Associations Between Genetic Polymorphisms Within Transporter Genes and Clinical Response to Methotrexate in Chinese Rheumatoid Arthritis Patients: A Pilot Study

Figures & data

Table 1 Baseline Characteristics of Rheumatoid Arthritis Patients Included in the Present Study

Characteristics	RA Patients (n = 100)
Age, years	52.23 ± 12.71
Female, n (%)	81 (81.00)
Disease duration, years, median (IQR)	0.50 (0.25–2.00)
Smoking^a, n (%)	12 (12.77)
Drinking^a, n (%)	12 (12.77)
RF-positive^b, n (%)	82 (84.54)
CCP-positive^c, n (%)	91 (92.86)
Tender joint count (per 28 joints), median (IQR)	5.0 (2.5–10.0)
Swollen joint count (per 28 joints), median (IQR)	4.0 (2.0–8.5)
ESR, mm/h, median (IQR)	37.0 (20.0–59.5)
DAS28-ESR	4.87 ± 1.15
Methotrexate dose, mg/week, median (IQR)	10 (10–10)
Concomitant GC use, n (%)	82 (82.00)
GC dose^d, mg/d, median (IQR)	5.0 (2.5–10.0)
Concomitant NSAIDs use, n (%)	23 (23.00)

Notes: Values are mean ± standard deviation unless otherwise stated. ^a6 Patients' data was missing. ^b3 Patients’ data was missing. ^c2 Patients’ data was missing. ^dPrednisolone equivalent.

Abbreviations: CCP, cyclic citrullinated peptide; DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; GC, glucocorticoids; IQR, interquartile range; NSAIDs, non-steroidal anti-inflammatory drugs; RF, rheumatoid factor.

Table 2 Significant Associations of Genetic Polymorphisms Within Transporter Genes with Clinical Response to Methotrexate Assessed According to European League Against Rheumatism (EULAR) Good and Moderate Response in Rheumatoid Arthritis Patients*

Gene	SNP	Allele^a	Dominant Model^b		Recessive Model^c
			RR (95% CI)	p	RR (95% CI)	p
SLC19A1	rs12659	A/G	1.42 (1.02–1.97)	0.04	1.09 (0.89–1.34)	0.39
SLC19A1	rs3788200	A/G	1.45 (1.04–2.01)	0.03	1.13 (0.93–1.37)	0.22
ABCC2	rs3740066	T/C	0.88 (0.80–0.98)	0.02	0.80 (0.65–0.98)	0.03
ABCC2	rs4148396	T/C	1.03 (0.67–1.58)	0.90	0.79 (0.65–0.96)	0.02
ABCC2	rs717620	T/C	1.17 (0.65–2.09)	0.60	0.77 (0.63–0.94)	0.01

Notes: Bold values indicate statistical significance at α = 0.05. *Adjusted for smoking, drinking, disease activity score in 28 joints- erythrocyte sedimentation rate (DAS28-ESR) and concomitant non-steroidal anti-inflammatory drugs (NSAIDs) use. ^aMinor allele/major allele. ^bDominant model: major allele carriers versus minor allele homozygotes. ^cRecessive model: major allele homozygotes versus minor allele carriers.

Abbreviations: CI, confidence interval; RR, relative risk.

Table 3 Significant Associations of Genetic Polymorphisms Within Transporter Genes with Clinical Response to Methotrexate Assessed According to Disease Activity Score in 28 Joints – Erythrocyte Sedimentation Rate (DAS28-ESR) Low Disease Activity in Rheumatoid Arthritis Patients*

Gene	SNP	Allele^a	Dominant Model^b		Recessive Model^c
			RR (95% CI)	P	RR (95% CI)	P
ABCC2	rs3740066	T/C	1.31 (0.49–3.54)	0.59	0.67 (0.47–0.94)	0.02
ABCC2	rs717620	T/C	1.71 (0.58–5.06)	0.33	0.66 (0.48–0.92)	0.02

Notes: Bold values indicate statistical significance at α = 0.05. *Adjusted for disease activity score in 28 joints - erythrocyte sedimentation rate (DAS28-ESR). ^aMinor allele/Major allele. ^bDominant model: major allele carriers versus minor allele homozygotes. ^cRecessive model: major allele homozygotes versus minor allele carriers.

Abbreviations: CI, confidence interval, RR, relative risk.

Table 4 Significant Associations of Genetic Polymorphisms Within Transporter Genes with Clinical Response to Methotrexate Assessed According to Change in Disease Activity Score in 28 Joints – Erythrocyte Sedimentation Rate (DAS28-ESR) in Rheumatoid Arthritis Patients*

Gene	SNP	Allele^a	Dominant Model^b		Recessive Model^c
			β (95% CI)	P	β (95% CI)	P
ABCB1	rs1128503	G/A	0.89 (0.28–1.50)	0.005	0.07 (−0.38–0.51)	0.77
ABCB1	rs4148737	C/T	0.90 (0.32–1.49)	0.003	0.06 (−0.37–0.49)	0.78
ABCC3	rs2277624	T/C	0.75 (0.04–1.46)	0.04	0.00 (−0.42–0.42)	0.99
ABCC3	rs4148416	T/C	−0.39 (−1.87–1.09)	0.60	0.52 (0.03–1.01)	0.04

Notes: Bold values indicate statistical significance at α = 0.05. *Adjusted for disease activity score in 28 joints - erythrocyte sedimentation rate (DAS28-ESR). ^aMinor allele/major allele. ^bDominant model: major allele carriers versus minor allele homozygotes. ^cRecessive model: major allele homozygotes versus minor allele carriers.

Table 5 Significant Associations of Genetic Polymorphisms Within Transporter Genes with Clinical Response to Methotrexate Assessed According to Change in Disease Activity Score in 28 Joints – Erythrocyte Sedimentation Rate (DAS28-ESR) > 0.6 in Rheumatoid Arthritis Patients*

Gene	SNP	Allele^a	Dominant Model^b		Recessive Model^c
			RR (95% CI)	P	RR (95% CI)	P
SLC19A1	rs1051266	T/C	1.45 (1.04–2.02)	0.03	1.23 (1.02–1.48)	0.03
SLC19A1	rs1131596	G/A	1.45 (1.04–2.02)	0.03	1.23 (1.02–1.48)	0.03
SLC19A1	rs12659	A/G	1.44 (1.07–1.96)	0.02	1.20 (0.99–1.44)	0.06
SLC19A1	rs2838956	G/A	1.39 (1.01–1.90)	0.04	1.23 (1.03–1.48)	0.02
SLC19A1	rs3788200	A/G	1.47 (1.08–1.99)	0.01	1.20 (1.00–1.45)	0.05
SLC19A1	rs79091853	T/C	–	–	0.81 (0.68–0.95)	0.01
ABCB1	rs3842	C/T	0.90 (0.68–1.19)	0.47	1.23 (1.01–1.49)	0.04
ABCC1	rs3743527	T/C	0.94 (0.76–1.16)	0.56	1.22 (1.02–1.46)	0.03
ABCC2	rs3740066	T/C	0.77 (0.55–1.07)	0.11	0.81 (0.67–0.99)	0.04
ABCC2	rs4148396	T/C	0.97 (0.59–1.60)	0.91	0.81 (0.68–0.98)	0.03
ABCC2	rs717620	T/C	1.08 (0.53–2.17)	0.84	0.79 (0.65–0.95)	0.01
ABCG2	rs4367138	G/A	0.74 (0.58–0.95)	0.02	0.88 (0.73–1.06)	0.18

Notes: Bold values indicate statistical significance at α = 0.05. *Adjusted for disease duration, drinking, disease activity score in 28 joints - erythrocyte sedimentation rate (DAS28-ESR) and concomitant NSAIDs use. ^aMinor allele/major allele. ^bDominant model: major allele carriers versus minor allele homozygotes. ^cRecessive model: major allele homozygotes versus minor allele carriers.

Abbreviations: CI, confidence interval; RR, relative risk.

Table 6 Associations Between Haplotypes Consisting of Genetic Polymorphisms Within Transporter Genes and Clinical Response to Methotrexate Assessed According to Different Response Criteria with Adjustment for Potential Confounding Factors

Haplotype				Frequency	OR (95% CI)	P
EULAR good and moderate response^a
SLC19A1 rs1051266	SLC19A1 rs1131596	SLC19A1 rs12659	SLC19A1 rs3788200
C	A	G	G	0.57	Reference
T	G	A	A	0.42	0.37 (0.14–0.98)	0.048
SLC19A1 rs2838956	SLC19A1 rs7867	SLC19A1 rs79091853
A	G	C		0.43	Reference
G	A	C		0.42	0.47 (0.17–1.27)	0.14
A	G	T		0.12	1.67 (0.30–9.36)	0.56
ABCC2 rs3740066	ABCC2 rs4148396	ABCC2 rs717620
C	C	C		0.73	Reference
T	T	T		0.20	8.83 (1.62–48.15)	0.01
DAS28-ESR low disease activity^b
SLC19A1 rs1051266	SLC19A1 rs1131596	SLC19A1 rs12659	SLC19A1 rs3788200
C	A	G	G	0.57	Reference
T	G	A	A	0.42	0.80 (0.43–1.47)	0.47
SLC19A1 rs2838956	SLC19A1 rs7867	SLC19A1 rs79091853
A	G	C		0.42	Reference
G	A	C		0.42	0.83 (0.42–1.63)	0.60
A	G	T		0.12	0.70 (0.26–1.88)	0.48
ABCC2 rs3740066	ABCC2 rs4148396	ABCC2 rs717620
C	C	C		0.72	Reference
T	T	T		0.21	1.87 (0.83–4.20)	0.13
Change in DAS28-ESR^c
SLC19A1 rs1051266	SLC19A1 rs1131596	SLC19A1 rs12659	SLC19A1 rs3788200
C	A	G	G	0.58	Reference
T	G	A	A	0.41	−0.08 (−0.39–0.22)^d	0.59
SLC19A1 rs2838956	SLC19A1 rs7867	SLC19A1 rs79091853
A	G	C		0.42	Reference
G	A	C		0.40	−0.07 (−0.34–0.20)^d	0.60
A	G	T		0.12	−0.06 (−0.45–0.33)^d	0.76
ABCC2 rs3740066	ABCC2 rs4148396	ABCC2 rs717620
C	C	C		0.72	Reference
T	T	T		0.22	0.16 (−0.20–0.52)^d	0.39
Change in DAS28-ESR > 0.6^e
SLC19A1 rs1051266	SLC19A1 rs1131596	SLC19A1 rs12659	SLC19A1 rs3788200
C	A	G	G	0.57	Reference
T	G	A	A	0.42	0.23 (0.07–0.71)	0.01
SLC19A1 rs2838956	SLC19A1 rs7867	SLC19A1 rs79091853
A	G	C		0.43	Reference
G	A	C		0.42	0.35 (0.12–1.03)	0.06
A	G	T		0.12	3.13 (0.34–29.27)	0.32
ABCC2 rs3740066	ABCC2 rs4148396	ABCC2 rs717620
C	C	C		0.73	Reference
T	T	T		0.20	14.96 (1.79–125.24)	0.01

Notes: Bold values indicate statistical significance at α = 0.05. ^aAdjusted for smoking, drinking, disease activity score in 28 joints- erythrocyte sedimentation rate (DAS28-ESR) and concomitant non-steroidal anti-inflammatory drugs (NSAIDs) use. ^bAdjusted for disease activity score in 28 joints - erythrocyte sedimentation rate (DAS28-ESR). ^cAdjusted for disease activity score in 28 joints - erythrocyte sedimentation rate (DAS28-ESR). ^dValues denoting beta and 95% CI. ^eAdjusted for disease duration, drinking, disease activity score in 28 joints - erythrocyte sedimentation rate (DAS28-ESR) and concomitant NSAIDs use.

Abbreviations: CI, confidence interval; DAS28-ESR, disease activity score in 28 joints - erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; OR, odds ratio.