Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn’s disease

doi:10.3748/wjg.v23.i27.4958

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World Journal of Gastroenterology

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World J Gastroenterol. Jul 21, 2017; 23(27): 4958-4967
Published online Jul 21, 2017. doi: 10.3748/wjg.v23.i27.4958

Table 1 Hardy weinberg equilibrium n (%)

	Genotype distribution		Hardy Weinberg equilibrium
SNP	Genotype	Frequency	Expected frequency (n)	P value¹
ATG16L1 rs10210302	CC	25 (21.0)	24	NS
	TC	57 (47.9)	59
	TT	37 (31.1)	36
ATG16L1 rs2241880	AA	27 (22.5)	26	NS
	GA	57 (47.5)	60
	GG	36 (30.0)	35
Fas Ligand rs763110	CC	42 (36.5)	41	NS
	TC	54 (47.0)	55
	TT	19 (16.5)	18
IBD5 rs2522057	CC	35 (29.2)	29	0.045
	GC	49 (40.8)	60
	GG	36 (30.0)	31
FCGR 3A rs396991	AA	70 (58.3)	62	0.0005
	AC	33 (27.5)	48
	CC	17 (14.2)	9
TNF gene (-308) rs1800629	AA	4 (3.4)	3	NS
	GA	31 (26.1)	33
	GG	84 (70.6)	83
TNF gene (-238) rs361525	AA	2 (1.7)	1	NS
	GA	15 (12.5)	17
	GG	103 (85.8)	102

¹Calculated using χ². TNF: Tumor necrosis factor; SNPs: Single nucleotide polymorphisms.

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Table 2 Clinical and demographic patient characteristics n (%)

Variables	Total	Anti-TNF treatment		P value
Variables	Total	Non-responders	Ever responders	P value
Total	121 (100)	21 (17)	100 (83)	NA
Patient demographics
Gender
Female	71 (59)	15 (71)	56 (56)	NS
Male	50 (41)	6 (29)	44 (44)	NS
Race
Caucasian	112 (93)	21 (100)	91 (91)	NS
African American	9 (7)	0 (0.0)	9 (9)	NS
Socioeconomic status¹
1^st Quartile	24 (20)	4 (19)	20 (20)	NS
2^nd Quartile	40 (33)	6 (29)	34 (34)
3^rd Quartile	29 (24)	3 (14)	26 (26)
4^th Quartile	28 (23)	8 (38)	20 (20)
Montreal classification
Age of onset (A)
A1 - below 16 years old	14 (12)	1 (5)	13 (13)	NS
A2 - between 17 and 40 years old	90 (74)	17 (81)	73 (73)
A3 - above 40 years old	17 (14)	3 (14)	14 (14)
Location (L)
L1 - ileal	15 (12)	1 (5)	14 (14)	NS
L2 - colonic	32 (26)	5 (24)	27 (27)
L3 - ileocolonic	74 (61)	15 (71)	59 (59)
Location (L4) upper
No upper GI disease	118 (98)	21 (100)	97 (97)	NS
L4 - upper GI disease	3 (2)	0 (0)	3 (3)	NS
Behavior (B)
B1 - non-stricturing, non-penetrating	36 (30)	4 (19)	32 (32)	0.1
B2 - stricturing	45 (37)	12 (57)	33 (33)
B3 - penetrating	40 (33)	5 (24)	35 (35)
Behavior (p) perianal disease
No perianal disease	84 (69)	18 (86)	66 (66)	0.08
p - perianal disease present	37 (31)	3 (14)	34 (34)	0.08
Anti-TNF treatment type
Drugs received
Infliximab	46 (38)	10 (48)	36 (36)	NS
Adalimumab	45 (38)	5 (24)	40 (40)
Infliximab and Adalimumab²	29 (24)	6 (29)	23 (23)
Certolizumab pegol	5	0	5

¹Calculated according to the national percentile of median household income;

²Received sequentially. TNF: Tumor necrosis factor.

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Table 3 Single nucleotide polymorphisms tested with genotype and allele distribution for entire patients group n (%)

				Genotype distribution		Allele distribution
SNP	Location relative to gene (Chromosome number)	Nucleotide change	Assay successful	Genotype	Frequency	Allele	Frequency
ATG16L1 rs10210302	2 kb upstream (2)	C/T	119 (98)	CC	25 (21.0)	Total	238
				TC	57 (47.9)	C	107 (45.0)
				TT	37 (31.1)	T	131 (55.0)
ATG16L1 rs2241880	Thr300Ala (2)	A/G	120 (99)	AA	27 (22.5)	Total	240
				GA	57 (47.5)	A	111 (46.3)
				GG	36 (30.0)	G	129 (53.7)
FAS ligand rs763110	-843 (1)	C/T	115 (95)	CC	42 (36.5)	Total	230
				TC	54 (47.0)	C	138 (60.0)
				TT	19 (16.5)	T	92 (40.0)
IBD5 rs2522057	Intergenic region (5)	C/G	120 (99)	CC	35 (29.2)	Total	240
				GC	49 (40.8)	C	119 (49.6)
				GG	36 (30.0)	G	121 (50.4)
FCGR 3A rs396991	Phe175Val (1)	C/G	120 (99)	AA	70 (58.3)	Total	240
				AC	33 (27.5)	A	173 (72.1)
				CC	17 (14.2)	C	67 (27.9)
TNF gene (-308) rs1800629	promotor region (6)	A/G	119 (98)	AA	4 (3.4)	Total	238
				GA	31 (26.1)	A	39 (19.6)
				GG	84 (70.6)	G	199 (80.4)
TNF gene (-238) rs361525	promotor region (6)	A/G	120 (99)	AA	2 (1.7)	Total	240
				GA	15 (12.5)	A	19 (7.9)
				GG	103 (85.8)	G	221 (92.1)

TNF: Tumor necrosis factor; SNPs: Single nucleotide polymorphisms.

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Table 4 Single nucleotide polymorphism genotypes according to anti-tumor necrosis factor treatment response

SNP	Genotype	Anti-TNF treatment response		P value¹
SNP	Genotype	Non-responders	Responders	P value¹
ATG16L1 rs10210302	CC	5 (25.0)	20 (20.2)	NS
	TC	9 (45.0)	48 (48.5)
	TT	6 (30.0)	31 (31.3)
ATG16L1 rs2241880	AA	5 (23.8)	22 (22.2)	NS
	GA	10 (47.6)	47 (47.5)
	GG	6 (28.6)	30 (30.3)
FAS Ligand rs763110	CC	12 (60.0)	30 (31.6)	0.042
	TC	5 (25.0)	49 (51.6)
	TT	3 (15.0)	16 (16.8)
FAS Ligand rs763110 (grouped)	CC	12 (60.0)	30 (31.6)	0.016 OR = 3.23, 95%CI: 1.20-8.78
FAS Ligand rs763110 (grouped)	TC + TT	8 (40.0)	65 (68.4)	0.016 OR = 3.23, 95%CI: 1.20-8.78
IBD5 rs2522057	CC	6 (28.6)	29 (29.3)	NS
	GC	9 (42.9)	40 (40.4)
	GG	6 (28.6)	30 (30.3)
FCGR 3A rs396991	AA	11 (52.4)	59 (59.6)	NS
	AC	6 (28.6)	27 (27.3)
	CC	4 (19.0)	13 (13.1)
TNF gene (-308) rs1800629	AA	2 (10.0)	2 (2.0)	0.088
	GA	7 (35.0)	24 (24.2)
	GG	11 (55.0)	73 (73.7)
TNF gene (-308) rs1800629 (grouped)	AA + GA	9 (45.0)	26 (26.3)	0.093 OR = 2.29, 95%CI: 0.85-6.17
TNF gene (-308) rs1800629 (grouped)	GG	11 (55.0)	73 (73.7)	0.093 OR = 2.29, 95%CI: 0.85-6.17
TNF gene (-238) rs361525	AA	0 (0.0)	2 (2.0)	NS
	GA	2 (10.0)	13 (13.0)
	GG	18 (90.0)	85 (85.0)

¹Calculated using χ². TNF: Tumor necrosis factor; SNPs: Single nucleotide polymorphisms.

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Table 5 Univariable logistic regression data regarding factors associated with anti-tumor necrosis factor treatment failure

Covariate	P value
Demographic variables
Gender	NS
Race	NS
Montreal Classification
Age of onset (A) Montreal	NS
Location (L) Montreal	NS
Location (L4) upper GI Montreal	NS
Behavior (B) Montreal	0.13¹
Behavior (p) perianal Montreal	0.09¹
SNP variables
ATG16L1 rs10210302	NS
ATG16L1 rs2241880	NS
FAS Ligand rs763110	0.057¹
FAS Ligand rs763110 (TC + TT grouped)	0.02¹
IBD5 rs2522057	NS
FCGR 3A rs396991	NS
TNF gene (-308) rs1800629	0.13¹
TNF gene (-308) rs1800629 (AA + GA grouped)	0.099¹
TNF gene(-238) rs361525	NS

¹Covariates included in the subsequent multivariable analysis. TNF: Tumor necrosis factor; SNPs: Single nucleotide polymorphisms.

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Table 6 Multivariable logistic regression models predicting anti-tumor necrosis factor treatment failure

Model	Variable	Class	Estimate	Global P value	OR (95%CI)
a	FAS ligand rs763110 (TC + TT grouped)	CC	1.460	0.009	4.30 (1.45-12.80)
	FAS ligand rs763110 (TC + TT grouped)	TC+TT	0
	Montreal behavior (B)	B1	-0.083	NS	0.92 (0.21-3.96)
		B2	1.158		3.18 (0.89-11.34)
		B3	0
	Montreal behavior (p) perianal	No	0.964	NS	2.62 (0.68-10.09)
	Montreal behavior (p) perianal	Yes	0
b	TNF gene (-308) rs1800629 (AA+GA grouped)	AA+GA	1.056	0.049	2.88 (1.01-8.22)
	TNF gene (-308) rs1800629 (AA+GA grouped)	GG	0
	Montreal Behavior (B)	B1	-0.153	NS	0.86 (0.20-3.59)
		B2	0.826		2.28 (0.68-7.61)
		B3	0
	Montreal Behavior (p) perianal	No	1.213	NS	3.36 (0.87-12.93)
	Montreal Behavior (p) perianal	Yes	0
c	FAS ligand (CC genotype) and TNF gene -308 (AA or GA genotype) combined	CC and AA or GA	1.560	0.015	4.76 (1.35-16.77)
		Other	0
	Montreal behavior (B)	B1	-0.022	NS	0.98 (0.23-4.22)
		B2	0.950		2.59 (0.73-9.17)
		B3	0
	Montreal behavior (p) perianal	No	0.970	NS	2.64 (0.69-10.10)
	Montreal behavior (p) perianal	Yes	0

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Citation: Netz U, Carter JV, Eichenberger MR, Dryden GW, Pan J, Rai SN, Galandiuk S. Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn’s disease. World J Gastroenterol 2017; 23(27): 4958-4967
URL: https://www.wjgnet.com/1007-9327/full/v23/i27/4958.htm
DOI: https://dx.doi.org/10.3748/wjg.v23.i27.4958