Genetic associations with adverse events from anti-tumor necrosis factor therapy in inflammatory bowel disease patients

Table 1 Adverse events based on type of inflammatory bowel disease and gender n (%)

Clinical traits	All adverse events	Infusion reactions	Allergic reactions	Lupus-like reactions	Rash	Other
Type of IBD
Crohn's disease (n = 954)	220 (23)	52 (5)	45 (5)	14 (1)	40 (4)	69 (7)
Ulcerative colitis (n = 260)	42 (16)	14 (5)	4 (2)	4 (2)	10 (4)	10 (4)
IBDU (n = 44)	7 (16)	0 (0)	0 (0)	1 (2)	2 (5)	4 (9)
Total	269 (21)	66 (5)	49 (4)	19 (1.5)	52 (4)	83 (7)
Gender
Male (n = 624)	108 (17)	28 (4)	24 (4)	3 (0.5)	17 (3)	36 (6)
Female (n = 634)	161 (25)	38 (6)	25 (4)	16 (3)	35 (6)	47 (7)

All values expressed as n (%). IBD: Inflammatory bowel disease.

Table 2 Serological associations with anti-tumor necrosis factor adverse reactions in patients with ulcerative colitis and Crohn’s disease (anti-I2, anti-Pseudomonasfluorescens-associated sequence I2; ASCA, anti-Saccharomyces cerevisiae antibodies)

IBD type	Adverse event	Serological marker	Serology levels in positive (U/mL)	Serology levels in negative (U/mL)	P value
CD	Any	IgA ASCA	7	10	0.040
CD	Any	IgG ASCA	18	26.5	0.020
UC	Infusion	Anti-I2	0	7	0.008

IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis.

Table 3 Inflammatory bowel disease-associated single nucleotide polymorphisms associated with different type of adverse events

Adverse event	Risk allele	SNP	Gene (s) of interest	P value	OR (95%CI)
Infusion	C	rs6740462	SPRED2	0.003	0.4 (0.2-0.7)
Infusion	G	rs1182188	GNA12	0.007	1.8 (1.2-2.6)
Infusion	G	rs10061469	TMEM174, FOXD1	0.010	0.5 (0.3-0.9)
Infusion	A	rs477515	HLA-DRB1	0.010	1.7 (1.1-2.5)
Allergic	A	rs4692386	SMIM20, RBPJ	0.010	0.5 (0.3-0.9)
Allergic	A	rs10761659	ZNF365	0.010	0.6 (0.3-0.9)
Lupus-like	G	rs13407913	ADCY3	0.003	3.5 (1.6-7.9)
Lupus-like	C	rs10051722	CHSY2, HINT1	0.010	2.7 (1.2-5.7)
Rash	A	rs1363907	ERAP2	0.003	3.0 (1.5-6.2)
Rash	G	rs11010067	PARD3	0.003	0.2 (0.1-0.6)
Rash	C	rs7746082	PREP	0.005	2.7 (1.3-5.3)
Any	C	rs6740462	SPRED2	0.0007	0.6 (0.5-0.8)
Any	C	rs10774482	ERC1	0.003	1.4 (1.1-1.8)

SNP: Single nucleotide polymorphisms.

Table 4 Pathway analyses from genetic associations with adverse events from immunochip analyses

Type of adverse event	Pathway	Number of genes	P value	P value (Bonferroni)
Any	JAK-STAT signaling pathway	13	3.98 × 10-6	7.96 × 10-4
Any	Measles	12	8.87 × 10-6	0.0018
Any	IBD	8	3.05 × 10-5	0.0061
Any	Cytokine-cytokine receptor interaction	16	5.03 × 10-5	0.0100
Any	Toxoplasmosis	10	5.49 × 10-5	0.0110
Infusion	JAK-STAT signaling pathway	12	3.68 × 10-5	0.0074
Infusion	Measles	12	8.24 × 10-6	0.0016
Infusion	IBD	7	2.11 × 10-4	0.0420
Infusion	Cytokine-cytokine receptor interaction	14	4.98 × 10-4	0.0990
Infusion	Toxoplasmosis	11	9.02 × 10-6	0.0018
Allergic	JAK-STAT signaling pathway	12	2.96 ×10-5	0.0060
Allergic	Measles	12	6.6 × 10-6	0.0010
Allergic	IBD	7	1.84 × 10-4	0.0370
Allergic	Cytokine-cytokine receptor interaction	14	4.02 ×10-4	0.0800
Allergic	Toxoplasmosis	9	2.25 ×10-4	0.0450

IBD: Inflammatory bowel disease.