Table 1 Summary of the findings for candidate proteins associated with IBD and its subtypes

From: Associations of 2923 plasma proteins with incident inflammatory bowel disease in a prospective cohort study and genetic analysis

Category^a	Protein Name	UKB-PPP cohort study^b	Main MR pQTL from UKB-PPP^c	Reverse MR^d	Steiger filtering analyses^e	Bayesian colocalization^f		Replication MR pQTL from deCODE^g	Replication MR pQTL from Fenland^h	Transcriptomic MR eQTL from GTExⁱ	Differential expression in enriched cells (IBD vs HC)^j	KO mouse models^k	PPI^l	Drug development^m		Interactions between proteins and IBD drug targetsⁿ
		Direction	Direction	FDR	Causal direction (P-value)	PPH4.abs	Evidence level	Direction	Direction	Direction				Drug name	Outcomes (Approved or Trial Phase)
IBD
Tier1	IL12B	+	+	0.140	True (9.51E-27)	0.979	High	+	+			Yes	Yes	Ustekinumab	Inflammatory bowel disease (Phase IV)	Yes
Tier1	CD6	+	+	0.825	True (2.59E-11)	0.996	High			+	+	Yes	Yes	Itolizumab	COVID-19 (Phase III) Psoriasis (Approved)	Yes
Tier1	MXRA8	−	−	0.140	True (8.02E-03)	0.643	High	−	−	−						Yes
Tier2	CCL20	+	+	0.825	True (1.13E-13)	0.080	Low			+	+		Yes	GSK-3050002	Psoriatic arthritis (Phase I)	Yes
Tier2	IL18	+	+	0.168	True (9.74E-17)	0.185	Low			+	+	Yes	Yes	GSK-1070806	Inflammatory bowel disease (Phase I)	Yes
Tier2	TNFRSF9	+	+	0.849	True (4.31E-32)	0.040	Low			+/−		Yes	Yes	Urelumab	Pancreatic Cancer (Phase II)	Yes
Tier2	CCL7	+	+	0.578	True (4.22E-19)	3.24E-06	Low	+	+			Yes	Yes			Yes
Tier2	IL1RL1	+	+	0.574	True (4.38E-60)	0.086	Low	+	+	+		Yes	Yes	Anakinra	Rheumatoid Arthritis (Approved)	Yes
Tier2	IL19	+	+	0.140	True (1.16E-05)	7.32E-18	Low			+/−		Yes	Yes			Yes
Tier2	CCL13	+	+	0.849	True (1.59E-139)	2.70E-04	Low			+/−			Yes			Yes
Tier2	CD72	+	+	0.813	True (2.83E-38)	0.230	Low	+	+			Yes	Yes
Tier2	EPHB4	+	+	0.535	True (5.11E-46)	0.015	Low	+		+/−			Yes	Dasatinib	Chronic Phase Chronic Myeloid Leukemia (Approved)	Yes
Tier2	SEPTIN8	+	+	0.813	True (4.82E-14)	4.57E-12	Low			+/−	+
Tier2	IFNG	+	+	0.628	True (3.77E-03)	3.88E-05	Low					Yes	Yes	Olsalazine	Inflammatory bowel disease (Approved)	Yes
Tier2	LY9	+	+	0.628	True (2.66E-114)	0.005	Low	+	+			Yes				Yes
Tier2	IL10RA	+	+	0.711	True (1.06E-34)	0.021	Low					Yes	Yes	Pegilodecakin	Pancreatic carcinoma (Phase III)	Yes
Tier2	IGLC2	+	+	0.666	True (1.99E-48)	0.031	Low			+			Yes
Tier2	ITGAV	-	-	0.578	True (2.11E-38)	0.267	Low			−	+	Yes	Yes	Cilengitide	Glioblastoma multiforme (Phase III)	Yes
CD
Tier1	CXCL9	+	+	0.535	True (4.30E-19)	0.820	High		+		+	Yes	Yes			Yes
Tier1	IL12B	+	+	0.132	True (6.94E-15)	0.889	High	+	+			Yes	Yes	Ustekinumab	Inflammatory bowel disease (Phase IV)	Yes
Tier1	IFNG	+	+	0.578	True (1.85E-04)	0.654	High					Yes	Yes	Olsalazine	Inflammatory bowel disease (Approved)	Yes
Tier1	CCN3	+	+	0.878	True (1.47E-97)	0.649	High		-			Yes				Yes
Tier1	RSPO3	+	+	0.849	True (3.68E-30)	0.810	High	+	+				Yes	Rosmantuzumab	Colorectal cancer/Neoplasm (Phase I)
Tier2	SEPTIN8	+	+	0.666	True (1.03E-09)	7.89E-16	Low			+/−	+		Yes
UC
Tier1	IL18	+	+	0.578	True (2.22E-11)	0.822	High			+	+	Yes	Yes	GSK-1070806	Inflammatory bowel disease (Phase I)	Yes
Tier2	CCL20	+	+	0.578	True (2.01E-11)	0.086	Low			+	+		Yes	GSK-3050002	Psoriatic arthritis (Phase I)	Yes
Tier2	CCL7	+	+	0.878	True (4.25E-19)	0.010	Low	+	+			Yes	Yes			Yes
Tier2	NOS3	+	+	0.578	True (2.19E-03)	0.024	Low			+		Yes	Yes	Tilarginine	Obesity/Type 2 diabetes (Phase IV) Breast cancer/Hyperlipidemia (Phase II)	Yes

^aTier 1 included the proteins that passed cohort study, main MR pQTL from UKB-PPP, and the colocalization analysis, and tier 2 included the proteins that only passed cohort study and main MR pQTL from UKB-PPP.
^bCox regression was used to evaluate the association between baseline plasma proteins and the incidence of IBD and its subtypes during follow-up in UKB-PPP study. All tests were two sided and adjusted for multiple comparisons, with an FDR < 0.05 considered as significant.
^cMeta-analysis of MR results (Wald ratio or inverse variance weighted method) was used to evaluate the association between proteins level from UKB-PPP (Olink) with IBD and its subtypes combined from IIBDGC and FinnGen. All tests were two sided and adjusted for multiple comparisons, with an FDR < 0.05 considered as significant.
^dReverse MR (Wald ratio or inverse variance weighted method) was used to IBD, CD, and UC from IIBDGC with candidate proteins from UKB-PPP, deCODE, and Fenland studies. All tests were two sided and adjusted for multiple comparisons. FDR < 0.05 indicates the presence of reverse causality.
^eSteiger filtering was used to evaluate the directionality of the association between proteins and IBD, “True” if the effect direction is from exposure to outcome at P < 0.05; “False” if reversed at P ≥ 0.05.
^fColocalization analysis was performed to evaluate whether the proteins and IBD shared common causal variants. PPH4 ≥ 0.6 indicated high-support evidence of colocalization, and PPH4 < 0.6 indicated low-support evidence of colocalization.
^gReplication MR (Wald ratio or inverse variance weighted method) meta-analysis was used to evaluate the association between proteins from deCODE (SoamScan) with IBD and its subtypes combined from IIBDGC and FinnGen. The “−” and “+” indicated the direction of replication MR analysis results.
^hReplication MR (Wald ratio or inverse variance weighted method) meta-analysis was used to evaluate the association between proteins from Fenland (SoamScan) with IBD and its subtypes combined from IIBDGC and FinnGen. The “−” and “+” indicated the direction of replication MR analysis results.
ⁱMeta-analysis of MR result (Wald ratio or inverse variance weighted method) was used to evaluate the association between protein-coding genes in different tissues from GTEx with IBD and its subtypes combined from IIBDGC and FinnGen. The “ − ” and “ + ” were used to indicate the direction of each protein on IBD, where “ − ” represented a negative association while “ + ” represented a positive association. The “ − / + ” represented the gene expression presenting different effects across different tissues.
^jWilcoxon rank-sum test was to compare the expression levels of candidate protein-coding genes in the specific enriched cell types between IBD cases and HC. The “ + ” indicates that the expression level of the protein-coding gene in the specifically enriched cell types is higher in IBD patients compared to healthy controls (HC), whereas the “ −” indicates lower expression in IBD patients. All tests were two-sided and |log2FC | > 0.25 and an FDR < 0.05 was considered as significant.
^kWhether knockout (KO) mouse models for these proteins show IBD-associated phenotypes, including immune and digestive/alimentary traits.
^lWhether interacted with other candidate proteins in protein–protein interaction (PPI) analysis.
^mDrugs targeting the candidate proteins that have been approved or are under clinical trials, along with their associated diseases, in the DrugBank database, OpenTargets database, and Therapeutic Target Database.
ⁿWhether interacted with known IBD drug targets in protein–protein interaction (PPI) analysis.
IBD inflammatory bowel disease, CD Crohn’s disease, UC ulcerative colitis.

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Table 1 Summary of the findings for candidate proteins associated with IBD and its subtypes

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