Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

MARIA CARMEN CÉNIT; CARMEN P. SIMEÓN; MADELON C. VONK; JOSE L. CALLEJAS-RUBIO; GERARD ESPINOSA; PATRICIA CARREIRA; FRANCISCO J. BLANCO; JAVIER NARVAEZ; CARLOS TOLOSA; JOSÉ A. ROMÁN-IVORRA; INMACULADA GÓMEZ-GARCÍA; FRANCISCO J. GARCÍA-HERNÁNDEZ; MARÍA GALLEGO; ROSA GARCÍA-PORTALES; MARÍA VICTORIA EGURBIDE; VICENTE FONOLLOSA; PALOMA GARCÍA de la PEÑA; FRANCISCO J. LÓPEZ-LONGO; MIGUEL A. GONZÁLEZ-GAY; The Spanish Scleroderma Group; ROGER HESSELSTRAND; GABRIELA RIEMEKASTEN; TORSTEN WITTE; ALEXANDRE E. VOSKUYL; ANNEMIE J. SCHUERWEGH; RAJAN MADHOK; CARMEN FONSECA; CHRISTOPHER DENTON; ANNIKA NORDIN; ØYVIND PALM; JACOB M. van LAAR; NICOLAS HUNZELMANN; JÖRG H.W. DISTLER; ALEXANDER KREUTER; ARIANE HERRICK; JANE WORTHINGTON; BOBBY P. KOELEMAN; TIMOTHY R.D.J. RADSTAKE; JAVIER MARTÍN

doi:10.3899/jrheum.120506

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Table 1.

Genotype and minor allele frequencies of SNP located within IL6 gene in patients with SSc and healthy controls of the different study cohorts.

			Genotype, n (%)			Allele Test
SNP	1/2	Subgroup (n)	1/1	1/2	2/2	MAF, %	p^*	p_BFN^**	OR (95% CI)^***
rs2069827	G/T	Controls (3189)	2687 (84.26)	473 (14.83)	29 (0.91)	8.33
		SSc (2739)	2339 (85.40)	379 (13.84)	21 (0.77)	7.69	0.018	0.162	0.85 (0.74–0.97)
		lcSSc (1848)	1574 (85.17)	257 (13.91)	17 (0.92)	7.87	0.083		0.87 (0.75–1.02)
		dcSSc (891)	765 (85.86)	122 (13.69)	4 (0.45)	7.30	0.024	0.216	0.79 (0.64–0.97)
		ACA+ (1049)	902 (85.99)	137 (13.06)	10 (0.95)	7.48	0.051		0.83 (0.69–1.00)
		ATA+ (611)	521 (85.27)	86 (14.08)	4 (0.65)	7.69	0.141		0.84 (0.66–1.06)
		FLA+ (715)	604 (84.48)	106 (14.83)	5 (0.70)	8.11	0.297		0.89 (0.72–1.11)
rs1800795	G/C	Controls (3179)	1215 (38.22)	1492 (46.93)	472 (14.85)	38.31
		SSc (2749)	1077 (39.18)	1250 (45.47)	422 (15.35)	38.09	0.252		0.96 (0.89–1.03)
		lcSSc (1850)	705 (38.11)	843 (45.57)	302 (16.32)	39.11	0.985		1.00 (0.92–1.09)
		dcSSc (899)	372 (41.38)	407 (45.27)	120 (13.35)	35.98	0.008	0.072	0.86 (0.77–0.96)
		ACA+ (1059)	401 (37.87)	494 (46.65)	164 (15.49)	38.81	0.829		0.99 (0.89–1.10)
		ATA+ (611)	244 (39.93)	281 (45.99)	86 (14.08)	37.07	0.141		0.91 (0.80–1.03)
		FLA+ (716)	251 (35.06)	352 (49.16)	113 (15.78)	38.09	0.575		1.00 (0.91–1.17)
rs2069840	C/G	Controls (3162)	1300 (41.11)	1459 (46.14)	403 (12.75)	35.82
		SSc (2725)	1176 (43.16)	1252 (45.94)	297 (10.90)	33.87	0.060		0.93 (0.86–1.00)
		lcSSc (1840)	819 (44.51)	835 (45.38)	186 (10.11)	32.80	0.004	0.036	0.88 (0.81–0.96)
		dcSSc (885)	357 (40.34)	417 (47.12)	111 (12.54)	36.10	0.497		1.04 (0.93–1.16)
		ACA+ (1044)	444 (42.53)	500 (47.89)	100 (9.58)	33.52	0.125		0.92 (0.83–1.02)
		ATA+ (612)	260 (42.48)	281 (45.92)	71 (11.60)	34.56	0.499		0.96 (0.84–1.09)
		FLA+ (705)	310 (43.97)	325 (46.10)	70 (9.93)	32.98	0.124		0.91 (0.80–1.03)

↵* Values calculated for the allelic model and Mantel-Haenszel test under fixed effect.
↵** Multiple testing Bonferroni (BFN) correction.
↵*** For the minor allele. SSc: systemic sclerosis; lcSSc: limited cutaneous SSc; dcSSc: diffuse cutaneous SSc; ACA: anticentromere antibodies; ATA: antitopoisomerase antibodies; FLA: fibrotic lung; MAF: minor allele frequency; SNP: single-nucleotide polymorphism.

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Table 2.

Pooled analysis of rs2069827-rs1800795-rs2069840 allelic combinations in white patients with SSc and healthy controls.

Allelic Combination	SSc, n (%)	Controls, n (%)	p_MH	p (covariates sex and population)	OR (95% CI)	p_BD
GGC	1598 (28.4)	1710 (26.5)	0.016^*	0.014	1.13 (1.04–1.23)	0.16
GCC	1693 (30.1)	1915 (29.7)	0.980	0.455	1.00 (0.93–1.09)	0.70
GGG	1920 (34.1)	2289 (35.5)	0.280	0.014	0.95 (0.88–1.03)	0.32
TCC	419 (7.4)	534 (8.3)	0.020^*	0.117	0.82 (0.72–0.94)	0.68

p_MH: allelic Mantel-Haenszel fixed-effects model. p_BD: Breslow-Day value.
↵* Multiple testing Bonferroni correction (× 4 analyzed haplotypes).

Genotype and minor allele frequencies of SNP within IL6 gene in patients with SSc and healthy controls from Germany.

					Genotype, n (%)			Allele Test
CHR	SNP	Locus	1/2	Subgroup (n)	1/1	1/2	2/2	MAF, %	p^*	p_FDR^**	OR (95% CI)^***
7	rs2069827	IL6	G/T	Controls (289)	226 (78.20)	57 (19.72)	6 (2.08)	11.94
				SSc (579)	466 (80.48)	107 (18.48)	6 (1.04)	10.28	0.29	0.44	0.84 (0.62–1.16)
				lcSSc (338)	267 (78.99)	67 (19.82)	4 (1.18)	11.09	0.64	0.90	0.92 (0.65–1.30)
				dcSSc (241)	199 (82.57)	40 (16.60)	2 (0.83)	9.13	0.14	0.21	0.74 (0.50–1.11)
				ACA+ (224)	182 (81.25)	39 (17.41)	3 (1.34)	10.04	0.34	0.51	0.82 (0.55–1.23)
				ATA+ (190)	154 (81.05)	35 (18.42)	1 (0.53)	9.74	0.29	0.43	0.80 (0.52–1.21)
7	rs1800795	IL6	G/C	Controls (290)	83 (28.62)	148 (51.03)	59 (20.34)	45.86
				SSc (568)	205 (36.09)	262 (46.13)	101 (17.78)	40.85	0.05	0.14	0.82 (0.67–1.00)
				lcSSc (331)	112 (33.84)	158 (47.73)	61 (18.43)	42.30	0.21	0.62	0.87 (0.69–1.08)
				dcSSc (237)	93 (39.24)	104 (43.88)	40 (16.88)	38.82	0.02	0.06	0.75 (0.59–0.96)
				ACA+ (219)	79 (36.07)	105 (47.95)	35 (15.98)	39.95	0.06	0.18	0.79 (0.61–1.01)
				ATA+ (189)	75 (39.68)	81 (42.86)	33 (17.46)	38.89	0.03	0.10	0.75 (0.58–0.98)
7	rs2069840	IL6	C/G	Controls (287)	125 (43.55)	136 (47.39)	26 (9.06)	32.75
				SSc (572)	254 (44.41)	251 (43.88)	67 (11.71)	33.65	0.71	0.71	1.04 (0.84–1.29)
				lcSSc (334)	149 (44.61)	149 (44.61)	36 (10.78)	33.08	0.90	0.90	1.02 (0.80–1.29)
				dcSSc (238)	105 (44.12)	102 (42.86)	31 (13.03)	34.45	0.56	0.56	1.08 (0.83–1.40)
				ACA+ (220)	90 (40.91)	109 (49.55)	21 (9.55)	34.32	0.60	0.60	1.07 (0.82–1.40)
				ATA+ (189)	84 (44.44)	78 (41.27)	27 (14.29)	34.92	0.49	0.49	1.10 (0.84–1.45)

↵* Values calculated for the allelic model.
↵** Multiple testing false discovery rate correction.
↵*** For the minor allele. SNP: single-nucleotide polymorphism; IL: interleukin; SSc: systemic sclerosis; MAF: minor allele frequency.

Genotype and minor allele frequencies of SNP within IL6 gene in patients with SSc and healthy controls from Sweden.

					Genotype, n (%)			Allele Test
CHR	SNP	Locus	1/2	Subgroup (n)	1/1	1/2	2/2	MAF, %	p^*	p_FDR^**	OR (95% CI)^***
7	rs2069827	IL6	G/T	Controls (268)	206 (76.87)	59 (22.01)	3 (1.12)	12.13
				SSc (254)	208 (81.89)	38 (14.96)	8 (3.15)	10.63	0.45	0.67	0.86 (0.59–1.26)
				lcSSc (184)	150 (81.52)	28 (15.22)	6 (3.26)	10.87	0.56	0.83	0.88 (0.58–1.34)
				dcSSc (70)	58 (82.86)	10 (14.29)	2 (2.86)	10.00	0.49	0.73	0.81 (0.44–1.48)
				ACA+ (71)	60 (84.51)	10 (14.08)	1 (1.41)	8.45	0.22	0.66	0.67 (0.35–1.38)
				ATA+ (44)	35 (79.55)	6 (13.64)	3 (6.82)	13.64	0.69	0.69	1.14 (0.59–2.22)
7	rs1800795	IL6	G/C	Controls (273)	83 (30.40)	138 (50.55)	52 (19.05)	44.32
				SSc (252)	81 (32.14)	117 (46.43)	54 (21.43)	44.64	0.92	0.92	1.01 (0.79–1.29)
				lcSSc (181)	56 (30.94)	87 (48.07)	38 (20.99)	45.03	0.83	0.83	1.03 (0.79–1.34)
				dcSSc (71)	25 (35.21)	30 (42.25)	16 (22.54)	43.66	0.89	0.89	0.97 (0.67–1.41)
				ACA+ (69)	25 (36.23)	31 (44.93)	13 (18.84)	41.30	0.52	0.74	0.88 (0.61–1.29)
				ATA+ (44)	11 (25.00)	21 (47.73)	12 (27.27)	51.14	0.23	0.54	1.32 (0.84–2.06)
7	rs2069840	IL6	C/G	Controls (270)	128 (47.41)	114 (42.22)	28 (10.37)	31.48
				SSc (255)	138 (54.12)	95 (37.25)	22 (8.63)	27.25	0.13	0.40	0.82 (0.62–1.06)
				lcSSc (184)	98 (53.26)	70 (38.04)	16 (8.70)	27.72	0.22	0.67	0.83 (0.62–1.12)
				dcSSc (71)	40 (56.34)	25 (35.21)	6 (8.45)	26.06	0.21	0.63	0.77 (0.51–1.16)
				ACA+ (70)	34 (48.57)	30 (42.86)	6 (8.57)	30.00	0.74	0.74	0.93 (0.62–1.40)
				ATA+ (45)	25 (55.56)	16 (35.56)	4 (8.89)	26.67	0.36	0.54	0.79 (0.48–1.31)

↵* Values calculated for the allelic model.
↵** Multiple testing false discovery rate correction.
↵*** For the minor allele. SNP: single-nucleotide polymorphism; IL: interleukin; SSc: systemic sclerosis; MAF: minor allele frequency.

Genotype and minor allele frequencies of SNP within IL6 gene in patients with SSc and healthy controls from The Netherlands.

					Genotype, n (%)			Allele Test
CHR	SNP	Locus	1/2	Subgroup (n)	1/1	1/2	2/2	MAF, %	p^*	p_FDR^**	OR (95% CI)^***
7	rs2069827	IL6	G/T	Controls (596)	529 (88.76)	63 (10.57)	4 (0.67)	5.96
				SSc (374)	329 (87.97)	45 (12.03)	0 (0.00)	6.02	0.96	0.96	1.01 (0.69–1.49)
				lcSSc (254)	229 (90.16)	25 (9.84)	0 (0.00)	4.92	0.40	0.60	0.82 (0.51–1.31)
				dcSSc (120)	100 (83.33)	20 (16.67)	0 (0.00)	8.33	0.17	0.51	1.44 (0.86–2.41)
				ACA+ (90)	79 (87.78)	11 (12.22)	0 (0.00)	6.11	0.93	0.93	1.03 (0.53–1.98)
				ATA+ (102)	89 (87.25)	13 (12.75)	0 (0.00)	6.37	0.82	0.45	1.08 (0.58–1.98)
7	rs1800795	IL6	G/C	Controls (585)	246 (42.05)	258 (44.10)	81 (13.85)	35.90
				SSc (375)	152 (40.53)	179 (47.73)	44 (11.73)	35.60	0.89	0.96	0.99 (0.82–1.20)
				lcSSc (254)	102 (40.16)	125 (49.21)	27 (10.63)	35.24	0.80	0.80	0.97 (0.78–1.21)
				dcSSc (121)	50 (41.32)	54 (44.63)	17 (14.05)	36.36	0.89	0.89	1.02 (0.77–1.36)
				ACA+ (92)	36 (39.13)	49 (53.26)	7 (7.61)	34.24	0.66	0.93	0.93 (0.67–1.29)
				ATA+ (102)	48 (47.06)	43 (42.16)	11 (10.78)	31.86	0.27	0.45	0.84 (0.61–1.15)
7	rs2069840	IL6	C/G	Controls (578)	204 (35.29)	277 (47.92)	97 (16.78)	40.74
				SSc (367)	149 (40.60)	181 (49.32)	37 (10.08)	34.74	0.01	0.03	0.77 (0.64–0.94)
				lcSSc (248)	106 (42.74)	118 (47.58)	24 (9.68)	33.47	0.01	0.02	0.73 (0.59–0.91)
				dcSSc (119)	43 (36.13)	63 (52.94)	13 (10.92)	37.39	0.34	0.51	0.87 (0.65–1.16)
				ACA+ (88)	35 (39.77)	46 (52.27)	7 (7.95)	34.09	0.09	0.28	0.75 (0.54–1.05)
				ATA+ (103)	40 (38.83)	50 (48.54)	13 (12.62)	36.89	0.30	0.82	0.85 (0.63–1.16)

↵* Values calculated for the allelic model.
↵** Multiple testing false discovery rate correction.
↵*** For the minor allele. SNP: single-nucleotide polymorphism; IL: interleukin; SSc: systemic sclerosis; MAF: minor allele frequency.

Genotype and minor allele frequencies of SNP within IL6 gene in patients with SSc and healthy controls from Spain.

					Genotype, n (%)			Allele Test
CHR	SNP	Locus	1/2	Subgroup (n)	1/1	1/2	2/2	MAF, %	p^*	p_FDR^**	OR (95% CI)^***
7	rs2069827	IL6	G/T	Controls (1400)	1208 (86.29)	180 (12.86)	12 (0.86)	7.29
				SSc (1012)	890 (87.94)	119 (11.76)	3 (0.30)	6.18	0.13	0.39	0.84 (0.67–1.06)
				lcSSc (689)	603 (87.52)	83 (12.05)	3 (0.44)	6.46	0.33	0.33	0.88 (0.68–1.14)
				dcSSc (323)	287 (88.85)	36 (11.15)	0 (0.00)	5.57	0.12	0.18	0.75 (0.52–1.08)
				ACA+ (502)	434 (86.45)	65 (12.95)	3 (0.60)	7.07	0.82	0.82	0.97 (0.73–1.28)
				ATA+ (234)	206 (88.03)	28 (11.97)	0 (0.00)	5.98	0.31	0.93	0.81 (0.54–1.22)
7	rs1800795	IL6	G/C	Controls (1412)	611 (43.27)	638 (45.18)	163 (11.54)	34.14
				SSc (1021)	444 (43.49)	448 (43.88)	129 (12.63)	34.57	0.75	0.75	1.02 (0.90–1.15)
				lcSSc (694)	298 (42.94)	293 (42.22)	103 (14.84)	35.95	0.24	0.33	1.08 (0.95–1.24)
				dcSSc (327)	146 (44.65)	155 (47.40)	26 (7.95)	31.65	0.23	0.23	0.89 (0.74–1.07)
				ACA+ (508)	212 (41.73)	221 (43.50)	75 (14.76)	36.52	0.17	0.32	1.11 (0.96–1.29)
				ATA+ (234)	94 (40.17)	121 (51.71)	19 (8.12)	33.97	0.95	0.95	0.99 (0.81–1.22)
7	rs2069840	IL6	C/G	Controls (1391)	568 (40.83)	648 (46.59)	175 (12.58)	35.87
				SSc (998)	411 (41.18)	475 (47.60)	112 (11.22)	35.02	0.54	0.76	0.96 (0.85–1.09)
				lcSSc (684)	302 (44.15)	313 (45.76)	69 (10.09)	32.97	0.06	0.19	0.88 (0.77–1.01)
				dcSSc (314)	109 (34.71)	162 (51.59)	43 (13.69)	39.49	0.09	0.18	1.17 (0.98–1.39)
				ACA+ (499)	213 (42.69)	236 (47.29)	50 (10.02)	33.67	0.21	0.32	0.91 (0.78–1.06)
				ATA+ (228)	87 (38.16)	117 (51.32)	24 (10.53)	36.18	0.90	0.95	1.01 (0.82–1.25)

↵* Values calculated for the allelic model.
↵** Multiple testing false discovery rate correction.
↵*** For the minor allele. SNP: single-nucleotide polymorphism; IL: interleukin; SSc: systemic sclerosis; MAF: minor allele frequency.

Genotype and minor allele frequencies of SNP within IL6 gene in patients with SSc and healthy controls from the United Kingdom.

					Genotype, n (%)			Allele Test
CHR	SNP	Locus	1/2	Subgroup (n)	1/1	1/2	2/2	MAF, %	p^*	p_FDR^**	OR (95% CI)^***
7	rs2069827	IL6	G/T	Controls (376)	305 (81.12)	68 (18.09)	3 (0.80)	9.84
				SSc (420)	363 (86.43)	54 (12.86)	3 (0.71)	7.14	0.05	0.16	0.70 (0.49–1.01)
				lcSSc (316)	273 (86.39)	40 (12.66)	3 (0.95)	7.28	0.09	0.27	0.72 (0.49–1.06)
				dcSSc (104)	90 (86.54)	14 (13.46)	0 (0.00)	6.73	0.17	0.25	0.66 (0.37–1.20)
				ACA+ (160)	144 (90.00)	14 (8.75)	2 (1.25)	5.63	0.02	0.07	0.55 (0.32–0.93)
				ATA+ (58)	51 (87.93)	7 (12.07)	0 (0.00)	6.03	0.19	0.28	0.59 (0.26–1.31)
7	rs1800795	IL6	G/C	Controls (373)	120 (32.17)	184 (49.33)	69 (18.50)	43.16
				SSc (434)	168 (38.71)	189 (43.55)	77 (17.74)	39.52	0.14	0.21	0.86 (0.71–1.05)
				lcSSc (323)	122 (37.77)	143 (44.27)	58 (17.96)	40.09	0.25	0.37	0.88 (0.71–1.09)
				dcSSc (111)	46 (41.44)	46 (41.44)	19 (17.12)	37.84	0.16	0.25	0.80 (0.59–1.09)
				ACA+ (169)	55 (32.54)	86 (50.89)	28 (16.57)	42.01	0.72	0.91	0.95 (0.74–1.24)
				ATA+ (59)	23 (38.98)	25 (42.37)	11 (18.64)	39.83	0.50	0.50	0.87 (0.59–1.30)
7	rs2069840	IL6	C/G	Controls (376)	157 (41.76)	171 (45.48)	48 (12.77)	35.51
				SSc (435)	179 (41.15)	207 (47.59)	49 (11.26)	35.06	0.85	0.85	0.98 (0.80–1.20)
				lcSSc (325)	129 (39.69)	161 (49.54)	35 (10.77)	35.54	0.99	0.99	1.00 (0.80–1.25)
				dcSSc (110)	50 (45.45)	46 (41.82)	14 (12.73)	33.64	0.61	0.61	0.92 (0.67–1.26)
				ACA+ (166)	61 (36.75)	91 (54.82)	14 (8.43)	35.84	0.91	0.91	1.02 (0.78–1.33)
				ATA+ (62)	33 (53.23)	23 (37.10)	6 (9.68)	28.23	0.11	0.28	0.71 (0.47–1.09)

↵* Values calculated for the allelic model.
↵** Multiple testing false discovery rate correction.
↵*** For the minor allele. SNP: single-nucleotide polymorphism; IL: interleukin; SSc: systemic sclerosis; MAF: minor allele frequency.

Genotype and minor allele frequencies of SNP within IL6 gene in patients with SSc and healthy controls from Norway.

					Genotype, n (%)			Allele Test
CHR	SNP	Locus	1/2	Subgroup (n)	1/1	1/2	2/2	MAF, %	p^*	p_FDR^**	OR (95% CI)^***
7	rs2069827	IL6	G/T	Controls (260)	213 (81.92)	46 (17.69)	1 (0.38)	9.23
				SSc (100)	83 (83.00)	16 (16.00)	1 (1.00)	9.00	0.92	0.97	0.97 (0.55–1.72)
				lcSSc (67)	52 (77.61)	14 (20.90)	1 (1.49)	11.94	0.35	0.35	1.33 (0.73–2.43)
				dcSSc (33)	31 (93.94)	2 (6.06)	0 (0.00)	3.03	0.09	0.15	0.31 (0.07–1.30)
				ACA+ (54)	44 (81.48)	9 (16.67)	1 (1.85)	10.19	0.76	0.82	1.12 (0.56–2.23)
				ATA+ (14)	13 (92.86)	1 (7.14)	0 (0.00)	3.57	0.31	0.31	0.36 (0.05–2.74)
7	rs1800795	IL6	G/C	Controls (246)	72 (29.27)	126 (51.22)	48 (19.51)	45.12
				SSc (99)	27 (27.27)	55 (55.56)	17 (17.17)	44.95	0.97	0.97	0.99 (0.71–1.38)
				lcSSc (67)	15 (22.39)	37 (55.22)	15 (22.39)	50.00	0.32	0.35	1.22 (0.83–1.78)
				dcSSc (32)	12 (37.50)	18 (56.25)	2 (6.25)	34.38	0.10	0.15	0.64 (0.37–1.10)
				ACA+ (54)	16 (29.63)	26 (48.15)	12 (22.22)	46.30	0.82	0.82	1.05 (0.69–1.59)
				ATA+ (14)	7 (50.00)	5 (35.71)	2 (14.29)	32.14	0.18	0.31	0.58 (0.26–1.30)
7	rs2069840	IL6	C/G	Controls (260)	118 (45.38)	113 (43.46)	29 (11.15)	32.88
				SSc (98)	45 (45.92)	43 (43.88)	10 (10.20)	32.14	0.85	0.97	0.97 (0.68–1.37)
				lcSSc (65)	35 (53.85)	24 (36.92)	6 (9.23)	27.69	0.26	0.35	0.78 (0.51–1.20)
				dcSSc (33)	10 (30.30)	19 (57.58)	4 (12.12)	40.91	0.19	0.19	1.41 (0.84–2.39)
				ACA+ (53)	27 (50.94)	20 (37.74)	6 (11.32)	30.19	0.59	0.82	0.88 (0.56–1.39)
				ATA+ (14)	4 (28.57)	8 (57.14)	2 (14.29)	42.86	0.28	0.31	1.53 (0.71–3.31)

↵* Values calculated for the allelic model.
↵** Multiple testing false discovery rate correction.
↵*** For the minor allele. SNP: single-nucleotide polymorphism; IL: interleukin; SSc: systemic sclerosis; MAF: minor allele frequency.

Pooled analysis of rs2069827-rs1800795-rs2069840 allelic combinations in white patients with dcSSc and healthy controls.

Haplotype	dcSSc, n (%), n = 1822	Controls, n (%), n = 6448	p_MH	p (covariates sex and population)	OR (95% CI)	p_BD
GGC	525 (28.8)	1710 (26.5)	0.080^*	0.064	1.16 (1.03–1.30)	0.09
GCC	518 (28.4)	1915 (29.7)	0.171	0.494	0.92 (0.82–1.04)	0.9
GGG	648 (35.6)	2289 (35.5)	0.642	0.806	1.03 (0.92–1.15)	0.14
TCC	131 (7.2)	534 (8.3)	0.080^*	0.089	0.78 (0.64–0.96)	0.24

p_MH: allelic Mantel-Haenszel fixed-effects model. p_BD: Breslow-Day value.
↵* Multiple testing Bonferroni correction (× 4 analyzed haplotypes). dcSSc: diffuse cutaneous systemic sclerosis.

Pooled analysis of rs2069827-rs1800795-rs2069840 allelic combinations in white patients with lcSSc and healthy controls.

Haplotype	lcSSc, n (%), n = 3765	Controls, n (%), n = 6448	p_MH	p (covariates sex and population)	OR (95% CI)	p_BD
GGC	1073 (28.5)	1710 (26.5)	0.016^*	0.014	1.14 (1.04–1.25)	0.36
GCC	1176 (30.2)	1915 (29.7)	0.180	0.149	1.06 (0.97–1.17)	0.69
GGG	1228 (32.6)	2289 (35.5)	0.024^*	0.001	0.89 (0.81–0.97)	0.40
TCC	288 (7.6)	534 (8.3)	0.160^*	0.185	0.85 (0.73–0.99)	0.60

p_MH: allelic Mantel-Haenszel fixed-effects model. p_BD: Breslow-Day value.
↵* Multiple testing Bonferroni correction (× 4 analyzed haplotypes). lcSSc: limited cutaneous systemic sclerosis.