Role of CARD15, DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases

doi:10.3748/wjg.v13.i8.1221

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Feb 28, 2007 (publication date) through Jan 23, 2025

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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

Clinical Research

World J Gastroenterol. Feb 28, 2007; 13(8): 1221-1229
Published online Feb 28, 2007. doi: 10.3748/wjg.v13.i8.1221

Table 1 Primers sequences, methodology, and restriction enzymes used for genotyping

Gene locus	SNPs		Sequence	Methods/enzyme
CARD15	R702W	For	5’ACCTTCAGATCACAGCAGCC3’	DHPLC
		Rev	5’GCTCCCCCATACCTGAAC3’
	G908R	For	5’AAGTCTGTAATGTAAAGCCAC3’	RFLP/Hha I
		Rev	5’CCCAGCTCCTCCCTCTTC3’
	L1007fsinsC	For	5’CTCACCATTGTATCTTCTTTTC3’	DHPLC
		Rev	5’GAATGTCAGAATCAGAAGGG3’
IBD5	IGR2198a_1	For	5’GGGGCAATTCTATGAGGACA3’	RFLP/Nla III
		Rev	5’CCAGAGACACTGGGACATCA3’
	IGR2096a_1	For	5’GTAGCGAGAGGCTCCACAGT3’	RFLP/Dra I
		Rev	5’TCCTCCATGCTACTGCTCTG3’
OCTN1	C1672T	For	5’GGGTAGTCTGACTGTCCTGATTG3’	TaqMan
SLC22A4		Rev	5’TCTGGAAGAGTCATTCCCAAACTTTC3’
		VIC	5’AAGGGTGAGGATTC3’
		FAM	5’AAGGGTGAAGATTC3’
OCTN2	G207C	For	5’CCGCTCTGCCTGCCA3’	TaqMan
SLC22A5		Rev	5’GCGGCTGGCCTTACATAGG3’
		VIC	5’CAGGCCCGGAACC3’
		FAM	5’CAGGCCCGCAACC3’
DLG5	R30Q		C_7432738_10	TaqMan

DHPLC: Denaturing high performance liquid chromatography; RFLP: Restriction fragment length polymorphisms; TaqMan: ABI Prism 7700 sequencer detector.

Table 2 Clinical and demographic characteristics of patients with CD and UC as evaluated in last follow-up (mean ± SD)

	Crohn’s disease(n = 200)		Ulcerative colitis(n = 186)
Age (yr)	21 ± 8		19 ± 9
Age at diagnosis (yr)	12 ± 4		11 ± 5
Duration of follow-up (yr)	9 ± 7		8 ± 8
Sex (male/female)	115/85		73/113
Localization CD: n (%)
- Ileum	38 (19)
- Ileo-colon	116 (58)
- Colon	45 (23)
- Upper G-I tract	35 (18)¹
Localization UC: n (%)
- Rectum-sigmoid			44 (24)
- Left colon			54 (29)
- Pancolitis			88 (47)
Disease type CD: n (%)	(Vienna)	(Montreal)
- Inflammatory	104 (52)	135 (67)
- Stricturing	40 (20)	45 (23)
- Penetrating	56 (28)	20 (10)
Growth delay: y/n (%)	60/84 (42)		21/126 (14)
Surgery: y/n (%)	51/149 (26)		13/137 (7)
EIM: y/n (%)	79/121 (40)		46/140 (25)
Perianal fistulae: y/n (%)	36/164 (18)		1/185 (0.5)
Family history: y/n (%)	18/182 (9)		22/164 (12)
ASCA: y/n (%)	77/32 (71)		18/57 (24)
ANCA: y/n (%)	18/86 (17)		65/50 (57)
Smoking y/n (%)	44/156 (22)		40/146 (21)

EIM: Extra-intestinal manifestations.

¹One patient had upper G-I involvement only.

Table 3 Genotype distributions of CARD15, OCTN1-2, DLG5 genes, and IBD5 locus polymorphisms

SNPs	Genotype	Crohn’sdisease	P valueOR 95% IC	Controls	P valueOR 95% IC	Ulcerativecolitis
CARD15 R702W	TT		TT and CT vs CC			0 (0)
CARD15 R702W	TT	5 (3)	P < 0.001	1 (0)	NS	0 (0)
	CT	38 (19)	3.47 (2.06-5.86)	25 (7)		17 (9)
	CC	153 (78)		321 (93)		167 (91)
G908R	CC	2 (1)	CC and CG vs GG	0 (0)	NS	1 (1)
	CG	25 (13)	P < 0.001	18 (5)		12 (7)
	GG	170 (86)	2.90 (1.55-5.42)	329 (95)		171 (93)
1007fsInsC	CC	1 (1)	CC and CG vs GG	0 (0)	NS	0 (0)
	CG	25 (13)	P = 0.0005	11 (3)		10 (5)
	GG	172 (87)	4.62 (2.23-9.57)	336 (97)		176 (95)
OCTN1/2 C1672T	TT	42 (24)	TT vs CT and CC	57 (16)	P = 0.10	36 (22)
	CT	79 (46)	P = 0.03	178 (51)		76 (47)
	CC	52 (30)	1.63 (1.04-2.56)	112 (32)		49 (30)
-G207C	CC	50 (29)	CC vs CG and GG	72 (21)	P = 0.05	46 (29)
	CG	84 (49)	P = 0.035	183 (53)		77 (48)
	GG	38 (22)	1.57 (1.03-2.38)	92 (27)		38 (24)
IBD5 IGR2198a_1	GG	40 (21)	GG vs CG and CC	55 (16)	P = 0.09	39 (22)
	CG	93 (49)	P = 0.13	175 (50)		86 (48)
	CC	58 (30)		117 (34)		54 (30)
IGR2096a_1	AA	44 (23)	AA vs AC and CC	50 (14)	NS	32 (18)
	AC	89 (47)	P = 0.01	176 (51)		91 (51)
	CC	58 (30)	1.78 (1.13-2.79)	121 (35)		56 (31)
DLG5 113G/A	AA	1 (1)	NS	2 (1)	NS	1 (1)
	AG	16 (10)		57 (16)		26 (15)
	GG	148 (90)		288 (83)		144 (84)

Table 4 Analysis of possible interaction between OCTN TC-haplotype and DLG5 variant with presence (or absence) of at least one CARD15 variant

		CD		UC		Controls
CARD15		DLG5	OCTNTC haplotype (%)	DLG5	OCTNTC haplotype (%)	DLG5	OCTNTC haplotype (%)
CARD15+	DLG5+	5 (3)	42.6	7 (4)	35.2	11 (3)	44.8
	DLG5-	56 (34)		27 (16)		38 (12)
CARD15-	DLG5+	12 (7)	46.2	20 (12)	48.7	44 (13)	39.1
	DLG5-	92 (56)		116 (68)		241 (72)

DLG5-positive was defined as the AA or AG genotypes. Data expressed as absolute values or percentages (between brackets). All comparison had a P value > 0.05.

Table 5 Genotype-phenotype correlation in CD patients evaluated by comparisons of carriers and non-carriers of at least one CARD15 variant (CARD15+), AA/AG genotypes of DLG5 variant (DLG5+) and presence of TC haplotype of OCTN1/2 variants (TC+)

CD n = 200	CARD15+(n = 75)		CARD15-(n = 121)		DLG5+(n = 17)		DLG5-(n = 148)		OCTNTC haplotype (%)
CD n = 200	CARD15+(n = 75)		CARD15-(n = 121)		DLG5+(n = 17)		DLG5-(n = 148)		+	-
Localization CD, n (%)
Ileum	17 (23)		21 (17)		1 (6)		33 (22)		46	54
Ileo-colon	48 (64)		64 (53)		13 (76)		80 (54)		47	53
Colon	10 (13)		35 (29)		3 (18)		34 (23)		39	61
Upper G-I tract	16 (21)		18 (15)		3 (18)		29 (20)		53	47
Ileo vs colon	P = 0.029 OR 2.83 (1.10-7.33)
Disease type CD, n (%)	Vienna-Montreal		Vienna-Montreal		Vienna-Montreal		Vienna-Montreal		V-M	V-M
- Inflammatory	37 (50)	48 (64)	66 (54)	86 (71)	7 41)	9 (52)	87 (59)	109 (74)	45/44	55/56
- Stenosing	19 (25)	21 (28)	19 (16)	22 (18)	4 (24)	4 (24)	26 (17)	30 (20)	40/41	60/59
- Penetrating	19 (25)	6 (8)	36 (30)	13 (11)	6 (35)	4 (24)	35 (24)	9 (6)	49/62	51/38
F vs S+ I (according to Montreal)					P = 0.011 OR 4.75 (1.29-17.57)				P = 0.038 OR 2.13 (1.03-4.4)
Growth delay y/n, (%)	24/35 (41)		36/47 (43)		4/5 (44)		54/62 (47)		49/44	51/56
Resective surgery y/n, (%)	23/52 (31)		27/94 (22)		5/12 (29)		26/122 (18)		42/46	58/54
EIM y/n, (%)	27/48 (36)		49/72 (41)		9/8 (53)		58/90 (39)		40/48	60/52
Perianal fistulae y/n, (%)	13/62 (17)		23/98 (19)		2/15 (12)		26/122 (18)		45/45	55/55
ASCA (pos/neg), (%)	31/8 (79)		46/24 (66)		8/3 (73)		63/29 (68)		46/58	54/42
ANCA (pos/neg), (%)	5/26 (16)		13/59 (18)		1/11 (8)		15/66 (19)		44/49	56/51
Steroids need, y/n (%)	48/27 (64)		86/35 (71)		12/5(71)		96/52 (65)		43/48	57/52

P values are corrected for multiple comparisons.

Table 6 Genotype-phenotype correlation in UC patients evaluated by comparison of carriers vs non-carriers of at least one CARD15 variant (CARD15+), the AA/AG genotypes of DLG5 variant (DLG5+), and presence of TC haplotype of OCTN1/2 variants (TC+)

UC n = 186	CARD15+(n = 36)	CARD15-(n = 148)	DLG5+(n = 27)	DLG5-(n = 144)	OCTNTC haplotype (%)
UC n = 186	CARD15+(n = 36)	CARD15-(n = 148)	DLG5+(n = 27)	DLG5-(n = 144)	+	-
Localization UC, n (%)
Rectum-sigmoid	7 (19)	36 (24)	9 (33)	28 (19)	45	55
Left colon	11 (31)	43 (29)	6 (22)	44 (31)	44	56
Pancolitis	18 (50)	69 (47)	12 (45)	72 (50)	47	53
Growth delay y/n, (%)	3/26 (10)	18/98 (16)	5/14 (26)	16/101 (14)	43/46	57/54
Resective surgery y/n, (%)	4/32 (11)	9/139 (6)	1/26 (4)	9/135 (6)	31/46	69/54
EIM y/n, (%)	9/27 (25)	37/111 (25)	4/23 (15)	40/104 (28)	51/44	49/56
ASCA (pos/neg), (%)	4/10 (29)	14/46 (23)	5/10 (33)	13/46 (22)	42/46	58/54
ANCA (pos/neg), (%)	13/6 (68)	52/43 (55)	11/8 (58)	52/40 (57)	43/40	57/60
Steroids need, y/n, (%)	26/10 (72)	109/39 (74)	21/6 (78)	105/39 (73)	46/46	54/54

Citation: Cucchiara S, Latiano A, Palmieri O, Staiano A, D’Incà R, Guariso G, Vieni G, Rutigliano V, Borrelli O, Valvano M, Annese V. Role of CARD15, DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases. World J Gastroenterol 2007; 13(8): 1221-1229
URL: https://www.wjgnet.com/1007-9327/full/v13/i8/1221.htm
DOI: https://dx.doi.org/10.3748/wjg.v13.i8.1221