CYP2D6 genetic polymorphisms in Saudi systemic lupus erythematosus patients: A cross-sectional study

Lena M. Hassen; Maha H. Daghestani; Mohammed A. Omair; Arwa K. Althomali; Fatimah B. Almukaynizi; Ibrahim A. Almaghlouth

doi:10.15537/smj.2023.44.3.20220581

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Table 1

- The selected cytochrome P450 2D6 single nucleotide polymorphisms for this study.

SNP ID/name	Position reference	SNP region	Genetic variation	Functional consequence	Phenotype prediction^{^*}	Global MAF†
rs1080985 (CYP2D6^{^}2*)	NC_000022.11:g.42132375G>C	Promotor	2KB upstream variant	No function	-	Samples = 14,996 G = 0.87 (Ref) C = 0.13 (Alt)
rs28624811 (CYP2D6^{^}36*)	NC_000022.11:g.42131531G>A	Promotor	2KB upstream variant	No function	-	Samples = 55,678 G = 0.66 (Ref) A = 0.34 (Alt)
rs1065852 (CYP2D6^{^}4*)	NC_000022.11:g.42130692G>A	Exon 1	Missense variant; splice defect	Decreased function	PM	Samples = 48,628 G = 0.79 (Ref) A = 0.21 (Alt)
rs28371725 (CYP2D6^{^}41*)	NC_000022.11:g.42127803C>T	Intron 6	Intron variant; splice defect	Decreased function	IM-PM	Samples = 43,504 C = 0.91 (Ref) T = 0.09 (Alt)
rs1135840 (CYP2D6^{^}10*)	NC_000022.11:g.42126611C>G	Exon 9	Missense variant	Decreased function	IM-PM	Samples = 24,724 C = 0.43 (Ref) G = 0.57 (Alt)

↵* Phenotype prediction is based on Clinical Pharmacogenetics Implementation Consortium recommendations. †Global minor allele frequency is based on Allele Frequency Aggregator project database. Alt: alternative allele, CYP2D6: cytochrome P450 2D6, ID: identification, IM: intermediate metabolizers, SNP: single nucleotide polymorphism, MAF: minor allele frequency, PM: poor metabolizers, Ref: reference allele

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Table 2

- Genotype and allele frequencies of the selected cytochrome P450 2D6 single nucleotide polymorphisms in the study sample (N=107).

SNPs	Genotypes (N=107)			Alleles (N=214)		P-values (for HWE)
rs1080985	G/G	G/C	C/C	G	C	0.90
rs1080985	56 (52.3)	43 (40.2)	8 (7.5)	155 (72.4)	59 (27.6)	0.90
rs28624811	G/G	G/A	A/A	G	A	0.77
rs28624811	30 (28.0)	52 (48.6)	25 (23.4)	112 (52.3)	102 (47.7)	0.77
rs1065852	G/G	G/A	A/A	G	A	<0.001
rs1065852	80 (74.8)	14 (13.1)	13 (12.2)	174 (81.3)	40 (18.7)	<0.001
rs28371725	C/C	C/T	T/T	C	T	0.86
rs28371725	76 (71.0)	29 (27.1)	2 (1.9)	181 (84.6)	33 (15.4)	0.86
rs1135840	G/G	G/C	C/C	G	C	0.36
rs1135840	40 (37.4)	55 (51.4)	12 (11.2)	135 (63.1)	79 (36.9)	0.36
Values are presented as numbers and precentages (%). P-values above 0.05 represents consistency of CYP2D6 genotypes with HWE principle. HWE: Hardy-Weinberg equilibrium, SNPs: single nucleotide polymorphisms

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Table 3

- Characteristics of the study sample stratified by the cytochrome P450 2D6 single nucleotide polymorphism genotypes.

Variables	CYP2D6 genotypes
	rs1080985		rs28624811		rs1065852		rs28371725		rs1135840
	0 (n=56)	1 (n=51)	0 (n=30)	1 (n=77)	0 (n=80)	1 (n=27)	0 (n=76)	1 (n=31)	0 (n=40)	1 (n=67)
Age, mean±SD	38.5±10.4	36.6±12.2	37.1±10.1	37.8±11.8	38.7±11.4	34.3±10.8	37.6±11.1	37.5±12.1	35.4±11.1	38.9±11.3
P-values	0.37		0.77		0.08		0.97		0.12
Gender (n=91)	48	43	26	65	67	24	67	24	34	57
P-values	0.84		0.77		0.52		0.16		0.99
Cutaneous (n=83)	45	38	25	58	61	22	59	24	31	52
P-values	0.47		0.37		0.57		0.98		0.99
Arthritis (n=86)	44	42	23	63	62	24	61	25	33	53
P-values	0.62		0.55		0.20		0.96		0.67
Serositis (n=20)	6	14	4	16	18	2	15	5	8	12
P-values	0.03		0.37		0.08		0.66		0.79
Renal (n=50)	29	21	19	31	35	15	38	12	20	30
P-values	0.27		0.03		0.29		0.29		0.60
Neurological (n=19)	7	12	2	17	16	3	13	6	10	9
P-values	0.14		0.06		0.30		0.78		0.13
Hematological (n=47)	23	24	14	33	32	15	34	13	22	25
P-values	0.53		0.72		0.16		0.79		0.07
Immunological (n=92)	45	47	24	68	68	24	66	26	36	56
P-values	0.08		0.27		0.61		0.69		0.35
Values are presented as numbers or proportion in a subgroup. P-values (Bonferroni-adjusted) below 0.05 represents a statistically significant relationship (contingency) between CYP2D6 genotypes and participant characteristics. CYP2D6: cytochrome P450 2D6, SD: standard deviation, SNP: single nucleotide polymorphism, CYP2D6 SNP genotype 0: reference variant (homozygous dominant), CYP2D6 SNP genotype 1: alternative variants (heterozygous and homozygous recessive)

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Table 4

- Univariate logistical regression of systemic lupus erythematosus feature (dependent variable) on recessive cytochrome P450 2D6 genotype (explanatory variable).

Variables	Unadjusted model			Adjusted model^*
	OR	95% CI	P-values	OR	95% CI	P-values
Cutaneous
rs1080985 (1)	0.71	0.29-1.78	0.47	0.65	0.25-1.68	0.38
rs28624811 (1)	0.61	0.21-1.82	0.38	0.63	0.21-1.95	0.43
rs1065852 (1)	1.37	0.46-4.11	0.57	1.08	0.34-3.40	0.90
rs28371725 (1)	0.99	0.36-2.69	0.98	1.08	0.38-3.08	0.89
rs1135840 (1)	1.01	0.39-2.57	0.99	1.20	0.45-3.20	0.72
Arthritis
rs1080985 (1)	1.27	0.49-3.33	0.62	1.29	0.47-3.51	0.62
rs28624811 (1)	1.37	0.49-3.82	0.55	1.48	0.51-4.31	0.47
rs1065852 (1)	2.32	0.63-8.61	0.21	2.09	0.54-8.11	0.28
rs28371725 (1)	1.02	0.36-2.94	0.96	1.27	0.42-3.91	0.67
rs1135840 (1)	0.80	0.29-2.20	0.67	0.83	0.29-2.36	0.72
Serositis
rs1080985 (1)	3.15	1.11-8.98	0.03	3.01	1.05-8.66	0.04
rs28624811 (1)	1.70	0.52-5.59	0.38	1.71	0.52-5.66	0.38
rs1065852 (1)	0.28	0.06-1.28	0.10	0.24	0.05-1.13	0.07
rs28371725 (1)	0.78	0.26-2.38	0.66	0.73	0.23-2.27	0.58
rs1135840 (1)	0.87	0.32-2.36	0.79	0.95	0.35-2.63	0.93
Renal
rs1080985 (1)	0.65	0.3-1.40	0.27	0.59	0.27-1.30	0.19
rs28624811 (1)	0.39	0.16-0.93	0.03	0.39	0.16-0.94	0.04
rs1065852 (1)	1.61	0.67-3.87	0.29	1.39	0.56-3.43	0.48
rs28371725 (1)	0.63	0.27-1.48	0.29	0.62	0.26-1.50	0.29
rs1135840 (1)	0.81	0.37-1.78	0.60	0.92	0.41-2.06	0.83
Neurological
rs1080985 (1)	2.15	0.77-5.99	0.14	2.11	0.75–5.91	0.16
rs28624811 (1))	3.97	0.86-18.36	0.08	4.13	0.89–19.24	0.07
rs1065852 (1	0.50	0.13-1.87	0.30	0.43	0.11–1.66	0.22
rs28371725 (1)	1.16	0.40-3.40	0.78	1.22	0.41–3.63	0.72
rs1135840 (1)	0.47	0.17-1.27	0.13	0.49	0.18–1.35	0.17
Hematological
rs1080985 (1)	1.28	0.59-2.74	0.53	1.18	0.54-2.60	0.67
rs28624811 (1)	0.86	0.37-2.00	0.72	0.87	0.37-2.07	0.75
rs1065852 (1)	1.87	0.78-4.53	0.16	1.63	0.66-4.03	0.29
rs28371725 (1)	0.89	0.38-2.08	0.79	0.88	0.37-2.12	0.78
rs1135840 (1)	0.49	0.22-1.08	0.08	0.54	0.24-1.22	0.14
Immunological
rs1080985 (1)	2.87	0.85-9.68	0.09	3.00	0.87-10.31	0.08
rs28624811 (1)	1.89	0.61-5.86	0.27	1.96	0.62-6.19	0.25
rs1065852 (1)	1.41	0.37-5.44	0.62	1.34	0.34-5.30	0.68
rs28371725 (1)	0.79	0.25-2.53	0.69	0.88	0.27-2.89	0.83
rs1135840 (1)	0.57	0.17-1.91	0.36	0.56	0.16-1.92	0.36

↵* Model adjusted for age and gender. P-values below 0.05 represents a statistically significant association between clinical features of systemic lupus erythematosus and variant CYP2D6 genotypes. Bootstrap test based on 1000 samples (bias corrected and accelerated method) was carried out to verify statistically significant findings. CI: confidence interval, OR: odds ratio, SNP: single nucleotide polymorphism, CYP2D6 SNP genotype (1): heterozygous or homozygous recessive versus homozygous dominant genotypes