Polymorphisms in NF-κB, PXR, LXR, PPARγ and risk of inflammatory bowel disease

Table 1 Description of study participants n (%)

	CD (n = 327)	UC (n = 495)	Controls (n = 779)
Sex
Male	129 (39)	239 (48)	400 (51)
Female	198 (61)	256 (51)	379 (49)
Age (yr)
Median (5%-95%)	43 (23-76)	49 (24-76)	43 (23-60)
Age at diagnosis (yr)
Median (5%-95%)	30 (15-64)	35 (17-68)
Smoking habits
Smokers	167 (51)	86 (17)	205 (26)
Never smokers	115 (35)	226 (46)	391 (50)
Former smokers	45 (14)	183 (37)	183 (23)
Location of UC
Proctitis (E1)		207 (42)
Left side (E2)		183 (37)
Extensive (E3)		93 (19)
Data not available		12 (2)
Location of CD
Colonic (L2)	151 (46)
Ileal (L1)	74 (23)
Ileocolonic (L3)	89 (27)
Data not available	13 (4)
Medication
Advanced1	140 (43)	103 (21)
No advanced medication2	182 (56)	389 (79)
Data not available	5 (2)	3 (1)
Operation
Yes	149 (46)	14 (3)
No	171 (52)	472 (95)
Data not available	7 (2)	9 (2)

Disease location was classified according to the WGO Montreal classification. Statistical analyses included subjects for whom all information was available.

¹Azathioprine, 6-mercaptopurine, tumor necrosis factor inhibitors, or methrotrexate;

²5-aminosalicylic acid, prednisolone. CD: Crohn’s disease; UC: Ulcerative colitis.

Table 2 Allele frequencies for the gene polymorphisms in Crohn’s disease and ulcerative colitis patients n (%)

	CD	UC	Controls
NF-κB -94ins/del
I	379 (58)	583 (59)	919 (59)
D	275 (42)	407 (41)	639 (41)
PPARγ Pro12Ala
C	564 (86)	844 (85)	1315 (84)
G	90 (14)	146 (15)	243 (16)
PPARγ C1431T
C	560 (86)	832 (84)	1327 (85)
T	94 (14)	158 (16)	231 (15)
PXR rs1523127
A	395 (60)	570 (58)	926 (59)
C	259 (40)	420 (42)	632 (41)
PXR rs2276707
C	540 (83)	825 (83)	1275 (82)
T	114 (17)	165 (17)	283 (18)
PXR rs6785049
A	426 (65)	615 (62)	1011 (65)
G	228 (35)	375 (38)	547 (35)
LXR rs1405655
T	435 (67)	675 (68)	1079 (69)
C	219 (33)	315 (32)	479 (31)
LXR rs2695121
T	292 (45)	430 (43)	727 (47)
C	362 (55)	560 (57)	831 (53)

NF-κB: Nuclear factor κB; PPARγ: Peroxisome proliferator-activated receptor γ; CD: Crohn’s disease; UC: Ulcerative colitis; PXR: Pregnane X receptor; LXR: Liver X receptor.

Table 3 Odds ratio for the studied gene polymorphisms in Crohn’s disease and ulcerative colitis patients

	CD	UC	Control	ORCD	95% CI1	P value	ORUC	95% CI1	P value
NF-κB -94ins/del
II	107	175	267	1.00	-		1.00	-
ID	165	233	385	1.08	0.80-1.46	0.62	0.94	0.72-1.21	0.62
DD	55	87	127	1.21	0.81-1.81	0.36	1.04	0.73-1.47	0.83
ID and DD	220	320	512	1.11	0.83-1.48	0.48	0.96	0.75-1.23	0.76
PPARγ Pro12Ala
CC	240	364	549	1.00	-		1.00	-
CG	84	116	217	0.88	0.65-1.20	0.43	0.83	0.63-1.09	0.17
GG	3	15	13	0.48	0.13-1.77	0.27	2.30	1.04-5.08	0.04
CG and GG	87	131	230	0.86	0.64-1.16	0.33	0.90	0.69-1.17	0.42
PPARγ C1431T
CC	241	352	561	1.00	-		1.00	-
CT	78	128	205	0.81	0.59-1.12	0.20	1.00	0.76-1.31	0.99
TT	8	15	13	1.36	0.54-3.42	0.52	1.95	0.90-4.27	0.09
CT and TT	86	143	218	0.85	0.62-1.15	0.29	1.05	0.81-1.37	0.69
PXR rs1523127
AA	114	160	280	1.00	-		1.00	-
AC	167	250	366	1.06	0.79-1.43	0.71	1.15	0.89-1.50	0.29
CC	46	85	133	0.89	0.59-1.35	0.59	1.11	0.78-1.56	0.57
AC and CC	213	335	499	1.02	0.77-1.35	0.91	1.14	0.89-1.46	0.30
PXR rs2276707
CC	223	339	517	1.00	-		1.00	-
CT	94	147	241	0.92	0.68-1.24	0.57	0.97	0.75-1.26	0.84
TT	10	9	21	1.25	0.56-2.76	0.58	0.67	0.30-1.51	0.33
CT and TT	104	156	262	0.94	0.71-1.26	0.69	0.95	0.74-1.22	0.68
PXR rs6785049
AA	137	184	334	1.00	-		1.00	-
AG	152	247	343	1.12	0.84-1.49	0.46	1.35	1.05-1.74	0.02
GG	38	64	102	0.91	0.58-1.40	0.66	1.18	0.81-1.71	0.39
AG and GG	190	311	445	1.07	0.81-1.40	0.65	1.31	1.03-1.66	0.03
LXR rs1405655
TT	143	229	383	1.00	-		1.00	-
CT	149	217	313	1.26	0.95-1.68	0.11	1.22	0.95-1.57	0.11
CC	35	49	83	1.12	0.71-1.78	0.62	1.01	0.67-1.51	0.97
CT and CC	184	266	396	1.23	0.94-1.62	0.13	1.18	0.93-1.49	0.17
LXR rs2695121
TT	62	88	170	1.00	-		1.00	-
CT	168	254	387	1.28	0.90-1.83	0.17	1.30	0.95-1.77	0.10
CC	97	153	222	1.21	0.82-1.79	0.34	1.41	1.00-1.98	0.05
CT and CC	265	407	609	1.26	0.89-1.76	0.19	1.34	0.99-1.79	0.06

Statistical analyses included subjects for whom all information was available.

¹Adjusted for age, sex and smoking status. NF-κB: Nuclear factor κB; PPARγ: Peroxisome proliferator-activated receptor γ; CD: Crohn’s disease; UC: Ulcerative colitis; OR: Odds ratio; PXR: Pregnane X receptor; LXR: Liver X receptor.

Table 4 Odds ratio for the gene polymorphisms among Crohn’s disease and ulcerative colitis never smokers

	NS-CD	NS-UC	NS-control	ORNS-CD	95% CI1	P value	ORNS-UC	95% CI1	P value	ORNS-IBD	95% CI1	P value
NF-κB -94ins/del
II	40	79	136	1.00	-		1.00	-		1.00	-
ID	56	109	194	0.99	0.62-1.57	0.97	0.98	0.68-1.42	0.93	0.98	0.71-1.36	0.92
DD	19	38	61	1.07	0.57-2.00	0.83	1.09	0.67-1.79	0.72	1.09	0.70-1.68	0.71
ID and DD	75	147	255	1.01	0.65-1.56	0.97	1.01	0.72-1.43	0.95	1.01	0.74-1.37	0.96
PPARγ Pro12Ala
CC	83	167	270	1.00	-		1.00	-		1.00	-
CG	31	50	117	0.86	0.54-1.38	0.54	0.71	0.48-1.04	0.08	0.75	0.54-1.05	0.09
GG	1	9	4	0.80	0.09-7.29	0.84	3.99	1.20-13.32	0.02	2.77	0.85-9.00	0.09
CG and GG	32	59	121	0.86	0.54-1.37	0.53	0.81	0.56-1.17	0.26	0.82	0.59-1.13	0.21
PPARγ C1431T
CC	85	163	285	1.00	-		1.00	-		1.00	-
CT	26	56	100	0.88	0.53-1.44	0.60	0.98	0.67-1.44	0.93	0.93	0.67-1.31	0.70
TT	4	7	6	2.16	0.59-7.90	0.24	2.05	0.67-6.26	0.21	2.06	0.75-5.67	0.16
CT and TT	30	63	106	0.95	0.59-1.53	0.83	1.04	0.72-1.51	0.82	1.00	0.72-1.39	0.99
PXR rs1523127
AA	43	74	149	1.00	-		1.00	-		1.00	-
AC	51	103	176	1.01	0.64-1.60	0.97	1.15	0.79-1.67	0.46	1.11	0.80-1.53	0.54
CC	21	49	66	1.10	0.60-1.99	0.77	1.52	0.95-2.41	0.08	1.36	0.90-2.05	0.15
AC and CC	72	152	242	1.03	0.67-1.59	0.89	1.25	0.88-1.77	0.21	1.17	0.87-1.59	0.30
PXR rs2276707
CC	73	150	260	1.00	-		1.00	-		1.00	-
CT	36	70	119	1.08	0.69-1.70	0.74	1.03	0.72-1.47	0.89	1.04	0.76-1.43	0.81
TT	6	6	12	1.76	0.64-4.86	0.27	0.86	0.31-2.34	0.76	1.16	0.51-2.63	0.73
CT and TT	42	76	131	1.14	0.74-1.76	0.55	1.01	0.71-1.43	0.96	1.05	0.77-1.43	0.75
PXR rs6785049
AA	42	77	168	1.00	-		1.00	-		1.00	-
AG	52	119	176	1.19	0.75-1.88	0.47	1.49	1.04-2.13	0.03	1.38	1.01-1.89	0.05
GG	21	30	47	1.79	0.97-3.31	0.06	1.40	0.82-2.39	0.22	1.53	0.97-2.43	0.07
AG and GG	73	149	223	1.31	0.85-2.02	0.21	1.47	1.04-2.07	0.03	1.41	1.05-1.91	0.02
LXR rs1405655
TT	43	95	203	1.00	-		1.00	-		1.00	-
CT	55	106	154	1.69	1.07-2.65	0.02	1.54	1.08-2.18	0.02	1.58	1.16-2.16	0.004
CC	17	25	34	2.32	1.19-4.55	0.01	1.66	0.93-2.95	0.09	1.85	1.12-3.07	0.02
CT and CC	72	131	188	1.80	1.18-2.77	0.01	1.56	1.11-2.17	0.01	1.63	1.21-2.20	0.001
LXR rs2695121
TT	15	30	90	1.00	-		1.00	-		1.00	-
CT	59	126	197	1.82	0.98-3.39	0.06	1.98	1.23-3.17	0.005	1.93	1.28-2.92	0.002
CC	41	70	104	2.37	1.23-4.57	0.01	2.09	1.25-3.49	0.005	2.18	1.39-3.41	0.0007
CT and CC	100	196	301	2.01	1.11-3.64	0.02	2.01	1.28-3.17	0.002	2.02	1.36-2.99	0.0005

Statistical analyses included subjects for whom all information was available.

¹Adjusted for age and sex. NS: Never smoker; NF-κB: Nuclear factor κB; PPARγ: Peroxisome proliferator-activated receptor γ; CD: Crohn’s disease; UC: Ulcerative colitis; OR: Odds ratio; PXR: Pregnane X receptor; LXR: Liver X receptor.

Table 5 Minor allele frequencies of pregnane X receptor polymorphisms in studied populations

	Controls	C-rs3814055-T	A-rs1523127-C	C-rs2276707-T	A-rs6785049-G
Danish	779		0.41	0.18	0.35	Present study
Irish	336	0.433	0.452	0.142	0.406	Dring et al[47]
Scottish	334		0.394			Ho et al[49]
Spanish	550	0.382		0.192		Martínez et al[50]

Rs3814055 and rs1523127 are closely linked.

Table 6 Published associations between pregnane X receptor polymorphisms and inflammatory bowel disease risk

	Cases	Controls	C-25385T (rs3814055)	A-24381C (rs1523127)	C8055T (rs2276707)	A7635G (rs6785049)
Danish1	822	779		Neg	Neg	Variant	Present study
Irish2	422	336	Wild-type	Wild-type	Variant	Wild-type	Dring et al[47]
Scottish2	715	334		Neg			Ho et al[49]
Spanish2	696	550	Variant		Wild-type		Martínez et al[50]
Canadian3	270	336		Neg		Neg	Amre et al[48]

No association is indicated by “neg”. The risk allele is indicated for positive associations between the pregnane X receptor polymorphisms and inflammatory bowel disease risk.

¹Associations adjusted for smoking status;

²Associations not adjusted for smoking status,

³Children with Crohn’s disease.