Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn&rsquo;s disease: Phenotype-genotype correlations

doi:10.3748/wjg.v11.i10.1489

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Mar 14, 2005 (publication date) through May 7, 2024

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastroenterol. Mar 14, 2005; 11(10): 1489-1495
Published online Mar 14, 2005. doi: 10.3748/wjg.v11.i10.1489

Table 1 Clinical characteristics of the different cohorts of Crohn’s disease (CD) patients.

	Budapest (n = 185)	Veszprem (n = 175)	Szeged (n = 167)
Male/Female	98/87	88/87	79/88
Age (yr)	35.6±11.4	37.8±13.3	37.1±12.7
Age at presentation (yr)	27.2±10.3	30.2±12.4	28.9±10.9
Duration (yr)	8.9±6.6	7.7±6.8	8.0±7.3
Familial IBD, n (%)	63 (11.9)	38 (11.1)	25 (13.5)
Location (n) L1	43	54	39
L2	37	47	52
L3	103	74	74
L4	2	0	2
Behavior (n) B1	88	65	62
B2	40	39	49
B3	56	71	56
Perianal disease, n (%)	41 (22.1)	49 (28.0)	50 (29.9)
Frequent relapse, n (%)	59 (31.9)	72 (41.1)	64 (38.6)
Extraintestinal manifestations, n (%)	67 (36.2)	61 (34.8)	47 (28.2)
Operation, n (%)	77 (41.6)	76 (43.4)	67 (40.1)
Smoking habits (n) No	115	96	98
Yes	55	61	55
Previous	15	20	14

Table 2 NOD2/CARD15 genotype in patients with Crohn’s disease (CD) and controls, n (%).

A	NOD2 genotype
A	Non-carrier	All carrier	Heterozygous	Homozygous	Compound heterozygous
Controls (n = 200)	167 (83.5)	33 (16.5)	33 (16.5)	0	0
CD (n = 527)	342 (64.9)	185 (35.1)	133 (25.2)¹	30 (5.7)²	26 (4.9)³

P<0.0001 between CD patients and controls,

¹OR_het = 1.71 (1.12–2.60),

²OR_hom = 14.43 (2.47–∞),

³OR_compound = 12.92 (2.2–∞).

Table 3 TLR4 D299G genotype in patients with Crohn’s disease (CD) and controls, n (%).

B	TLR4 D299G
B	Non-carrier	All carrier	Heterozygous	Homozygous
Controls (n = 200)	176 (88.0)	24 (12.0)	23(11.5)	1 (0.5)
CD (n = 527)	475 (90.1)	52 (9.9)	50 (9.5)	2(0.4)

Table 4 NOD2/CARD15 SNP8, 12 and 13 in patients with Crohn’s disease (CD) and controls.

	R702W (SNP8)¹		G908R(SNP12)		3020insC (SNP13)¹
	CD n (%)	Controls n (%)	CD n (%)	Controls n (%)	CD n (%)	Controls n (%)
Wild type	466 (88.4)	188 (94.0)	494 (96.7)	193 (96.5)	425 (80.6)	190 (95.0)
All carriers	61 (11.6)	12 (6.0)	33 (6.3)	7 (3.5)	102 (19.4)	10 (5.0)
Heterozygous	45 (8.5)	12 (6.0)	33 (6.3)	7 (3.5)	89 (16.9)	10 (5.0)
Homozygous	16 (3.1)	0	0	0	13 (2.5)	0

¹P = 0.02 and P<0.0001 between patients and controls for genotype frequency by χ²-test, OR_{SNP8 allele} = 2.41 (1.30–4.44), OR_{SNP13 allele} = 4.78 (2.50–9.11).

Table 5 NOD2/CARD15 and TLR4 D299G mutations in different cohorts of CD patients, n (%).

	Budapest(n = 185)	Veszprem(n = 175)	Szeged(n = 167)
NOD2/CARD15	64 (34.6)¹	61 (34.9)¹	60 (35.9)¹
SNP8	17 (9.2)	23 (13.1)²	21 (12.6)³
SNP12	12 (6.5)	10 (5.7)	11 (6.6)
SNP13	39 (21.1)¹	33 (18.9)¹	30 (18.0)⁴
TLR4 D299G	21 (11.4)	20 (11.4)	11 (6.6)

¹P<0.0001,

²P = 0.0002,

³P = 0.0005,

⁴P = 0.04 cohort vs controls (Tables 2, 3).

Table 6 Further exon4 mutations in patients with Crohn’s disease (CD) and controls.

	CD (n = 527)	Controls (n = 200)
R703C¹	11 (1 homozygous)	0
R713C	1	0
A755V	2	1
E778K	0	1
R791Q	5	1
V793M	2	1

¹P = 0.02 between patients and controls for allele frequency, ORR703C = 6.89 (1.18–∞).

Table 7 Clinical characteristics of CD patients, with respect to the presence or absence of NOD2/CARD15 mutations.

		Total (n = 527)	Non carrier (n = 342)	Carrier (n = 185)	1 allele (n = 133)	2 alleles (n = 52)
Male/Female		265/262	174/168	91/94	71/62	20/32
Age (yr)		36.9±9.1	37.9±13.0	34.9±11.6¹	35.2±11.7	34.3±11.4
Age at presentation (yr)		37.1±7.6	29.8±12.1	26.4±9.7¹	26.4±9.6	26.5±10.2
Duration (yr)		8.2±5.0	8.1±7.0	8.5±6.7	8.8±7.0	7.9±5.8
Familiar IBD n (%)		63 (11.9)	38 (11.1)	25 (13.5)	17 (12.8)	8 (15.4)
Location (n)	L1	136	84	52¹	36²	162
	L2	136	103	33	26	7
	L3	251	152	99	71	28
	L4	4	3	1	0	1
Behavior (n)	B1	216	151	65¹	48³	17
	B2	128	71	57	42	15
	B3	183	120	63	43	20
Perianal disease n (%)		140 (26.6)	89 (26.0)	51 (27.6)	36 (27.1)	15 (28.9)
Frequent relapse n (%)		195 (37.1)	126 (36.9)	69 (37.3)	47 (35.3)	22 (42.3)
Extraintestinal manifestations n (%)		175 (33.2)	117 (34.2)	58 (31.3)	45 (33.8)	13 (25)
Arthritis n (%)		147 (27.9)	98 (28.7)	49 (26.5)	36 (27.1)	13 (25)
Occular n (%)		27 (5.1)	18 (5.2)	9 (4.9)	9 (6.8)	0
Erythema nodosum/Pyoderma n (%)		48 (9.1)	30 (8.8)	18 (9.7)	15 (11.3)	3 (5.8)
PSCa		18 (3.4)	15 (4.4)	3 (1.6)	3 (2.3)	0
Steroid use/		440 (83.5)/	282 (82.4)/	158 (85.4)/	114 (85.7)/	44 (84.6)/
refractory n (%)		44 (10)	28 (9.3)	16 (10.1)	10 (8.8)	6 (13.6)
Azathioprine use/		337 (64.1)/	208 (60.8)/	129 (69.7)¹/	89 (66.9)/	40 (76.9)⁴/
refractory n (%)		19 (5.6)	10 (4.8)	9 (7.0)	7 (7.8)	2 (5)
Operation n (%)		220 (41.8)	128 (37.4)	92 (49.7)¹	66 (49.6)²	26 (50.0)²
Smoking (n)	Never	308	191	117	80	37
	Active	170	115	55	42	13
	Previous	49	36	13	11	2

¹P<0.03 between carriers and non-carriers,

²P<0.03 between patients carrying one or two mutant allele and non-carriers,

³P = 0.043 between patients carrying one mutant allele and non-carriers,

⁴P = 0.025 between patients carrying two mutant allele and non-carriers.

Table 8 Genotype–phenotype associations with particular NOD2/CARD15 alleles in CD patients.

		None (n = 342)	SNP8 (n = 61)	SNP12 (n = 33)	SNP13 (n = 102)
Male/Female		174/168	28/33	14/19	51/51
Age (yr)		37.9±13.0	35.9±13.0	37.1±11.4	33.7±10.4¹
Age at presentation (yr)		29.8±12.1	26.6±10.9	28.8±10.0	26.0±8.4¹
Duration (yr)		8.1±7.0	9.3±7.6	11.4±6.4²	7.7±6.1
Familiar IBD n (%)		38 (11.1)	9 (14.8)	7 (21.1)	11 (10.8)
Location	L1	84	16	7	32²
	L2	103	12	5	16
	L3	152	33	20	53
	L4	3	0	1	1
Behavior	B1	151	22	8	34
	B2	71	15	13	31
	B3	120	14	12	37
Perianal disease n (%)		89 (26.0)	18 (29.5)	7 (21.1)	32 (31.4)
Frequent relapse n (%)		126 (36.9)	24 (39.3)	13 (39.4)	38 (37.3)
Extraintestinal manifestations n (%)		117 (34.2)	17 (27.8)	14 (42.4)	31 (30.4)
Arthritis n (%)		98 (28.7)	16 (26.2)	14 (42.2)	24 (23.5)
Occular n (%)		18 (5.2)	1 (1.6)	2 (6.1)	4 (3.9)
Erythema nodosum/
Pyoderma n (%)		30 (8.8)	5 (8.2)	4 (12.1)	7 (6.9)
PSC n (%)		15 (4.4)	1 (1.6)	0	2 (1.9)
Steroid use/		282 (82.4)/	51 (83.6)/	31 (93.9)/	88 (86.3)/
refractory n (%)		28 (9.3)	7 (13.7)	2 (16.1)	6 (6.8)
Azathioprine use/ refractory n (%)		208 (60.8)/	38 (62.3)/	32 (97)¹/	69 (67.6)/
		10 (4.8)	4 (10.5)	2 (11.1)	3 (4.3)
Operationn (%)		128 (37.4)	27 (44.3)	23 (69.7)¹	53 (52.0)²
Smoking habits	Never	191	44	21	65
	Active	115	12	9	33
	Previous	36	5	3	4

¹P<0.001 between carriers and non-carriers;

²P<0.03 between carriers and non-carriers.

Citation: Lakatos PL, Lakatos L, Szalay F, Willheim-Polli C, Österreicher C, Tulassay Z, Molnar T, Reinisch W, Papp J, Mozsik G, Group HIS, Ferenci P. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn’s disease: Phenotype-genotype correlations. World J Gastroenterol 2005; 11(10): 1489-1495
URL: https://www.wjgnet.com/1007-9327/full/v11/i10/1489.htm
DOI: https://dx.doi.org/10.3748/wjg.v11.i10.1489