.1E‐13	5.51E‐14	1.96E‐09	1.18E‐05	0.000114	9.52E‐14	1.22E‐18	1.49E‐13	8.7E‐13	9.44E‐19	5.36E‐22	3.73E‐15	9.09E‐15
VDR	rs1544410	‐	‐	‐	‐	1.84E‐32	6.68E‐34	8.32E‐41	9.63E‐32	3.72E‐39	1.53E‐32	1.05E‐23	5.25E‐23	3.01E‐33	1.15E‐30	2.88E‐16	1.08E‐11	2.12E‐07	6.27E‐31	1.78E‐21	6.31E‐18	5.56E‐20	9.73E‐16	3.26E‐18	1.07E‐14	2.09E‐20
VDR	rs2239185	0.000247	0.000476	8E‐05	0.000488	1.38E‐14	1.98E‐12	2.36E‐19	5.47E‐13	1.73E‐20	1.61E‐15	1.59E‐12	3.64E‐08	8.23E‐14	2.6E‐15	3.62E‐10	3.14E‐06	0.00023	4.55E‐15	3.08E‐19	1.72E‐10	1.84E‐13	1.48E‐15	1.19E‐18	1.45E‐12	2.95E‐15
VDR	rs1540339	5.87E‐05	0.000405	0.000288	4.04E‐07	4.83E‐17	3.51E‐21	2.97E‐26	5.31E‐14	1.7E‐22	3.81E‐23	4.38E‐15	5.97E‐16	9.66E‐23	6.06E‐21	3.81E‐23	3.52E‐16	5.53E‐16	1.3E‐22	3.45E‐33	8.8E‐24	4.04E‐30	4.34E‐33	1.06E‐39	3.31E‐32	3.24E‐34
VDR	rs2239179	7.79E‐05	0.000507	0.000164	5.06E‐06	2.43E‐11	2.39E‐14	7.74E‐21	6.4E‐10	1.29E‐16	2.06E‐15	2.5E‐09	1.92E‐06	5.37E‐12	3.02E‐09	6.65E‐07	8.81E‐05	0.000124	2.97E‐11	6.28E‐06	6.67E‐06	6.62E‐05	0.000434	1.35E‐06	0.000215	5.97E‐05
VDR	rs3782905	0.000283	0.000422	2.27E‐05	0.000217	3.18E‐05	8.48E‐06	3.52E‐09	1.54E‐06	4.02E‐06	2.44E‐10	2.87E‐12	2.75E‐05	7.83E‐10	2.63E‐09	2.02E‐05	0.000189	7.89E‐05	4.37E‐08	3.75E‐05	0.000153	0.000123	0.000231	7.27E‐05	0.000199	8.09E‐05
VDR	rs4516035	‐	‐	‐	‐	8.8E‐14	1.88E‐14	9.43E‐15	1.05E‐17	3.63E‐16	1.46E‐28	3.69E‐42	5.94E‐32	2E‐29	2.51E‐34	9.55E‐22	4.68E‐18	1.58E‐12	3.65E‐28	‐	1.28E‐07	‐	‐	‐	‐	‐
VDR	rs11568820	3.84E‐05	0.000425	0.000443	0.000206	0.00028	0.000244	2.05E‐07	6.19E‐06	0.000425	1.65E‐09	2.24E‐11	6.65E‐10	2.2E‐08	1.64E‐08	2.9E‐11	1.51E‐11	4.12E‐17	1.76E‐07	1.6E‐21	3.56E‐10	1.23E‐28	3.79E‐31	2.12E‐22	9.36E‐30	2.09E‐38
CYP1A2	rs762551	0.000273	2.27E‐06	1.64E‐07	0.000487	3.14E‐08	3.68E‐11	2.19E‐10	8.43E‐10	6.92E‐13	0.000222	4.95E‐05	0.000152	3.14E‐06	8.62E‐07	0.000164	1.3E‐05	1.78E‐06	0.000225	7.53E‐07	2.14E‐05	2.62E‐11	1.73E‐08	1.69E‐13	3.3E‐08	2.41E‐10
SULT1A1	rs3760091	0.000129	0.00013	0.000323	0.000292	0.000259	5.95E‐07	0.000219	0.00021	9.09E‐05	0.00019	6.5E‐07	0.00035	3.14E‐05	3.52E‐07	0.00026	1.44E‐05	4.95E‐09	0.00018	0.000239	0.000257	0.000172	0.000392	0.000434	7.94E‐05	0.000203
NQO1	rs1800566	1.36E‐06	3.07E‐05	7.3E‐07	0.000182	5.77E‐06	1.51E‐05	1.71E‐05	4.31E‐07	9.92E‐06	6.85E‐14	8.85E‐13	2.47E‐12	5.9E‐12	2.57E‐10	3.25E‐08	6.58E‐05	0.000198	1.58E‐08	4.12E‐12	1.36E‐11	6.61E‐13	7.45E‐16	1.43E‐14	2.73E‐17	2.87E‐14
CYP4F2	rs2108622	0.000237	9.48E‐05	2.06E‐06	1.91E‐05	3.84E‐13	2.91E‐15	2.4E‐13	6.2E‐12	2.96E‐14	5.08E‐06	9.99E‐05	2.21E‐07	1.13E‐10	5.06E‐10	7.02E‐07	3.18E‐05	0.000144	3.02E‐07	2.31E‐05	5.91E‐05	2.61E‐08	8.67E‐07	0.000104	8.28E‐05	1.04E‐07
CYP2A6	rs8192726	0.000317	0.000176	0.000126	0.000119	0.000407	0.000366	0.000364	0.000371	0.000284	2.98E‐06	6.49E‐05	1.24E‐06	2.36E‐06	1.05E‐05	6.61E‐07	1.1E‐05	3.83E‐06	9.14E‐07	1.19E‐05	0.000244	0.000138	7.02E‐06	0.000109	2E‐05	0.00016
CYP2A6	rs1801272	‐	‐	‐	‐	3.21E‐05	4.34E‐05	‐	‐	4.27E‐05	2.32E‐07	5.27E‐06	1.24E‐06	1.44E‐07	2.02E‐08	‐	1.6E‐05	3.14E‐05	0.000115	‐	7.26E‐05	‐	‐	‐	‐	‐
CYP2A6	rs28399433	1.42E‐06	1.32E1‐08	1.24E‐11	3.13E‐07	6.96E‐06	1.09E‐06	3.03E‐07	1.4E‐07	2.01E‐06	‐	‐	4.58E‐09	1.9E‐08	‐	‐	‐	‐	1.65E‐06	9.12E‐08	1.4E‐05	6.51E‐06	‐	3.83E‐06	‐	2.79E‐07
CYP2B6	rs3211371	‐	‐	‐	‐	‐	‐	2.02E‐53	‐	‐	1.26E‐52	3.32E‐46	1.08E‐48	‐	1.42E‐51	2.27E‐57	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐
PTGIS	rs5629	2.14E‐06	5.39E‐05	0.000252	0.000356	4.44E‐05	0.000126	0.000386	4.22E‐05	8.53E‐05	0.00036	0.000409	0.000152	1.12E‐05	1.22E‐06	7.28E‐06	1.95E‐05	0.000107	0.00034	0.000154	0.000254	1.74E‐05	9.5E‐08	1.39E‐06	1.17E‐05	0.000318
SLC19A1	rs1051298	0.000399	3.6E‐05	0.000344	0.000382	0.000326	0.000496	0.000154	7.13E‐05	0.000321	2E‐08	2.67E‐06	5.74E‐08	8.3E‐05	4.42E‐07	8.97E‐06	5.54E‐09	5.06E‐08	2.44E‐06	0.000403	0.000312	4.09E‐05	0.00022	0.000191	0.000485	0.000307
SLC19A1	rs1051296	0.000456	6.37E‐05	0.000376	0.000452	7.96E‐05	0.00014	2.73E‐06	3.1E‐05	5.8E‐05	3.27E‐08	3.94E‐06	6.76E‐08	8.02E‐05	4.78E‐07	1.22E‐05	5.9E‐09	2.63E‐08	2.84E‐06	0.000345	2.42E‐05	1.9E‐06	2.4E‐05	8.57E‐05	0.00011	1.52E‐05
SLC19A1	rs1051266	0.000478	0.000279	0.000424	0.000275	3.33E‐06	5.45E‐06	1.18E‐05	1.58E‐05	4.65E‐05	1.79E‐05	0.000148	2.32E‐06	0.000272	0.000105	0.000382	2.55E‐07	1.51E‐06	5.6E‐05	3.54E‐07	0.000346	2.2E‐05	1.02E‐10	2.25E‐07	2.95E‐07	1.02E‐06
COMT	rs4680	0.000432	0.000176	0.000391	0.000456	8.39E‐08	4.86E‐08	2.92E‐09	1.05E‐11	2.35E‐05	5.02E‐09	5.86E‐16	7.86E‐12	1.2E‐09	9.07E‐09	2.61E‐05	7.66E‐06	1.96E‐05	1.72E‐06	0.000131	0.000183	0.000474	0.000301	0.000379	0.000266	0.000271
CYP2D6	rs59421388	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	3.61E‐11	6.5E‐07	5.99E‐11	‐	4.14E‐18	‐	1.51E‐13
CYP2D6	rs28371725	3.52E‐05	‐	‐	‐	1.02E‐05	2.01E‐08	5.98E‐08	‐	3.38E‐07	3.1E‐07	‐	7.23E‐05	1.09E‐05	3.11E‐09	3.76E‐05	‐	‐	2.16E‐07	4.9E‐05	‐	‐	‐	‐	‐	‐
CYP2D6	rs61736512	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	‐	3.61E‐11	6.5E‐07	5.99E‐11	‐	4.14E‐18	‐	1.51E‐13

Bold values mean statistical significant.

‘‐’ means no data.

Abbreviations: ACB, African Caribbean in Barbados; ASW, Americans of African Ancestry in southwest United States; BEB, Bengali from Bangladesh; CDX, Chinese Dai in Xishuangbanna, China; CEU, Utah Residents with Northern and Western European Ancestry; CHB, Han Chinese in Beijing, China; CLM, Colombians from Medellin, Colombia; ESN, Esan in Nigeria; FIN, Finnish in Finland; GBR, British in England and Scotland; GIH, Gujarati Indian from Houston, Texas; GWD, Gambian in Western Divisions in the Gambia; IBS, Iberian Population in Spain; ITU, Indian Telugu from the United Kingdom; JPT, Japanese in Tokyo, Japan; KHV, Kinh in Ho Chi Minh City, Vietnam; LWK, Luhya in Webuye, Kenya; MSL, Mende in Sierra Leone; MXL, Mexican Ancestry from Los Angeles, United States; PEL, Peruvians from Lima, Peru; PJL, Punjabi from Lahore, Pakistan; PUR, Puerto Ricans from Puerto Rico; STU, Sri Lankan Tamil from the United Kingdom; TSI, Toscani in Italia; VIP, very important pharmacogenetic; YRI, Yoruba in Ibadan, Nigeria.

Table 3

The allele frequencies of VIP variants in 26 populations

Gene	SNP	Allele	Dai	CDX	CHB	JPT	KHV	BEB	GIH	ITU	PJL	STU	CEU	FIN	GBR	IBS	TSI	CLM	MXL	PEL	PUR	ACB	ASW	ESN	GWD	LWK	MSL	YRI
PTGS2	rs5275	G	0.283	0.204	0.175	0.240	0.212	0.395	0.379	0.362	0.473	0.397	0.379	0.237	0.297	0.332	0.304	0.394	0.359	0.394	0.322	0.625	0.574	0.677	0.602	0.626	0.676	0.667
		A	0.718	0.796	0.825	0.760	0.788	0.605	0.621	0.638	0.527	0.603	0.621	0.763	0.703	0.668	0.696	0.606	0.641	0.606	0.678	0.375	0.426	0.323	0.398	0.374	0.324	0.333
PTGS2	rs20417	G	0.015	0.043	0.053	0.043	0.020	0.174	0.165	0.171	0.231	0.206	0.172	0.106	0.137	0.150	0.187	0.218	0.211	0.206	0.212	0.333	0.311	0.399	0.336	0.283	0.412	0.375
		C	0.985	0.957	0.947	0.957	0.980	0.526	0.835	0.829	0.769	0.794	0.828	0.894	0.863	0.850	0.813	0.782	0.789	0.794	0.788	0.667	0.689	0.601	0.664	0.717	0.588	0.625
PTGS2	rs689466	C	0.380	0.522	0.471	0.442	0.449	0.151	0.126	0.138	0.134	0.113	0.192	0.202	0.198	0.150	0.196	0.229	0.258	0.329	0.245	0.104	0.131	0.101	0.058	0.030	0.076	0.074
		T	0.620	0.478	0.529	0.558	0.551	0.849	0.874	0.862	0.866	0.887	0.808	0.798	0.802	0.850	0.804	0.771	0.742	0.671	0.755	0.896	0.869	0.899	0.942	0.970	0.924	0.926
TPMT	rs1142345	T	0.980	0.032	0.005	0.019	0.025	0.030	0.024	0.019	0.011	0.005	0.030	0.025	0.033	0.042	0.014	0.021	0.047	0.065	0.091	0.052	0.098	0.040	0.040	0.116	0.076	0.060
		C	0.020	0.968	0.995	0.981	0.975	0.971	0.976	0.981	0.989	0.995	0.970	0.975	0.967	0.958	0.986	0.978	0.953	0.935	0.909	0.948	0.902	0.960	0.960	0.884	0.924	0.940
CYP2A6	rs8192726	A	0.143	0.151	0.189	0.192	0.187	0.122	0.136	0.119	0.167	0.113	0.051	0.131	0.044	0.051	0.065	0.037	0.047	0.047	0.043	0.063	0.098	0.096	0.062	0.091	0.065	0.102
		C	0.858	0.849	0.811	0.808	0.813	0.878	0.864	0.881	0.833	0.887	0.949	0.869	0.956	0.949	0.935	0.963	0.953	0.953	0.957	0.938	0.902	0.904	0.938	0.909	0.935	0.898
CYP2A6	rs1801272	T	0.010	0	0	0	0	0.012	0.010	0	0	0.010	0.035	0.020	0.027	0.037	0.047	0	0.016	0.012	0.005	0	0.008	0	0	0	0	0
		A	0.990	1	1	1	1	0.988	0.990	1	1	0.990	0.965	0.980	0.973	0.962	0.953	1	0.984	0.988	0.995	1	0.992	1	1	1	1	1
CYP2A6	rs28399433	C	0.158	0.177	0.267	0.279	0.202	0.151	0.189	0.138	0.194	0.103	0.051	0.141	0.044	0.056	0.065	0.101	0.102	0.094	0.101	0.063	0.107	0.096	0.058	0.091	0.071	0.102
		A	0.843	0.823	0.733	0.721	0.798	0.849	0.811	0.862	0.806	0.897	0.949	0.859	0.956	0.944	0.935	0.899	0.898	0.906	0.899	0.938	0.893	0.904	0.942	0.910	0.929	0.898

Abbreviations: ACB, African Caribbean in Barbados; ASW, Americans of African Ancestry in southwest United States; BEB, Bengali from Bangladesh; CDX, Chinese Dai in Xishuangbanna, China; CEU, Utah Residents with Northern and Western European Ancestry; CHB, Han Chinese in Beijing, China; CLM, Colombians from Medellin, Colombia; ESN, Esan in Nigeria; FIN, Finnish in Finland; GBR, British in England and Scotland; GIH, Gujarati Indian from Houston, Texas; GWD, Gambian in Western Divisions in the Gambia; IBS, Iberian Population in Spain; ITU, Indian Telugu from the United Kingdom; JPT, Japanese in Tokyo, Japan; KHV, Kinh in Ho Chi Minh City, Vietnam; LWK, Luhya in Webuye, Kenya; MSL, Mende in Sierra Leone; MXL, Mexican Ancestry from Los Angeles, United States; PEL, Peruvians from Lima, Peru; PJL, Punjabi from Lahore, Pakistan; PUR, Puerto Ricans from Puerto Rico; SNP, single‐nucleotide polymorphism; STU, Sri Lankan Tamil from the United Kingdom; TSI, Toscani in Italia; VIP, very important pharmacogenetic; YRI, Yoruba in Ibadan, Nigeria.

Figure 1

The allele frequencies of PTGS2 rs20417, TPMT rs1142345, and CYP2A6 rs28399433 in 26 populations. 1: Dai, 2: CDX, 3: CHB, 4: JPT, 5: KHV, 6: BEB, 7: GIH, 8: ITU, 9: PJL, 10: STU, 11: CEU, 12: FIN, 13: GBR, 14: IBS, 15: TSI, 16: CLM, 17: MXL, 18: PEL, 19: PUR, 20: ACB, 21: ASW, 22: ESN, 23: GWD, 24: LWK, 25: MSL, 26: YRI

Structure analysis is the visualizing patterns of genetic similarity and differentiation between Dai and other 25 populations. In Figure 2, we divided all individuals into six clusters to display the genetic relationship by the structure analysis. The results indicated that Dai is closest to CDX, followed by CHB, JPT, and KHV. Then, we calculated pair‐wise Fst values to evaluate the genetic differentiation between Dai and other 25 populations (0 means no divergence, 1 means complete separation). In Table 4, pair‐wise Fst distances of all populations ranged from 0 to 0.24295. And, the distances of Dai with CDX, CHB, JPT, and KHV were close (CDX: Fst = 0.01754; CHB: Fst = 0.02500; JPT: Fst = 0.02409; KHV: Fst = 0.01499), whereas there was greater divergence of Dai with ESN, GWD, LWK, MSL, and YRI (ESN: Fst = 0.20949; GWD: Fst = 0.21972; LWK: Fst = 0.2252; MSL: Fst = 0.22374; YRI: Fst = 0.21152).

Figure 2

Structure analysis of the genetic relationship of Dai and the other 25 populations

Table 4

Distribution of pair‐wise F‐statistics distances among the 26 populations

	Dai	CDX	CHB	JPT	KHV	BEB	GIH	ITU	PJL	STU	CEU	FIN	GBR	IBS	TSI	CLM	MXL	PEL	PUR	ACB	ASW	ESN	GWD	LWK	MSL	YRI
Dai	0
CDX	0.01754	0
CHB	0.02500	0.01435	0
JPT	0.02409	0.01462	0.00445	0
KHV	0.01499	0.00259	0.01028	0.01012	0
BEB	0.11872	0.10218	0.12876	0.11480	0.10946	0
GIH	0.11621	0.10300	0.12766	0.11554	0.10751	0.00146	0
ITU	0.13758	0.12276	0.15106	0.13833	0.12916	0.00224	0.00446	0
PJL	0.12593	0.11076	0.13737	0.12351	0.11782	0.00150	0.00249	0.00655	0
STU	0.13688	0.12145	0.15075	0.13440	0.12829	0.00258	0.00505	0.00164	0.00770	0
CEU	0.14564	0.12684	0.14914	0.13957	0.13394	0.04283	0.03840	0.04426	0.02971	0.04969	0
FIN	0.13430	0.12014	0.14166	0.13221	0.12690	0.03884	0.03535	0.04335	0.02433	0.04907	0.00688	0
GBR	0.13736	0.12035	0.14041	0.13299	0.12726	0.04038	0.03710	0.04842	0.02732	0.05412	0.00395	0.00484	0
IBS	0.14216	0.12407	0.14190	0.13195	0.12774	0.03806	0.03531	0.04232	0.02778	0.04832	0.00487	0.00963	0.00547	0
TSI	0.13635	0.11644	0.13330	0.12537	0.12225	0.04219	0.04046	0.04773	0.03108	0.05353	0.00400	0.01002	0.00470	−0.00007	0
CLM	0.11131	0.09156	0.10694	0.10080	0.09627	0.03939	0.03528	0.05001	0.03038	0.05258	0.01868	0.01972	0.01511	0.01398	0.01244	0
MXL	0.11337	0.09162	0.10788	0.10718	0.09974	0.05152	0.04901	0.06355	0.03994	0.06724	0.03041	0.02881	0.02264	0.03235	0.02558	0.00836	0
PEL	0.12606	0.10026	0.12100	0.12008	0.10945	0.08690	0.08131	0.10347	0.07833	0.10402	0.08246	0.07843	0.06914	0.08417	0.07856	0.03768	0.02158	0
PUR	0.12375	0.10186	0.12164	0.11430	0.10998	0.03501	0.03084	0.03970	0.02577	0.04346	0.00742	0.01252	0.01010	0.00635	0.00484	0.00538	0.01760	0.05691	0
ACB	0.19229	0.17847	0.20780	0.19006	0.18368	0.11721	0.11249	0.12365	0.11137	0.11814	0.14383	0.14453	0.15165	0.13675	0.14095	0.11138	0.13733	0.14687	0.10228	0
ASW	0.1638	0.14857	0.17838	0.16393	0.15481	0.09328	0.08785	0.10011	0.08495	0.09778	0.11495	0.11207	0.11907	0.11125	0.11175	0.08179	0.09806	0.11035	0.07568	0.00318	0
ESN	0.20949	0.19871	0.22516	0.20895	0.20242	0.14426	0.13752	0.15078	0.13701	0.14446	0.17674	0.17586	0.18383	0.17173	0.17442	0.14120	0.16179	0.16442	0.13297	0.00514	0.00855	0
GWD	0.21972	0.21100	0.23883	0.22131	0.21545	0.15289	0.14693	0.16022	0.14453	0.15416	0.18252	0.17934	0.18820	0.17463	0.17895	0.14378	0.16818	0.17471	0.13746	0.00526	0.01178	0.00730	0
LWK	0.22572	0.21451	0.24295	0.22642	0.21968	0.15150	0.14401	0.15648	0.14230	0.15180	0.17724	0.17476	0.18603	0.17020	0.17405	0.14431	0.16743	0.17559	0.13270	0.00699	0.01337	0.00806	0.00547	0
MSL	0.22374	0.21473	0.24250	0.22517	0.21977	0.16058	0.15348	0.16759	0.15134	0.15978	0.18868	0.18761	0.19595	0.18265	0.18492	0.15109	0.17499	0.18228	0.14254	0.00831	0.01411	0.00858	0.00254	0.00865	0
YRI	0.21152	0.20068	0.22682	0.20939	0.20473	0.14335	0.13900	0.15134	0.13739	0.14437	0.17935	0.17722	0.18564	0.17224	0.17502	0.14179	0.16542	0.16957	0.13430	0.00304	0.00853	0	0.00409	0.00804	0.00427	0

Abbreviations: ACB, African Caribbean in Barbados; ASW, Americans of African Ancestry in southwest United States; BEB, Bengali from Bangladesh; CDX, Chinese Dai in Xishuangbanna, China; CEU, Utah Residents with Northern and Western European Ancestry; CHB, Han Chinese in Beijing, China; CLM; Colombians from Medellin, Colombia; ESN, Esan in Nigeria; FIN, Finnish in Finland; GBR, British in England and Scotland; GIH, Gujarati Indian from Houston, Texas; GWD, Gambian in Western Divisions in the Gambia; IBS, Iberian Population in Spain; ITU, Indian Telugu from the United Kingdom; JPT, Japanese in Tokyo, Japan; KHV, Kinh in Ho Chi Minh City, Vietnam; LWK, Luhya in Webuye, Kenya; MSL, Mende in Sierra Leone; MXL, Mexican Ancestry from Los Angeles, United States; PEL, Peruvians from Lima, Peru; PJL, Punjabi from Lahore, Pakistan; PUR, Puerto Ricans from Puerto Rico; STU, Sri Lankan Tamil from the United Kingdom; TSI, Toscani in Italia; YRI, Yoruba in Ibadan, Nigeria.

DISCUSSION

In this study, we genotyped 81 variants related to pharmacogenomics in the Dai population for the first time and compared the differences between Dai and other population. The results showed that 12, 10, 17, 11, 39, 46, 46, 45, 43, 49, 46, 46, 46, 49, 45, 41, 42, 48, 53, 45, 50, 50, 51, 47, and 50 significantly VIP variants differed between Dai and other 25 populations (CDX, CHB, JPT, KHV, BEB, GIH, ITU, PJL, STU, CEU, FIN, GBR, IBS, TSI, CLM, MXL, PEL, PUR, ACB, ASW, ESN, GWD, LWK, MSL, and YRI). The genotype frequencies of PTGS2 rs20417, TPMT rs1142345, and CYP2A6 rs28399433 in the selected populations are significantly different. In addition, structure analysis and pair‐wise Fst values indicated that the VIP variants in Dai had a close genetic affinity with CDX, CHB, JPT, and KHV.

Prostaglandin‐endoperoxide synthase 2 (PTGS2), known as cyclooxygenase, is a key enzyme in prostaglandin biosynthesis, which catalyzes arachidonic acid to prostaglandins is response to inflammatory stimuli (Xie & Herschman, 1996). The overexpression of PTGS2 is involved in the pathogenesis of many diseases, such as PTGS2 rs20417 may contribute to coronary artery disease development, especially in Asians. PTGS2 rs689465 influence susceptibility of prostate cancer in Japanese men. PTGS2 and CYP2E1 polymorphisms had potentially synergistic association with the underlying cause of lung cancer in northeastern Chinese (Daraei, Salehi, & Mohamadhashem, 2012; Guo et al., 2012; Lin, Yao, & Ren, 2015; Sugie et al., 2014; Wang et al., 2014).

PTGS2 is also associated with drug reaction. For example, aspirin is a nonsteroidal anti‐inflammatory drug (NSAID) and operates directly on PTGS2. Rs20417 (−765G > C) is one of PTGS2 polymorphisms, which are more prone to aspirin resistance in stroke patients(Sharma et al., 2013). However, no studies specially focused on the Dai population. In our study, the χ2 test showed genotype frequency of PTGS2 rs20417 is significantly different in Dai compared with 25 other populations, including CDX and CHB. It may be account for the difference of genetic background, lifestyle, and environmental factors. It suggests PTGS2 could be a genetic marker involved in drug response and the effect is ethnicity dependent.

Thiopurine S‐methyltransferase (TPMT) encodes a crucial enzyme that metabolizes thiopurine drugs, such as azathioprine and 6‐mercaptopurine (Skrzypczak‐Zielinska et al., 2016). Study on TPMT genetic variants is one of the most advanced pharmacogenetic researches (Lennard, Loon, & Weinshilboum, 1989). Clinical studies showed that TPMT was associated with mercaptopurine toxicity, ototoxicity, inflammatory bowel disease, and hypoglycemic effect of drugs (Li et al., 2013; Liu et al., 2017; Steponaitiene et al., 2016; Thiesen et al., 2017). TPMT rs1142345 (TPMT∗3B) alters Ala154Thr and decreases the activity of TPMT. Genetic testing found that TPMT rs1142345 could prevent treatment‐related complications in East Asians, including China. In this study, we observed that the genotype and allele distributions of TPMT rs1142345 are varied in Dai and other 25 populations. It implied that rs1142345 could influence drug reaction in different populations.

Cytochrome P450 family 2 subfamily A member 6 (CYP2A6) mainly expresses in the human respiratory tract, which catalyzes many reactions involved in nicotine, drug metabolism, and synthesis of lipids (Ariyoshi et al., 2002). CYP2A6 genetic polymorphisms were related to the risk of many diseases, such as lung cancer, bladder cancer, and liver cancer (Ezzeldin et al., 2018; Kumondai et al., 2016; Tanner et al., 2017). Rs28399433 (−48 T > G) is one of the most common polymorphisms of CYP2A6 and it adjusts the level of enzyme expression (Pitarque et al., 2001). The frequency of rs283994433 was 6%‐8% and 21% in European and African and Asian, and Middle East population had a high frequency of rs283994433 (Minematsu et al., 2006; Park et al., 2016). Our resulted not only showed the significantly distribution differences of rs283994433 in the Dai population and other populations but also distribution differences between Dai and other Chinese populations (CDX and CHB). Similarly, Cong et al. reported that the frequencies of CYP2A6*4 allele were 7.9%, 15%, 0%, and 2% in Han, Uighur, Bouyei, and Tibetan, respectively (Pang, Liu, Xu, Chen, & Dai, 2015). It greatly expanded our understanding of the distribution of CYP2A6*4 in Chinese population. Our results complement the current data on the pharmacogenomics of Dai and provide more scientific basis for effective drug usage in different populations.

However, some limitations exist in the present study. First, sample size is relatively small, further study in the larger population is necessary to verify our results. Second, we selected 73 VIP variants from PharmGKB, more variant should be investigated in the future. Third, we did not conduct the stratification analysis and explore more populations due to the limited information. Further studies are needed in the future.

CONCLUSION

This study firstly provided the pharmacogenomics information in the Dai population and indicated differences between Dai and other 25 populations (CDX, CHB, JPT, KHV, BEB, GIH, ITU, PJL, STU, CEU, FIN, GBR, IBS, TSI, CLM, MXL, PEL, PUR, ACB, ASW, ESN, GWD, LWK, MSL, and YRI), which will be helpful for the prevention, diagnosis, individual treatment of certain diseases in the Dai population.

CONFLICT OF INTEREST

We declare no conflict of interest in this study.

AUTHOR CONTRIBUTION

Yujing Cheng and Tonghua Yang designed this study; Yujing Cheng, Run Dai, and Wanlu Chen mainly performed this study; Qi Li managed the data; and Chan Zhang and Yujing Cheng wrote the draft.