Association between inflammatory bowel disease and the risk of parenteral malignancies: A two-sample Mendelian randomization study

Su, Peizhu; Wang, Yilin; Huang, Huiwen; Lu, Qinghua; Wu, Qinyan; Li, Zhaotao

doi:10.1016/j.clinsp.2024.100421

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Original articles • Clinics 79 • 2024 • https://doi.org/10.1016/j.clinsp.2024.100421 copy

Association between inflammatory bowel disease and the risk of parenteral malignancies: A two-sample Mendelian randomization study

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Aim:

Using Mendelian Randomization (MR) analysis to investigate the potential causal association between Inflammatory Bowel Disease (IBD) and the occurrence of parenteral malignancies, in order to provide some reference for the parenteral malignancy prevention in patients with IBD.

Methods:

This was a two-sample MR study based on independent genetic variants strongly linked to IBD selected from the Genome-Wide Association Study (GWAS) meta-analysis carried out by the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). Parenteral malignancy cases and controls were obtained from the FinnGen consortium and the UK Biobank (UKB) release data. Inverse Variance Weighted (IVW), weighted median, MR-Egger, and strength test (F) were utilized to explore the causal association of IBD with parenteral malignancies. In addition, Cochran’s Q statistic was performed to quantify the heterogeneity of Instrumental Variables (IVs).

Results:

The estimates of IVW showed that patients with IBD had higher odds of diffuse large B-cell lymphoma (OR = 1.2450, 95% CI: 1.0311‒1.5034). UC had potential causal associations with non-melanoma skin cancer (all p < 0.05), melanoma (OR = 1.0280, 95% CI: 0.9860‒1.0718), and skin cancer (OR = 1.0004, 95% CI: 1.0001‒1.0006). Also, having CD was associated with higher odds of non-melanoma skin cancer (all p < 0.05) and skin cancer (OR = 1.0287, 95% CI: 1.0022‒1.0559). In addition, results of pleiotropy and heterogeneity tests indicated these results are relatively robust.

Conclusions:

IBD has potential causal associations with diffuse large B-cell lymphoma and skin cancers, which may provide some information on the prevention of parenteral malignancies in patients with IBD. Moreover, further studies are needed to explore the specific mechanisms of the effect of IBD on skin cancers.

Keywords:
Inflammatory bowel disease; Parenteral malignancies; Skin cancer; Mendelian randomization study; Causal relationship

HIGHLIGHTS

To provide some reference for parenteral malignancy prevention in patients with IBD.

IBD was potentially associated with diffuse large B-cell lymphoma and skin cancers.

Some information on preventing parenteral malignancies in IBD was provided.

Further studies are needed to explore mechanisms of the effect of IBD on skin cancers.

Variables Exposures		GWAS ID
IBD	ieu-a-294
UC	ieu-a-32
CD	ieu-a-10
Outcomes
Breast cancer	finn-b-C3_BREAST	ukb-b-16890
Glioma	finn-b-C3_GBM
Brain cancer	finn-b-C3_BRAIN
Meningioma	finn-b-C3_MENINGES
Thyroid cancer	finn-b-C3_THYROID_GLAND
Oral and pharyngeal cancer	finn-b-C3_LIP_ORAL_PHARYNX	ieu-b-4961
Urinary organs cancer	finn-b-C3_URINARY_TRACT	ukb-d-C3_URINARY_TRACT
Bladder cancer	finn-b-C3_BLADDER	ukb-d-C67
Kidney cancer (except renal pelvis)	finn-b-C3_KIDNEY_NOTRENALPELVIS	ukb-b-1316
Skin cancer	finn-b-C3_SKIN	ukb-b-12339
Melanoma	finn-b-C3_MELANOMA_SKIN	ieu-b-4969
Non-melanoma skin cancer	finn-b-C3_OTHER_SKIN	ieu-b-4959
Respiratory system cancers	finn-b-C3_RESPIRATORY_INTRATHORACIC	ukb-d-C3_RESPIRATORY_INTRATHORACIC
Bronchogenic carcinoma and lung cancer	finn-b-C3_BRONCHUS_LUNG	ukb-d-C34
Non-small cell lung cancer	finn-b-C3_LUNG_NONSMALL
Small cell lung cancer	finn-b-C3_SCLC
Gastric carcinoma	finn-b-C3_STOMACH
Esophagus cancer	finn-b-C3_OESOPHAGUS
Liver cancer	finn-b-C3_LIVER_INTRAHEPATIC_BILE_DUCTS
Pancreatic cancer	finn-b-C3_PANCREAS
Female genital organs cancers	finn-b-C3_FEMALE_GENITAL	ukb-d-C_FEMALE_GENITAL
Cervical cancer	finn-b-C3_CERVIX_UTERI	ukb-b-8777
Uterine cancer	finn-b-C3_CORPUS_UTERI	ukb-d-C3_CORPUS_UTERI
Ovarian cancer	finn-b-C3_OVARY	ukb-b-18157
Hematopoietic system cancer	finn-b-CD2_PRIMARY_LYMPHOID_HEMATOPOIETIC finn-b-CD2_HODGKIN_LYMPHOMA	leukaemiaukb-d-C3_PRIMARY_LYMPHOID_HEMATOPOIETIC
Diffuse large B-cell lymphoma	finn-b-C3_DLBCL
Follicular lymphoma	finn-b-CD2_FOLLICULAR_LYMPHOMA
Mature T/NK-cell lymphomas	finn-b-CD2_TNK_LYMPHOMA
Lymphoid leukaemia	finn-b-CD2_LYMPHOID_LEUKAEMIA
Multiple myeloma and malignant plasma cell cancers	finn-b-CD2_MULTIPLE_MYELOMA_PLASMA_CELL	ieu-b-4957
Male genital organs cancers	finn-b-C3_MALE_GENITAL	ukb-d-C_MALE_GENITAL
Prostatic cancer	finn-b-C3_PROSTATE	ukb-b-2160

Exposures	Phenotypes	Outcomes	Selected SNPs (p < 5×10^-8)	Omitted LD SNPs	Drop all palindromic SNPs	Horizontal pleiotropic	Heterogeneity		Strength
Exposures	Phenotypes	Outcomes	Selected SNPs (p < 5×10^-8)	Omitted LD SNPs	Drop all palindromic SNPs	MR-Egger intercept test, p	MR-Egger Q, p	IVW, p	F-value, R²
IBD	Others	Breast cancer	7495	132	125	-0.01, 0.09	153.83, 0.01	157.76, 0.01	31.858,0.061
		Glioma	7495	132	127	-0.02, 0.56	90.99, 0.96	91.33, 0.96	32.14,0.062
		Brain cancer	7495	132	125	-0.01, 0.41	94.63, 0.91	95.32, 0.91	32.672,0.062
		Meningioma	7495	132	129	-0.01, 0.72	113.55, 0.60	113.68, 0.62	32.288,0.064
		Thyroid cancer	7495	132	127	0.01, 0.55	91.72, 0.96	92.08, 0.96	32.733,0.063
		Oral and pharyngeal cancer	7495	132	127	0.02, 0.57	110.19, 0.63	110.51, 0.65	32.48,0.063
	Urinary system	Urinary organs cancer	7495	132	128	-0.00, 0.74	112.17, 0.61	112.28, 0.63	32.457,0.063
		Bladder cancer	7495	132	125	-0.01, 0.25	87.72, 0.97	89.07, 0.97	32.182,0.061
		Kidney cancer (except renal pelvis)	7495	132	125	0.01, 0.35	119.53, 0.39	120.43, 0.40	31.793,0.061
	Skin	Skin cancer	7495	132	120	0.00, 0.98	110.60, 0.44	110.60, 0.47	33.015,0.06
		Melanoma	7495	132	129	0.00, 0.98	97.14, 0.92	97.14, 0.93	32.462,0.064
		Non-melanoma skin cancer	7495	132	120	0.00, 0.98	110.64, 0.44	110.64, 0.47	33.015,0.06
	Respiratory system and intrathoracic organs	Respiratory system cancers	7495	132	123	0.00, 0.63	99.02, 0.80	99.26, 0.82	31.488,0.059
		Bronchogenic carcinoma and lung cancer	7495	132	121	-0.00, 0.65	90.58, 0.91	90.78, 0.92	32.045,0.059
		Non-small cell lung cancer	7495	132	127	-0.01, 0.12	116.77, 0.46	119.28, 0.42	32.691,0.063
		Small cell lung cancer	7495	132	127	0.02, 0.37	101.70, 0.83	102.51, 0.83	32.618,0.063
	Digestive system	Gastric carcinoma	7495	132	130	-0.00, 0.91	104.66, 0.82	104.68, 0.84	32.331,0.064
		Esophagus cancer	7495	132	129	-0.02, 0.42	106.40, 0.77	107.06, 0.78	31.998,0.063
		Liver cancer	7495	132	125	0.00, 0.9	92.95, 0.93	92.97, 0.93	32.157,0.061
		Pancreatic cancer	7495	132	130	-0.00, 0.83	112.04, 0.66	112.09, 0.68	32.331,0.064
	Female genital organs	Female genital organs cancers	7495	132	127	0.01, 0.23	97.09, 0.90	98.57, 0.89	32.503,0.063
		Cervical cancer	7495	132	126	0.01, 0.44	98.86, 0.86	99.46, 0.86	32.099,0.062
		Uterine cancer	7495	132	125	0.01, 0.55	93.39, 0.92	93.74, 0.93	32.978,0.063
		Ovarian cancer	7495	132	128	-0.01, 0.56	103.07, 0.82	103.40, 0.83	32.071,0.063
	Primary lymphoid and hematopoietic system	Hematopoietic system cancer	7495	132	127	0.01, 0.38	147.46, 0.03	148.44, 0.03	32.846,0.064
		Hodgkin lymphoma	7495	132	122	0.00, 0.92	100.10, 0.78	100.11, 0.80	32.908,0.061
		Diffuse large B-cell lymphoma	7495	132	129	-0.04, 0.15	119.13, 0.45	121.27, 0.42	32.123,0.063
		Follicular lymphoma	7495	132	126	-0.01, 0.41	128.21, 0.19	128.98, 0.19	31.277,0.06
		Mature T/NK-cell lymphomas	7495	132	129	-0.02, 0.52	106.17, 0.77	106.58, 0.79	31.928,0.063
		Lymphoid leukaemia	7495	132	129	0.03, 0.06	105.33, 0.81	108.81, 0.76	32.582,0.064
		Multiple myeloma and malignant plasma cell cancers	7495	132	126	0.01, 0.72	106.39, 0.70	106.52, 0.72	32.018,0.062
	Male genital organs	Male genital organs cancers	7495	132	121	0.01, 0.14	102.09, 0.69	104.25, 0.66	33.259,0.061
		Prostatic cancer	7495	132	122	0.00, 0.46	114.96, 0.38	115.54, 0.39	32.938,0.061
UC	Others	Breast cancer	6616	38	35	0.00, 0.75	33.50, 0.18	33.63, 0.21	17.389,0.022
		Glioma	6616	38	35	0.07, 0.43	14.34, 0.98	14.99, 0.99	20.099,0.026
		Brain cancer	6616	38	35	0.03, 0.46	23.78, 0.64	24.33, 0.66	19.171,0.024
		Meningioma	6616	38	35	0.03, 0.34	17.47, 0.92	18.41, 0.92	19.215,0.025
		Thyroid cancer	6616	38	35	0.01, 0.68	22.69, 0.75	22.87, 0.78	20.099,0.026
		Oral and pharyngeal cancer	6616	38	36	0.05, 0.53	28.48, 0.44	28.90, 0.47	19.54,0.026
	Urinary system	Urinary organs cancer	6616	38	36	-0.02, 0.25	23.90, 0.69	25.30, 0.66	19.54,0.026
		Bladder cancer	6616	38	35	-0.03, 0.25	11.50, 1.00	12.90, 1.00	20.099,0.026
		Kidney cancer (except renal pelvis)	6616	38	36	-0.00, 0.93	33.08, 0.23	33.09, 0.27	19.54,0.026
	Skin	Skin cancer	6616	38	34	-0.02, 0.05	19.53, 0.81	23.87, 0.64	17.512,0.022
		Melanoma	6616	38	36	-0.10, 0.27	23.05, 0.73	24.30, 0.71	19.54,0.026
		Non-melanoma skin cancer	6616	38	34	-0.02, 0.05	19.54, 0.81	23.84, 0.64	17.512,0.022
	Respiratory system and intrathoracic organs	Respiratory system cancers	6616	38	34	-0.00, 0.86	27.11, 0.46	27.14, 0.51	19.971,0.025
		Bronchogenic carcinoma and lung cancer	6616	38	35	-0.02, 0.45	30.18, 0.35	30.80, 0.37	20.099,0.026
		Non-small cell lung cancer	6616	38	36	-0.04, 0.11	27.10, 0.51	29.91, 0.42	19.54,0.026
		Small cell lung cancer	6616	38	35	-0.02, 0.81	16.53, 0.94	16.59, 0.96	19.726,0.025
	Digestive system	Gastric carcinoma	6616	38	36	0.00, 0.93	29.14, 0.41	29.15, 0.46	19.54,0.026
		Esophagus cancer	6616	38	35	-0.08, 0.26	34.54, 0.15	36.26, 0.14	19.47,0.025
		Liver cancer	6616	38	35	-0.06, 0.21	22.87, 0.69	24.52, 0.65	19.197,0.024
		Pancreatic cancer	6616	38	36	-0.06, 0.11	21.17, 0.82	23.92, 0.73	19.54,0.026
	Female genital organs	Female genital organs cancers	6616	38	36	0.02, 0.14	29.95, 0.37	32.48, 0.30	19.54,0.026
		Cervical cancer	6616	38	33	0.03, 0.25	25.74, 0.48	27.10, 0.46	17.974,0.022
		Uterine cancer	6616	38	35	0.00, 0.9	17.13, 0.93	17.15, 0.95	19.918,0.025
		Ovarian cancer	6616	38	34	-0.02, 0.64	20.47, 0.81	20.70, 0.84	20.301,0.025
	Primary lymphoid and hematopoietic system	Hematopoietic system cancer	6616	38	34	0.00, 0.93	24.84, 0.53	24.84, 0.58	17.308,0.021
		Hodgkin lymphoma	6616	38	35	-0.02, 0.72	31.34, 0.26	31.49, 0.30	17.389,0.022
		Diffuse large B-cell lymphoma	6616	38	34	-0.05, 0.52	20.47, 0.77	20.89, 0.79	17.299,0.021
		Follicular lymphoma	6616	38	33	-0.00, 0.97	30.74, 0.24	30.74, 0.28	19.723,0.024
		Mature T/NK-cell lymphomas	6616	38	35	0.10, 0.18	24.19, 0.62	26.05, 0.57	19.152,0.024
		Lymphoid leukaemia	6616	38	35	0.04, 0.28	28.08, 0.46	29.29, 0.45	20.099,0.026
		Multiple myeloma and malignant plasma cell cancers	6616	38	34	-0.06, 0.08	25.01, 0.57	28.28, 0.45	20.505,0.025
	Male genital organs	Male genital organs cancers	6616	38	35	0.01, 0.52	22.35, 0.72	22.77, 0.74	19.057,0.024
		Prostatic cancer	6616	38	35	0.01, 0.52	22.62, 0.71	23.05, 0.73	19.057,0.024
CD	Others	Breast cancer	2860	104	96	-0.00, 0.76	104.52, 0.16	104.62, 0.17 19.884,0.058
		Glioma	2860	104	101	0.04, 0.28	93.01, 0.57	94.19, 0.56	20.173,0.062
		Brain cancer	2860	104	99	0.00, 0.84	97.09, 0.39	97.13, 0.42	20.15,0.061
		Meningioma	2860	104	101	-0.00, 0.86	99.84, 0.37	99.87, 0.40	20.222,0.062
		Thyroid cancer	2860	104	100	0.01, 0.42	89.58, 0.64	90.23, 0.65	20.396,0.062
		Oral and pharyngeal cancer	2860	104	102	0.03, 0.34	73.16, 0.97	74.09, 0.97	20.326,0.063
	Urinary system	Urinary organs cancer	2860	104	101	-0.01, 0.45	110.78, 0.14	111.43, 0.15 20.304,0.062
		Bladder cancer	2860	104	96	-0.01, 0.47	83.72, 0.69	84.24, 0.71	20.337,0.059
		Kidney cancer (except renal pelvis)	2860	104	97	-0.01, 0.6	88.62, 0.58	88.89, 0.60	19.478,0.057
	Skin	Skin cancer	2860	104	98	-0.00, 0.69	92.82, 0.49	92.99, 0.51	20.446,0.061
		Melanoma	2860	104	101	0.04, 0.31	83.45, 0.82	84.48, 0.81	20.503,0.063
		Non-melanoma skin cancer	2860	104	98	-0.00, 0.69	93.05, 0.48	93.21, 0.50	20.446,0.061
	Respiratory system and intrathoracic organs	Respiratory system cancers	2860	104	99	0.01, 0.37	101.31, 0.29	102.18, 0.29 20.202,0.061
		Bronchogenic carcinoma and lung cancer	2860	104	97	0.00, 0.68	79.83, 0.81	80.00, 0.83	20.347,0.06
		Non-small cell lung cancer	2860	104	100	-0.00, 0.9	114.42, 0.09	114.44, 0.10 20.404,0.062
		Small cell lung cancer	2860	104	100	-0.01, 0.72	86.60, 0.72	86.73, 0.74	20.048,0.061
	Digestive system	Gastric carcinoma	2860	104	103	-0.02, 0.27	80.06, 0.91	81.31, 0.90	20.232,0.063
		Esophagus cancer	2860	104	102	-0.05, 0.06	95.57, 0.52	99.27, 0.45	20.183,0.062
		Liver cancer	2860	104	98	0.00, 0.91	95.98, 0.40	96.00, 0.42	19.997,0.059
		Pancreatic cancer	2860	104	102	0.01, 0.5	94.89, 0.54	95.35, 0.56	20.275,0.063
	Female genital organs	Female genital organs cancers	2860	104	102	-0.00, 0.72	96.28, 0.50	96.41, 0.53	20.352,0.063
		Cervical cancer	2860	104	99	-0.02, 0.11	81.63, 0.81	84.21, 0.78	20.415,0.061
		Uterine cancer	2860	104	101	0.02, 0.14	95.31, 0.50	97.58, 0.46	20.416,0.063
		Ovarian cancer	2860	104	102	-0.01, 0.46	91.09, 0.65	91.65, 0.66	20.063,0.062
	Primary lymphoid and hematopoietic system	Hematopoietic system cancer	2860	104	98	0.01, 0.44	85.09, 0.71	85.69, 0.72	20.571,0.061
		Hodgkin lymphoma	2860	104	101	0.04, 0.07	107.44, 0.20	111.32, 0.15 20.28,0.062
		Diffuse large B-cell lymphoma	2860	104	101	-0.01, 0.75	87.64, 0.72	87.75, 0.74	20.265,0.062
		Follicular lymphoma	2860	104	100	-0.02, 0.17	82.30, 0.82	84.25, 0.80	19.239,0.058
		Mature T/NK-cell lymphomas	2860	104	103	0.03, 0.36	104.92, 0.30	105.84, 0.30 20.232,0.063
		Lymphoid leukaemia	2860	104	101	0.02, 0.26	80.92, 0.86	82.20, 0.86	19.788,0.061
		Multiple myeloma and malignant plasma cell cancers	2860	104	98	-0.01, 0.72	92.18, 0.50	92.32, 0.53	20.521,0.061
	Male genital organs	Male genital organs cancers	2860	104	100	0.00, 0.71	82.23, 0.82	82.37, 0.84	20.459,0.062
		Prostatic cancer	2860	104	100	0.00, 0.7	84.75, 0.77	84.91, 0.78	20.459,0.062

Exposures	Outcomes	IVW
		OR (95% CI)	p	Power (%)
IBD	FinnGen Diffuse large B-cell lymphoma	1.2450 (1.0311‒1.5034)	0.023	100
UC	FinnGen
	Non-melanoma skin cancer	1.0449 (1.0030‒1.0886)	0.035	100
	Melanoma	1.0280 (0.9860‒1.0718)	0.019	98
	Skin cancer	0.8581 (0.6283‒1.1720)	0.336
	UKB
	Non-melanoma skin cancer	1.0034 (1.0015‒1.0052)	<0.001	8
	Melanoma	1.0003 (0.9998‒1.0008)	0.311
	Skin cancer	1.0004 (1.0001‒1.0006)	0.007	9
CD	FinnGen
	Non-melanoma skin cancer	1.0288 (1.0023‒1.0560)	0.034	99
	Melanoma	1.0004 (0.7892‒1.2680)	0.998
	Skin cancer	1.0287 (1.0022‒1.0559)	0.033	99
	UKB
	Non-melanoma skin cancer	1.0017 (1.0001‒1.0033)	0.033	6
	Melanoma	1.0004 (0.9999 ‒1.0008)	0.076
	Skin cancer	1.0002 (0.9999 ‒1.0005)	0.078

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[1] *Corresponding author. E-mail address:LZT_foshanfirsthsp@outlook.com (Z. Li).