Interaction of the major inflammatory bowel disease susceptibility alleles in Crohn&rsquo;s disease patients

doi:10.3748/wjg.v16.i2.176

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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. Jan 14, 2010; 16(2): 176-183
Published online Jan 14, 2010. doi: 10.3748/wjg.v16.i2.176

Table 1 Primer sequences for the analysed variants

Gene	SNP	Primers (5’-3’)
IL23R	rs1004819	F: GCATTCTAGGACCGTTTTGG
		R: ATCTGGTGGAAATATGTGAAACCTA
IL23R	rs2201841	F: GGCAAAAGGGAATTGAGAGG
		R: GGCCTATGATTATGCTTTTTCCTG¹
ATG16L1	rs2241880	F: CTCTGTCACCATATCAAGCGTGG
		R: TCTAGAAGGACAGGCTATCAACAGATG
CARD15	rs2066844	F: GAGCCGCACAACCTTCAGATC
		R: ACTTGAGGTGCCCAACATTCAG
CARD15	rs2066845	F: GAGGCCACTCTGGGATTGAG
		R: TAGACTCTGAAGCTTACCTGCGC¹
CARD15	rs2066847	F: TGGCTAACTCCTGCAGTCTC
		R: GATCCTCAAAATTCTGCCATTC
IGR2198a_1	rs11739135	F: AGACACTGGGACATCATCTGTCTG
		R: GGGCAATTCTATGAGGACATTTAGA
IGR2096a_1	rs12521868	F: CAAGATTTCTGCCATAGCCTCCT
		R: GGAGGGTGGTGTAGCCAGAGTAG

¹Mismatch bases are underlined.

F: Forward; R: Reverse; IL23R: Interleukin-23 receptor; ATG16L1: Autophagy-related 16-like 1; CARD15: Caspase recruitment domain-containing protein 15.

Table 2 Case-control genotypes and allele frequencies of variants in IL23R, ATG16L1, CARD15 and IBD5 n (%)

	CD (n = 315)	Controls (n = 314)	OR (95% CI)¹	P
IL23R (rs1004189)
GG	119 (37.8)	151 (48.1)
GA	152 (48.3)	140 (44.6)
GA+AA	196 (62.2)	163 (51.9)	1.50 (1.09-2.08)	0.013^a
AA	44 (14.0)	23 (7.3)	2.05 (1.20-3.50)	0.008^a
RAF	0.381	0.296		0.001^a
IL23R (rs2201841)
TT	131 (41.6)	152 (48.4)
TC	139 (44.1)	145 (46.2)
TC+CC	184 (58.4)	162 (25.8)	1.28 (0.93-1.76)	0.14
CC	45 (14.3)	17 (5.4)	2.97 (1.65-5.33)	< 0.001^a
RAF	0.363	0.285		0.003^a
ATG16L1 T300A (rs2241880)
AA	56 (17.8)	72 (22.9)
AG	151 (47.9)	163 (51.9)
AG+GG	259 (82.2)	242 (77.1)	1.45 (0.98-2.17)	0.06
GG	108 (34.3)	79 (25.2)	1.69 (1.19-2.41)	0.004^a
RAF	0.583	0.511		0.011^a
CARD15 R702W (rs2066844)
CC	275 (87.3)	294 (93.6)
CT	38 (12.1)	18 (5.7)
CT+TT	40 (12.7)	20 (6.4)	2.13 (1.19-3.80)	0.011^a
TT	2 (0.6)	2 (0.6)	0.62 (0.06-6.98)	0.70
RAF	0.067	0.035		0.011^a
CARD15 G908R (rs2066845)
GG	299 (94.9)	305 (97.1)
GC	16 (5.1)	9 (2.9)
GC+CC	16 (5.1)	9 (2.9)	1.65 (0.71-3.86)	0.24
CC	0 (0.0)	0 (0.0)	NC	NC
RAF	0.025	0.014		0.17
CARD15 L1007fs (rs2066847)
- -	264 (83.8)	291 (92.7)
- insC	42 (13.3)	23 (7.3)
- insC+insC insC	51 (16.2)	23 (7.3)	2.57 (1.51-4.36)	< 0.001^a
insC insC	9 (2.9)	0 (0.0)	NC	NC
RAF	0.095	0.037		< 0.001^a
CARD15 status²
-	220 (69.8)	262 (83.4)
+	95 (30.2)	52 (16.6)	2.17 (1.46-3.21)	< 0.001^a
IGR2198a_1 (rs11739135)
GG	91 (28.9)	120 (38.2)
GC	160 (50.8)	144 (45.9)
GC+CC	251 (79.7)	194 (61.8)	1.54 (1.10-2.15)	0.013^a
CC	64 (20.3)	50 (15.9)	1.32 (0.87-1.99)	0.19
RAF	0.457	0.389		0.014^a
IGR2096a_1 (rs12521868)
GG	94 (29.8)	120 (38.2)
GT	149 (47.3)	142 (45.2)
GT+TT	296 (94.0)	262 (83.4)	1.44 (1.03-2.02)	0.034^a
TT	72 (22.9)	52 (16.6)	1.45 (0.97-2.17)	0.07
RAF	0.465	0.392		0.009^a

¹Adjusted for age and gender;

²CARD15 status is denoted - (wild type) and + (at least one mutation in any of the three SNPs).

^aP < 0.05 vs controls.

RAF: Risk allele frequency; NC: Not calculated; OR: Odds ratio.

Table 3 Pairwise analysis of interactions of CARD15, IBD5 (IGR2198a_1), ATG16L1 and IL23R to risk of CD

Model	OR (95% CI)	P
IL23R rs1004189 * ATG16L1	1.51 (0.73-3.11)	0.26
IL23R rs2201841 * ATG16L1	1.01 (0.29-3.57)	0.99
IL23R rs1004189 * CARD15 status¹	1.20 (0.54-2.67)	0.65
IL23R rs2201841 * CARD15 status	1.57 (0.30-8.31)	0.60
IL23R rs1004189 * IGR2198a_1	1.30 (0.71-2.36)	0.40
IL23R rs2201841 * IGR2198a_1	0.46 (0.12-1.75)	0.25
ATG16L1 * CARD15 status	1.49 (0.59-3.80)	0.40
ATG16L1 * IGR2198a_1	0.95 (0.45-2.00)	0.89
CARD15 status * IGR2198a_1	0.75 (0.33-1.71)	0.49

¹CARD15 status is denoted - (wild type) and + (at least one mutation in any of the three SNPs).

CD: Crohn’s disease.

Table 4 Genotype-specific CD odds ratios¹ (with 95% CI) for combinations of variants in IL23R, ATG16L1 and CARD15

	CARD15 R702W		CARD15 G908R		CARD15 L1007fs		CARD15 status		ATG16L1
	CC	CT+TT	GG	GC+CC	- -	- insC+insC insC	-	+	AA+AG	GG
IL23R rs1004189
GG	1	2.35 (1.03-5.34)^a	1	1.55 (0.46-5.21)	1	2.85 (1.28-6.35)^a	1	2.100 (1.17-3.76)^a	1	1.16 (0.68-1.99)
GA+AA	1.56 (1.12-2.19)^a	3.18 (1.45-6.97)^a	1.51 (1.09-2.09)^a	3.23 (0.99-10.57)	1.57 (1.12-2.20)^a	3.40 (1.69-6.82)^a	1.50 (1.04-2.16)^a	3.33 (1.96-5.67)^a	1.34 (0.92-1.95)	2.51 (1.55-4.08)^a
IL23R rs2201841
TT+TC	1	2.25 (1.26-4.03)^a	1	1.49 (0.62-3.59)	1	2.43 (1.42-4.18)^a	1	2.12 (1.42-3.16)^a	1	1.48 (1.03-2.14)^a
CC	3.04 (1.67-5.57)^a	4.75 (0.53-42.81)	2.69 (1.49-4.86)^a	NC	2.89 (1.57-5.32)^a	8.52 (1.04-69.74)^a	2.70 (1.42-5.15)^a	9.15 (2.05-40.74)^a	2.67 (1.31-5.44)^a	4.68 (1.72-12.78)^a
ATG16L1
AA+AG	1	2.20 (1.14-4.26)^a	1	1.44 (0.56-3.72)	1	2.37 (1.29-4.34)^a	1	2.12 (1.35-3.31)^a	-	-
GG	1.57 (1.09-2.25)^a	3.18 (1.11-9.08)^a	1.51 (1.06-2.14)^a	6.91 (0.83-57.92)	1.54 (1.07-2.22)^a	4.27 (1.54-11.79)^a	1.54 (1.04-2.27)^a	3.82 (1.86-7.86)^a	-	-

¹CARD15 R702W, G908R and L1007fs: OR relative to wild type genotype; CARD15 status: OR relative to - (wild type) group; ATG16L1: OR relative to wild and heterozygous genotypes together.

^aP < 0.05 vs controls.

Table 5 Genotype-specific CD odds ratios¹ (with 95% CI) for combinations of variants in IBD5, IL23R and ATG16L1

	IL23R rs1004189		IL23R rs2201841		ATG16L1
	GG	GA+AA	TT+TC	CC	AA+AG	GG
IGR2198a_1
GG	1	1.43 (0.80-2.53)	1	4.83 (1.52-15.37)^a	1	1.71 (0.94-3.09)
GC+CC	1.45 (0.84-2.48)	2.44 (1.43-4.15)^a	1.58 (1.11-2.24)^a	3.66 (1.81-7.41)^a	1.60 (1.07-2.38)^a	2.38 (1.46-3.87)^a
IGR2096a_1
GG	1	1.55 (0.88-2.73)	1	4.03 (1.39-11.62)^a	1	1.63 (0.91-2.92)
GT+TT	1.49 (0.87-2.56)	2.41 (1.42-4.09)^a	1.50 (1.06-2.13)^a	3.71 (1.80-7.67)^a	1.50 (1.01-2.24)^a	2.32 (1.42-3.79)^a

¹IGR2198a_1, IGR2096a_1 and IL23R rs1004189: OR relative to wild type genotype; ATG16L1 and IL23R rs2201841: OR relative to wild and heterozygous genotypes together.

^aP < 0.05 vs controls.

Table 6 Genotype-specific CD odds ratios¹ (with 95% CI) for combinations of variants in IBD5 and CARD15

	CARD15 R702W		CARD15 G908R		CARD15 L1007fs		CARD15 status
	CC	CT+TT	GG	GC+CC	- -	- insC+insC insC	-	+
IGR2198a_1
GG	1	3.17 (1.15-8.69)^a	1	1.79 (0.39-8.22)	1	3.04 (1.30-7.14)^a	1	2.65 (1.36-5.17)^a
GC+CC	1.60 (1.13-2.27)^a	2.819 (1.39-5.72)^a	1.52 (1.08-2.13)^a	2.69 (0.97-7.45)	1.61 (1.13-2.31)^a	3.58 (1.80-7.16)^a	1.63 (1.11-2.39)^a	3.19 (1.90-5.37)^a
IGR2096a_1
GG	1	3.07 (1.20-7.86)^a	1	2.19 (0.51-9.41)	1	2.43 (1.06-5.59)^a	1	2.46 (1.29-4.69)^a
GT+TT	1.55 (1.09-2.20)^a	2.75 (1.32-5.70)^a	1.47 (1.05-2.06)^a	2.41 (0.86-6.77)	1.48 (1.03-2.11)^a	3.74 (1.85-7.54)^a	1.54 (1.05-2.26)^a	3.18 (1.87-5.39)^a

¹IGR2198a_1, IGR2096a_1, CARD15 R702W, G908R and L1007fs: OR relative to wild type genotype; CARD15 status: OR relative to - (wild type) group.

^aP < 0.05 vs controls.

Citation: Csöngei V, Járomi L, Sáfrány E, Sipeky C, Magyari L, Faragó B, Bene J, Polgár N, Lakner L, Sarlós P, Varga M, Melegh B. Interaction of the major inflammatory bowel disease susceptibility alleles in Crohn’s disease patients. World J Gastroenterol 2010; 16(2): 176-183
URL: https://www.wjgnet.com/1007-9327/full/v16/i2/176.htm
DOI: https://dx.doi.org/10.3748/wjg.v16.i2.176