Usefulness of Cytokine Gene Polymorphisms for the Therapeutic Choice in Japanese Patients with Rheumatoid Arthritis

Figures & data

Table 1 Baseline Characteristics of the RA Patients and Healthy Controls

	RA	Control
N	100	50
Age (years)	61.1±14.3	39.2±7.6
Age Range	17–85	26–61
Gender (F/M)	85/15	29/21
Disease duration (months)	103.4±104.9	―
Positive RF (%)	74 (74%)	―
Positive ACPA (%)	70 (70%)	―
The history of the treatment of RA (N)	MTX (56) Biological DMARD (66)  TNF blocker (42)  IL-6 blocker (24)	―
Complications (%)	Hypertension (22%) Lipid abnormalities (19%) Diabetes (12%) Hyperuricemia (11%) Heart diseases (5%) Autoimmune diseases (10%)	―

Abbreviations: RA, rheumatoid arthritis; RF, rheumatoid factor; ACPA, anti-cyclic citrullinated peptide antibody; MTX, methotrexate; DMARD, disease-modifying antirheumatic drugs; TNF, tumor necrosis factor; IL-6, interleukin-6.

Table 2 Frequencies of Cytokine Gene Polymorphisms in RA and Normal Controls

Polymorphism	Genotype	100 Patients N (%)	50 Controls N (%)	χ^2 value	P value	OR	95% CI
TNF-α-308	G/G	99 (99)	50 (100)	0.0017	0.96730	0.990	0.612–1.601
	A/A	0 (0)	0 (0)	―	―	―	―
	G/A	1 (10)	0 (0)	0.4983	0.48023	―	―
TGF-β1 +869	T/T	20 (20)	13 (26)	0.4401	0.50707	0.769	0.354–1.672
	C/C	28 (28)	11 (22)	0.3724	0.54170	1.273	0.586–2.764
	T/C	52 (52)	26 (52)	―	―	―	―
TGF-β1 +915	C/C	0 (0)	0(0)	―	―	―	―
	G/G	100 (100)	50 (100)	―	―	―	―
	C/G	0 (0)	0(0)	―	―	―	―
IL-10-592	C/C	8 (8)	12 (24)	5.4162	0.01995	0.333	0.128–0.868
	A/A	46 (46)	20 (40)	0.1921	0.66114	1.150	0.615–2.149
	C/A	46 (46)	18 (36)	0.5613	0.45372	1.278	0.672–2.428
IL-10-819	C/C	8 (8)	12 (24)	5.4162	0.01995	0.333	0.128–0.868
	T/T	46 (46)	20 (40)	0.1921	0.66114	1.150	0.615–2.149
	C/T	46 (46)	18 (36)	0.5613	0.45372	1.278	0.672–2.428
IL-10-1082	G/G	0 (0)	0 (0)	―	―	―	―
	A/A	94 (94)	47 (94)	―	―	―	―
	G/A	6 (6)	3 (6)	―	―	―	―
IFN-γ +874	T/T	0 (0)	3 (6)	5.7736	0.01627	―	―
	A/A	79 (49)	39 (78)	0.0024	0.96112	1.013	0.607–1.690
	T/A	21 (21)	8 (16)	0.3665	0.54494	1.313	0.543–3.171

Note: Bold numbers are statistically significant (p < 0.05).

Abbreviations: N, absolute number; OR, odds ratio; CI, confidence interval; TNF, tumor necrosis factor; TGF, transforming growth factor; IL-10, interleukin-10; IFN, interferon.

Table 3 Distribution of Cytokine Genotypes in ACPA-Positive and -Negative Patients with RA

Polymorphism	Genotype	ACPA-(+) 70 Patients N (%)	ACPA-(−) 30 Patients N (%)	χ^2 value	P value	OR	95% CI
TNF-α-308	G/G	70 (100)	29 (97)	0.0119	0.91305	1.034	0.563–1.901
	A/A	0 (0)	0 (0)	―	―	―	―
	G/A	0 (0)	1 (3)	2.2806	0.13100	―	―
TGF-β1 +869	T/T	14 (20)	6 (20)	―	―	―	―
	C/C	14 (20)	14 (47)	3.8788	0.04890	0.429	0.182–1.008
	T/C	42 (60)	10 (33)	2.0462	0.15259	1.800	0.800–4.052
TGF-β1 +915	C/C	0 (0)	0(0)	―	―	―	―
	G/G	70 (100)	30 (100)	―	―	―	―
	C/G	0 (0)	0(0)	―	―	―	―
IL-10-592	C/C	7 (10)	1 (3)	1.1085	0.29241	3.000	0.353–25.460
	A/A	30 (43)	16 (53)	0.3340	0.56334	0.804	0.382–1.688
	C/A	33 (47)	13 (43)	0.0459	0.83042	1.088	0.503–2.353
IL-10-819	C/C	7 (10)	1 (3)	1.1085	0.29241	3.000	0.353–25.460
	T/T	30 (43)	16 (53)	0.3340	0.56334	0.804	0.382–1.688
	C/T	33 (47)	13 (43)	0.0459	0.83042	1.088	0.503–2.353
IL-10-1082	G/G	0 (0)	0 (0)	―	―	―	―
	A/A	64 (91)	30 (100)	0.0832	0.77305	0.914	0.194–1.681
	G/A	6 (9)	0 (0)	2.5105	0.11309	―	―
IFN-γ +874	T/T	0 (0)	0 (0)	―	―	―	―
	A/A	56 (80)	23 (77)	0.0166	0.89741	1.043	0.546–1.993
	T/A	14 (20)	7 (23)	0.0908	0.76311	0.857	0.314–2.337

Note: Bold numbers are statistically significant (p < 0.05).

Abbreviations: ACPA-(+), anti-cyclic citrullinated peptide antibody-positive; ACPA-(−), anti-cyclic citrullinated peptide antibody-negative; other abbreviations, see Table 2.

Table 4 Distribution of Cytokine Genotypes in MTX-Responder and -Nonresponder Patients with RA

Polymorphism	Genotype	MTX-Res. 33 Patients N (%)	MTX-Non. 23 Patients N (%)	χ^2 value	P value	OR	95% CI
TNF-α-308	G/G	33 (100)	23 (100)	―	―	―	―
	A/A	0 (0)	0 (0)	―	―	―	―
	G/A	0 (0)	0 (0)	―	―	―	―
TGF-β1 +869	T/T	6 (18)	7 (30)	0.7006	0.40257	0.597	0.178–2.010
	C/C	9 (27)	6 (26)	0.0056	0.94024	1.045	0.327–3.342
	T/C	18 (55)	10 (44)	0.2246	0.63556	1.255	0.491–3.207
TGF-β1 +915	C/C	0 (0)	0(0)	―	―	―	―
	G/G	33 (100)	23 (100)	―	―	―	―
	C/G	0 (0)	0(0)	―	―	―	―
IL-10-592	C/C	1 (3)	2 (8)	0.7639	0.38210	0.348	0.030–4.074
	A/A	15 (45)	10 (44)	0.0082	0.92777	1.045	0.400–2.733
	C/A	17 (52)	11 (48)	0.0247	0.87510	1.077	0.426–2.721
IL-10-819	C/C	1 (3)	2 (8)	0.7639	0.38210	0.348	0.030–4.074
	T/T	15 (45)	10 (44)	0.0082	0.92777	1.045	0.400–2.733
	C/T	17 (52)	11 (48)	0.0247	0.87510	1.077	0.426–2.721
IL-10-1082	G/G	0 (0)	0 (0)	―	―	―	―
	A/A	30 (91)	22 (96)	0.0170	0.89640	0.950	0.442–2.044
	G/A	3 (9)	1 (4)	0.4018	0.52617	2.091	0.204–21.382
IFN-γ +874	T/T	0 (0)	0 (0)	―	―	―	―
	A/A	29 (88)	21 (91)	0.0094	0.92284	0.962	0.444–2.084
	T/A	4 (12)	2 (9)	0.1349	0.71345	1.394	0.235–8.257

Abbreviations: MTX-res, methotrexate-responder; MTX-non, methotrexate-nonresponder; other abbreviations, see Table 2.

Table 5 Distribution of Cytokine Genotypes in BDM-Responder and -Nonresponder Patients with RA

Polymorphism	Genotype	BDM.-Res. 48 Patients N (%)	BDM.-Non. 18 Patients N (%)	χ^2 value	P value	OR	95% CI
TNF-α-308	G/G	48 (100)	18 (100)	―	―	―	―
	A/A	0 (0)	0 (0)	―	―	―	―
	G/A	0 (0)	0 (0)	―	―	―	―
TGF-β1 +869	T/T	11 (23)	5 (28)	0.1009	0.75070	0.825	0.252–2.706
	C/C	9 (19)	3 (17)	0.0267	0.87030	1.125	0.273–4.629
	T/C	28 (58)	10 (55)	0.0112	0.91563	1.050	0.426–2.589
TGF-β1 +915	C/C	0 (0)	0(0)	―	―	―	―
	G/G	48 (100)	18 (100)	―	―	―	―
	C/G	0 (0)	0(0)	―	―	―	―
IL-10-592	C/C	2 (4)	4 (22)	4.0225	0.04490	0.188	0.032–1.114
	A/A	25 (52)	6 (33)	0.7102	0.39939	1.563	0.551–4.433
	C/A	21 (44)	8 (45)	0.0010	0.97482	0.984	0.370–2.618
IL-10-819	C/C	2 (4)	4 (22)	4.0225	0.04490	0.188	0.032–1.114
	T/T	25 (52)	6 (33)	0.7102	0.39939	1.563	0.551–4.433
	C/T	21 (44)	8 (45)	0.0010	0.97482	0.984	0.370–2.618
IL-10-1082	G/G	0 (0)	0 (0)	―	―	―	―
	A/A	43 (90)	15 (83)	0.0315	0.85923	1.075	0.483–2.391
	G/A	5 (10)	3 (17)	0.3672	0.54454	0.625	0.135–2.888
IFN-γ +874	T/T	0 (0)	0 (0)	―	―	―	―
	A/A	35 (73)	15 (83)	0.1040	0.74714	0.875	0.388–1.971
	T/A	13 (27)	3 (17)	0.4910	0.48348	1.625	0.414–6.378

Note: Bold numbers are statistically significant (p < 0.05).

Abbreviations: BDM-res, biological disease-modifying antirheumatic drug-responder; BDM-non, biological disease-modifying antirheumatic drug-nonresponder; other abbreviations, see Table 2.