Apolipoprotein E variants correlate with the clinical presentation of paediatric inflammatory bowel disease: A cross-sectional study

Table 1 Demographic and clinical expression of Crohn’s disease and ulcerative colitis

Variables median (IQR) or n (%)	n	Crohn’s disease	Ulcerative colitis	P value
Age in yr
At inclusion	397	15.18 (13.32-17.05)	15.11 (11.70-16.75)	0.044
At diagnosis	404	12.58 (10.02-14.32)	12.14 (7.89-14.94)	0.365
At worst flare	355	13.63 (11.54-15.85)	13.76 (10.13-15.84)	0.244
Duration of the disease (yr)	390	2.23 (0.82-4.25)	1.88 (0.36-3.77)	0.239
Female	173	86 (40.2)	87 (45.3)	0.297
Nutritional status
Weight at diagnosis in kg	387	38.0 (27.0-49.8)	40.0 (27.8-53.9)	0.490
Weight at diagnosis, z score	383	-0.82 [(-1.39)-(-0.04)]	-0.51 [(-1.12)-0.22]	0.003
Height at diagnosis in cm	382	151.0 (137.0-164.5)	152.0 (130.5-168.3)	0.718
Height at diagnosis, z score	378	-0.37 [(-1.29)-0.47]	0.06 [(-0.67)-0.81]	0.001
Body mass index at diagnosis in kg/m2	382	16.6 (14.5-18.4)	17.4 (15.5-19.3)	0.019
Body mass index at diagnosis, z score	378	-0.79 [(-1.47)-(-0.04)]	-0.49 [(-1.00)-0.16]	0.006
Albumin level at diagnosis in g/dL	345	3.90 (3.51-4.25)	4.10 (3.70-4.40)	< 0.003
Parameter of inflammation
CRP at diagnosis in mg/L1	386	12.94 (2.10-29.25)	2.24 (0.50-10.80)	< 0.001
CRP at worst flare in mg/L	347	13.95 (3.03-32.43)	2.70 (0.63-13.44)	< 0.001
Disease activity scales
PCDAI/PUCAI at diagnosis	190/166	32 (23-48)	45 (28-60)
PCDAI/PUCAI at worst flare	170/155	40 (30-53)	50 (35-65)
Treatment
Systemic steroids2	406	115 (53.7)	138 (71.9)	< 0.001
Immunosuppressive treatment3	405	168 (78.5)	112 (58.6)	< 0.001
Biological therapy4	406	107 (50.0)	49 (25.5)	< 0.001
Operative treatment5	406	29 (13.6)	4 (2.1)	< 0.001

¹C-reactive protein reference range 0-5 mg/L.

²Systemic steroid therapy included: methylprednisolone, prednisone, hydrocortisone.

³Immunosuppressive and anti-inflammatory agents included: Azathioprine, methotrexate, mercaptopurine, cyclosporine, mycophenolate mofetil, tacrolimus, sulfasalazine.

⁴Biological agents included: infliximab, adalimumab, golimumab, vedolizumab.

⁵Only surgery related to inflammatory bowel disease-specific problems (e.g., colectomy, resection, fistula, perforation, abscess) was included. CRP: C-reactive protein; IBD: Inflammatory bowel disease; IQR: Interquartile range; PCDAI: Pediatric Crohn’s Disease Activity Index; PUCAI: Pediatric Ulcerative Colitis Activity Index.

Table 2 Apolipoprotein E genotype and allele distribution compared between ulcerative colitis and Crohn’s disease

Genotype/allele	UC, n = 192	CD, n = 214	P value, two-tailed Fisher exact	Odds ratio (95%CI)
ε3/ε3	118	135	0.7590	0.93 (0.62-1.40)
ε3/ε4	47	41	0.2278	1.37 (0.85-2.20)
ε2/ε3	18	35	0.0397	0.53 (0.29-0.97)
ε3+	183	211	0.0757	0.29 (0.08-1.08)
ε4+	54	43	0.0629	1.56 (0.98-2.46)
ε2+	24	37	0.2108	0.68 (0.39-1.19)

CD: Crohn’s disease; CI: Confidence interval; UC: Ulcerative colitis.

Table 3 Clinical characteristics in patients with ulcerative colitis depending on major apolipoprotein E genotypes

Variables median (IQR) or n (%)	n	ε2/ε3	ε3/ε3	ε3/ε4	P value
Age in yr
At inclusion	184	15.7 (12.5-16.9)	15.3 (11.9-16.9)	14.3 (11.5-16.3)	0.2464
At diagnosis	191	11.4 (7.9-14.6)	12.4 (7.9-15.0)	12.4 (8.2-14.9)	0.9070
At worst flare	171	14.6 (9.9-16.4)	13.7 (10.4-16.0)	13.7 (10.0-15.7)	0.7255
Duration of the disease in yr	179	3.0 (1.4-6.2)	1.9 (0.4-3.5)	1.2 (0.0-3.5)	0.0868
Nutritional status
Weight at diagnosis in kg	180	40.0 (28.8-59.5)	39.0 (27.8-54.0)	43.8 (29.5-53.4)	0.9704
Weight at diagnosis, z score	179	-0.20 [(-0.86)-0.43]	-0.5 [(-1.1)-0.1]	-0.24 [(-0.95)-0.63]	0.3037
Height at diagnosis in cm	175	146.5 (129.0-169.0)	153.0 (131.0-168.5)	156.0 (131.5-169.0)	0.9175
Height at diagnosis, z score	174	0.12 [(-0.62)-0.75]	0.09 [(-0.69)-0.79]	0.22 [(-0.44)-1.06]	0.5823
Body mass index at diagnosis in kg/m2	175	17.61 (16.02-19.74)	17.0 (15.4-19.1)	17.9 (15.4-20.3)	0.5121
Body mass index at diagnosis, z score	174	-0.11 [(-0.70)-0.29)]	-0.56 [(-0.99)-0.11]	-0.30 [(-1.12)-0.56]	0.2293
Weight at worst flare in kg	164	46.1 (31.6-62.0)	46.2 (31.9-55.6)	50.0 (28.0-61.0)	0.9600
Weight at worst flare, z score	161	-0.33 [(-1.00)-0.56]	-0.58 [(-0.95)-0.16]	-0.52 [(-0.90)-0.40]	0.6559
Height at worst flare in cm	162	162.5 (138.5-173.5)	159.0 (140.9-171.0)	160.0 (135.0-172.0)	0.9688
Height at worst flare, z score	161	0.11 [(-0.72)-1.16]	-0.09 [(-0.62)-0.78]	0.06 [(-0.62)-0.89]	0.8376
Body mass index at worst flare in kg/m2	160	18.20 (16.47-19.74)	17.36 (15.75-19.71)	17.93 (15.89-20.96)	0.6013
Body mass index at worst flare, z score	159	-0.22 [(-1.16)-0.14]	-0.68 [(-1.10)-0.16]	-0.43 [(-1.12)-0.63]	0.6789
Albumin level
At diagnosis in g/dL	159	4.2 (4.0-4.6)	4.1 (3.7-4.4)	4.1 (3.6-4.4)	0.2569
At worst flare in g/ dL	148	4.3 (4.0-4.7)	4.1 (3.6-4.4)	4.2 (4.0-4.4)	0.3488
Parameter of inflammation
CRP at diagnosis in mg/L	178	3.8 (0.7-6.6)	2.5 (0.7-12.2)	1.1 (0.2-8.0)	0.0515
CRP at worst flare in mg/L	162	2.1 (1.1-23.3)	3.7 (1.1-19.0)	0.8 (0.3-2.9)	0.0012
Disease activity scales
PUCAI at diagnosis	166	40 (18-55)	45 (30-60)	50 (25-60)	0.5144
PUCAI at worst flare	155	48 (20-65)	55 (40-65)	50 (30-65)	0.3766
Disease localisation and behaviour
E1 at diagnosis	19/192	3 (16.7)	10 (8.5)	6 (12.8)	0.4694
E2 at diagnosis	33/192	8 (44.4)	16 (13.6)	9 (19.1)	0.0063
E3 at diagnosis	28/192	1 (5.6)	18 (15.3)	9 (19.1)	0.3953
E4 at diagnosis	83/192	5 (27.8)	60 (50.8)	18 (38.3)	0.0990
S0 at diagnosis	110/192	13 (72.2)	69 (58.5)	28 (59.6)	0.5383
S1 at diagnosis	37/192	3 (16.7)	23 (19.5)	11 (23.4)	0.7885
E1 at worst flare	9/192	1 (5.6)	4 (3.4)	4 (8.5)	0.3863
E2 at worst flare	27/192	3 (16.7)	18 (15.3)	6 (12.8)	0.8943
E3 at worst flare	23/192	3 (16.7)	16 (13.6)	4 (8.5)	0.5814
E4 at worst flare	75/192	7 (38.9)	50 (42.4)	18 (38.3)	0.8750
S0 at worst flare	83/192	9 (50.0)	52 (44.1)	22 (46.8)	0.8713
S1 at worst flare	49/192	5 (27.8)	34 (28.8)	10 (21.3)	0.6114
Treatment
Systemic steroids1	192	11 (61.1)	92 (78.0)	29 (61.7)	0.0599
Number of courses of steroid treatment	190	1 (0-2)	1 (1-2)	1 (0-2)	0.0672
Immunosuppressive treatment2	191	9 (50.0)	74 (63.2)	25 (53.2)	0.3451
Number of immunosuppressants	191	1 (0-1)	1 (0-1)	1 (0-1)	0.2572
Time-to-first dose of immunosuppressive treatment in mo	109	3.0 (2.0-17.0)	4.0 (0.0-10.0)	2.8 (0.0-8.0)	0.4356
Age at first intake of immunosuppressive treatment in yr	109	14.7 (10.4-16.1)	12.3 (7.8-14.1)	11.0 (7.3-15.5)	0.2381
Biological therapy3	192	4 (22.2)	29 (24.8)	13 (27.7)	0.8781
Total number of biologics	192	0 (0-0)	0 (0-0)	0 (0-1)	0.8164
Time-to-first dose of biological treatment in mo	48	19.9 (12.8-50.3)	16.4 (9.1-28.1)	10.8 (4.0-27.7)	0.3152
Age at first biological treatment	49	15.7 (14.7-15.9)	11.5 (7.9-14.6)	10.7 (4.5-15.5)	0.0852
Operative treatment4	192	0 (0.0)	3 (2.5)	1 (2.1)	0.7893
Age at first surgery in yr	6	7.7 (5.9-9.6)	14.8 (6.8-17.1)	13.0 (10.4-15.6)	0.2969
Time-to-first surgery in mo	4		16.7 (5.0-28.7)	19.1 (0.9-37.4)	1.0000
Hospitalisations, if duration ≥ 1 yr
Hospitalisations for relapse, per 1 yr of the disease	98	0.3 (0.3-0.8)	0.6 (0.3-1.6)	0.9 (0.5-1.3)	0.2518
Days of hospitalisation for relapse, per 1 yr of the disease	98	2.5 (0.6-4.5)	4.8 (1.8-9.3)	7.3 (3.8-8.7)	0.1362
Relapses from diagnosis, per 1 yr of the disease	98	0.3 (0.1-0.8)	0.6 (0.3-1.2)	0.8 (0.3-1.3)	0.3491
Severe relapses from diagnosis, per 1 yr of the disease	100	0.0 (0.0-0.3)	0.1 (0.0-0.6)	0.2 (0.0-0.4)	0.7150
Concomitant diseases5	192	9 (50.0)	41 (34.7)	15 (31.9)	0.3781
Extraintestinal manifestations	192	3 (16.7)	23 (19.5)	10 (21.3)	0.9131

¹Systemic steroid therapy included: methylprednisolone, prednisone, hydrocortisone.

²Immunosuppressive and anti-inflammatory agents included: azathioprine, methotrexate, mercaptopurine, cyclosporine, mycophenolate mofetil, tacrolimus, sulfasalazine.

³Biological agents included: Infliximab, adalimumab, golimumab, vedolizumab.

⁴Only surgery related to inflammatory bowel disease-specific problems (e.g., colectomy, resection, fistula, perforation, abscess) was included.

⁵e.g., celiac disease, bronchial asthma, obesity, gastroesophageal reflux disease, epilepsy, hypothyroidism. CRP: C-reactive protein; IBD: Inflammatory bowel disease; IQR: Interquartile range; PUCAI: Pediatric Ulcerative Colitis Activity Index.

Table 4 Clinical characteristics in patients with Crohn’s disease depending on major apolipoprotein E genotypes

Variables median (IQR) or n (%)	n	ε2/ε3	ε3/ε3	ε3/ε4	P value
Age in yr
At inclusion	213	15.5 (13.2-16.8)	15.2 (13.3-17.2)	15.2 (13.4-16.2)	0.8055
At diagnosis	213	11.8 (10.1-14.6)	12.7 (9.9-14.5)	12.6 (10.0-13.9)	0.8796
At worst flare	184	13.3 (11.6-15.2)	13.6 (11.3-15.8)	14.3 (12.8-15.9)	0.5121
Duration of the disease in yr	211	2.8 (0.6-5.4)	2.0 (0.8-4.0)	2.3 (0.8-4.1)	0.7843
Nutritional status
Weight at diagnosis in kg	207	38.3 (27.6-48.0)	37.3 (25.3-49.5)	38.4 (28.3-57.6)	0.5360
Weight at diagnosis, z score	204	-0.53 [(-1.02)-(-0.02)]	-0.91 [(-1.46)-(-0.12)]	-0.73 [(-1.34)-0.38]	0.2062
Height at diagnosis in cm	207	148.3 (141.0-164.0)	151.5 (134.0-164.0)	151.3 (141.0-170.0)	0.6757
Height at diagnosis, z score	204	-0.17 [(-0.85)-0.51]	-0.47 [(-1.43)-0.32]	0.05 [(-1.10)-0.96]	0.0617
Body mass index at diagnosis in kg/m2	207	16.73 (14.28-18.42)	16.59 (14.41-18.22)	16.40 (14.78-20.78)	0.8397
Body mass index at diagnosis, z score	204	-0.72 [(-1.33)-(-0.16)]	-0.79 [(-1.53)-(-0.08)]	-0.88 [(-1.29)-0.49]	0.7878
Weight at worst flare in kg	181	41.8 (34.8-50.3)	41.9 (29.6-52.6)	46.8 (36.2-58.9)	0.2294
Weight at worst flare, z score	178	-0.67 [(-1.16)-0.10]	-1.14 [(-1.64)-(-0.25)]	-0.60 [(-1.22)-0.02]	0.0756
Height at worst flare in cm	183	153.0 (148.5-166.0)	158.0 (141.5-167.0)	162.0 (148.5-171.5)	0.3088
Height at worst flare, z score	180	-0.15 [(-1.09)-0.61]	-0.52 [(-1.41)-0.21]	-0.24 [(-1.10)-0.43]	0.1234
Body mass index at worst flare in kg/m2	181	17.29 (15.53-18.60)	16.89 (14.87-19.03)	17.09 (15.56-21.74)	0.4172
Body mass index at worst flare, z score	178	-0.87 [(-1.38)-0.01]	-1.03 [(-1.55)-(-0.19)]	-0.53 [(-1.46)-0.49]	0.3913
Albumin level
At diagnosis in g/dL	186	3.9 (3.7-4.3)	3.8 (3.4-4.2)	3.9 (3.4-4.3)	0.5796
At worst flare in g/dL	179	3.9 (3.8-4.3)	3.9 (3.4-4.1)	3.9 (3.6-4.3)	0.0611
Parameter of inflammation
CRP at diagnosis in mg/L	208	13.8 (0.8-40.0)	13.0 (2.1-29.6)	12.0 (3.4-24.9)	0.8818
CRP at worst flare in mg/L	185	18.3 (1.7-31.5)	14.0 (3.3-38.5)	13.6 (3.2-26.8)	0.7672
Disease activity scales
PCDAI at diagnosis	190	25 (20-35)	35 (25-50)	30 (25-43)	0.0282
PCDAI at worst flare	170	35 (23-50)	45 (30-53)	38 (30-53)	0.1898
Disease localisation and behaviour
L1 at diagnosis	53/213	9 (25.7)	35 (26.1)	8 (19.5)	0.6852
L2 at diagnosis	40/213	9 (25.7)	19 (14.2)	11 (26.8)	0.0935
L3 at diagnosis	99/213	13 (37.1)	67 (50.0)	16 (39.0)	0.2507
L4a at diagnosis	23/213	4 (11.4)	14 (10.4)	4 (9.8)	0.9721
L4b at diagnosis	8/213	1 (2.9)	7 (5.2)	0 (0.0)	0.2950
B1 at diagnosis	146/213	24 (68.6)	89 (66.4)	33 (80.5)	0.2287
B2 at diagnosis	15/213	3 (8.6)	11 (8.2)	1 (2.4)	0.4263
B3 at diagnosis	19/213	3 (8.6)	15 (11.2)	1 (2.4)	0.2304
B2B3 at diagnosis	4/213	1 (2.9)	3 (2.2)	0 (0.0)	0.5927
G0 at diagnosis	145/213	24 (68.6)	92 (68.7)	29 (70.7)	0.9667
G1 at diagnosis	33/213	3 (8.6)	24 (17.9)	6 (14.6)	0.3921
P at diagnosis	19/213	0 (0.0)	16 (11.9)	3 (7.3)	0.0824
L1 at worst flare	40/213	5 (14.3)	26 (19.4)	9 (22.0)	0.6873
L2 at worst flare	27/213	7 (20.0)	14 (10.4)	6 (14.6)	0.3007
L3 at worst flare	92/213	10 (28.6)	66 (49.3)	16 (39.0)	0.0708
L4a at worst flare	18/213	3 (8.6)	12 (9.0)	3 (7.3)	0.9477
L4b at worst flare	9/213	1 (2.9)	5 (3.7)	3 (7.3)	0.5507
B1 at worst flare	114/213	17 (48.6)	74 (55.2)	23 (56.1)	0.7549
B2 at worst flare	19/213	2 (5.7)	12 (9.0)	5 (12.2)	0.6165
B3 at worst flare	21/213	1 (2.9)	16 (11.9)	4 (9.8)	0.2798
B2B3 at worst flare	5/213	1 (2.9)	4 (9.8)	0 (0.0)	0.5367
G0 at worst flare	121/213	18 (51.4)	79 (59.0)	24 (58.5)	0.7184
G1 at worst flare	34/213	2 (5.7)	24 (17.9)	8 (19.5)	0.1776
P at worst flare	20/213	0 (0.0)	17 (12.7)	3 (7.3)	0.0649
Treatment
Systemic steroids1	214	19 (34.3)	73 (54.1)	21 (51.2)	0.9455
Number of courses of steroid treatment	212	1 (0-2)	1 (0-2)	1 (0-1)	0.5535
Immunosuppressive treatment2	214	25 (71.4)	110 (81.5)	31 (75.6)	0.3756
Number of immunosuppressants	214	1 (0-1)	1 (1-1)	1 (1-1)	0.2632
Time-to-first dose of immunosuppressive treatment in mo	166	1.3 (0.0-13.0)	2.0 (0.0-7.0)	1.0 (0.0-9.6)	0.8866
Age at first intake of immunosuppressive treatment in yr	166	12.9 (10.3-13.9)	13.0 (10.7-14.9)	12.7 (9.6-14.3)	0.6668
Biological therapy3	214	15 (42.9)	73 (54.1)	18 (43.9)	0.3303
Total number of biologics	214	0 (0-1)	1 (0-1)	0 (0-1)	0.2243
Time-to-first dose of biological treatment in mo	102	17.8 (6.3-44.0)	12.6 (5.6-25.9)	13.3 (6.1-26.7)	0.6313
Age at first biological treatment	102	13.8 (12.7-14.8)	13.6 (11.3-15.3)	14.0 (10.7-15.6)	0.8880
Operative treatment4	214	2 (5.7)	19 (14.1)	8 (19.5)	0.2158
Age at first surgery in yr	30	11.3 (9.4-13.1)	14.5 (12.5-16.5)	14.9 (14.0-15.7)	0.1698
Time-to-first surgery in mo	26	12.0	19.4 (0.0-41.1)	25.1 (7.9-43.5)	0.7807
Hospitalisations, if duration ≥ 1 yr
Hospitalisations for relapse, per 1 yr of the disease	133	0.4 (0.2-0.7)	0.5 (0.3-0.8)	0.4 (0.2-1.3)	0.6615
Days of hospitalisation for relapse, per 1 yr of the disease	132	2.7 (0.7-5.6)	4.7 (1.6-7.5)	4.0 (1.1-7.6)	0.4001
Relapses from diagnosis, per 1 yr of the disease	132	0.4 (0.2-0.9)	0.5 (0.2-0.9)	0.4 (0.2-1.4)	0.8664
Severe relapses from diagnosis, per 1 yr of the disease	129	0.0 (0.0-0.3)	0.2 (0.0-0.5)	0.2 (0.0-0.5)	0.1996
Concomitant diseases5	214	16 (45.7)	40 (29.6)	8 (19.5)	0.0446
Extraintestinal manifestations	214	7 (20.0)	34 (25.2)	11 (26.8)	0.7660

¹Systemic steroid therapy included: methylprednisolone, prednisone, hydrocortisone.

²Immunosuppressive and anti-inflammatory agents included: azathioprine, methotrexate, mercaptopurine, cyclosporine, mycophenolate mofetil, tacrolimus, sulfasalazine.

³Biological agents included: infliximab, adalimumab, golimumab, vedolizumab.

⁴Only surgery related to inflammatory bowel disease-specific problems (e.g. colectomy, resection, fistula, perforation, abscess) was included.

⁵e.g., celiac disease, bronchial asthma, obesity, gastroesophageal reflux disease, epilepsy, hypothyroidism. CRP: C-reactive protein; IQR: Interquartile range; PCDAI: Pediatric Crohn’s Disease Activity Index.

Table 5 Summary of relevant findings depending on apolipoprotein E genotypes and alleles

Variables median (IQR) or n (%)	n	ε3/ε3	APOEε2-positive	APOEε4-positive	P value
IBD
Albumin level at worst flare in g/dL	327	3.9 (3.4-4.3)	4.0 (3.9-4.5)	4.1 (3.8-4.4)	0.0176a
CRP at worst flare in mg/L	347	7.7 (1.9-31.3)	4.3 (1.1-28.3)	3.2 (0.5-16.7)	0.0146b
Age at first surgery in yr	36	14.5 (11.7-16.7)	9.5 (7.7-11.4)	14.9 (14.0-15.6)	0.0378
Days of hospitalisation for relapse, per 1 yr of the disease	230	4.7 (1.6-8.3)	2.2 (0.7-4.8)	6.1 (1.7-8.7)	0.0440c
CD
Albumin level at worst flare in g/dL	327	3.9 (3.4-4.1)	3.9 (3.8-4.4)	4.4 (3.6-4.3)	0.0363
PCDAI at diagnosis	190	35 (25-50)	25 (20-35)	30 (25-45)	0.0204c
Height at diagnosis, z score	378	-0.47 [(-1.43)-0.32]	-0.16 [(-0.85)-0.61]	0.00 [(-1.10)-0.96]	0.0482
UC
CRP at diagnosis in mg/L	386	2.5 (0.7-12.2)	3.8 (0.8-7.3)	1.1 (0.2-8.2)	0.0435
CRP at worst flare in mg/L	347	3.7 (1.1-19.0)	2.1 (1.8-7.3)	0.9 (0.3-3.6)	0.0013
Age at first biological treatment	151	11.5 (7.9-14.6)	15.7 (15.3-15.7)	10.7 (4.8-15.5)	0.0432
E2 at diagnosis	192	16 (13.6)	8 (40.0)	9 (18.0)	0.0160

^a Post hoc APOEε3ε3 vs APOEε2-positive P = 0.0383 (Bonferroni and Holm); APOEε3ε3 vs APOEε4-positive P = 0.0417 (Bonferroni) and P = 0.0383 (Holm).

^b Post hoc APOEε3ε3 vs APOEε4-positive P = 0.0056 (Bonferroni and Holm).

^c APOEε3ε3 vs APOEε2-positive P = 0.0534 (Bonferroni) and P = 0.0356 (Holm), APOEε2-positive vs APOEε4-positive P = 0.0216 (Bonferroni and Holm). CD: Crohn’s disease; CRP: C-reactive protein; IBD: Inflammatory bowel disease; PCDAI: Pediatric Crohn’s Disease Activity Index; UC: Ulcerative colitis.