Causal relationship between inflammatory cytokines and pancreatic ductal adenocarcinoma: a Mendelian randomization study

doi:10.3877/cma.j.issn.2095-3232.2025.06.020

Abstract

Abstract:

Objective

To investigate the causal relationship between inflammatory cytokines and pancreatic ductal adenocarcinoma (PDAC) by two-sample Mendelian randomization (MR) method.

Methods

The genetic variation data of 91 inflammation-related proteins collected from genome-wide association studies (GWAS) and PDAC outcome data from FinnGen database were used for data analysis. The result of inverse variance weighted (IVW) analysis was utilized as the main outcome index. MR-Egger, weighted median, simple mode and weighted mode methods were used as supplementary analyses. A series of sensitivity analyses, including heterogeneity test, pleiotropic test and leave-one-out analysis, were used to evaluate the reliability of the results.

Results

A total of 46 single nucleotide polymorphism (SNP) related to PDAC were screened in this study, and all SNP showed robust correlations (F>10). MR analysis showed that interleukin-22 receptor subunit α1 (IL22RA1), interleukin-15 receptor subunit α (IL15RA), IL-1α and cysteine aspartatespecific proteinase 8 (caspase-8) might have causal relationship with PDAC, among which IL22RA1 (OR=1.79, 95%CI: 1.01-3.19) was positively correlated with the risk of PDAC. However, IL15RA (OR=0.82, 95%CI: 0.69-0.98), IL-1α (OR=0.59, 95%CI: 0.42-0.83) and caspase-8 (OR=0.70, 95%CI: 0.50-0.96) had negative causal relationships with the incidence of PDAC (all P<0.05). In addition, the results of MR-Egger, weighted median, simple mode and weighted mode methods were basically consistent with those of IVW analysis. MR-Egger and Cochran's Q tests found no horizontal pleiotropy or heterogeneity. Leave-one-out analysis detected no SNP which had significant impact on the estimated effect, indicating that the causal relationship was stable to certain extent.

Conclusions

MR analysis shows that IL22RA1 is positively correlated with the risk of PDAC, whereas IL15RA, IL-1α and caspase-8 are negatively correlated with the incidence of PDAC. Analysis of PDAC-related inflammatory cytokines offers evidence for novel treatment strategy for PDAC in clinical practice.

Key words: Inflammatory cytokines, Pancreatic ductal adenocarcinoma, Mendelian randomization (MR), Genome-wide association study (GWAS)

Hongyu Meng, Jinhui Dai, Jiajin Hu, Guanghui Li. Causal relationship between inflammatory cytokines and pancreatic ductal adenocarcinoma: a Mendelian randomization study[J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 14(06): 948-955.

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References 36

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炎症细胞因子	rsID	效应值	标准误	效应等位基因	其他等位基因	F值
IL22RA1	rs117263973	0.346 7	0.075 2	A	G	21.25
	rs12240324	0.220 3	0.047 0	A	G	21.97
	rs13257574	0.271 4	0.058 4	T	C	21.59
	rs1473089	0.267 9	0.056 1	A	C	22.80
	rs4811167	0.063 2	0.013 4	T	C	22.24
	rs56282088	0.281 5	0.057 1	A	G	24.30
	rs75590335	0.172 2	0.037 0	A	G	21.66
	rs78594373	-0.127 1	0.027 3	T	C	21.67
	rs79229049	-0.210 2	0.041 2	A	T	26.03
IL15RA	rs10125254	0.065 1	0.013 8	A	C	22.25
	rs117428573	-0.313 2	0.068 4	A	C	20.96
	rs117484888	0.379 4	0.079 9	A	G	22.54
	rs12570881	-0.086 7	0.017 4	A	T	24.82
	rs145793996	-0.227 8	0.049 2	A	G	21.43
	rs151041734	-0.382 5	0.074 6	T	C	26.29
	rs192538756	0.115 9	0.024 1	A	T	23.12
	rs200144408	-0.068 2	0.014 7	T	TG	21.52
	rs2228059	0.369 2	0.012 7	T	G	844.97
	rs2836464	0.079 6	0.016 9	A	G	22.18
	rs4459616	0.140 0	0.029 4	T	C	22.67
	rs6845172	0.077 8	0.016 2	C	G	23.06
	rs7898286	-0.196 7	0.013 5	T	G	212.26
IL-1α	rs10233998	0.131 0	0.028 6	T	G	20.98
	rs115602471	0.221 5	0.046 9	T	C	22.30
	rs117537822	0.217 6	0.043 9	T	C	24.56
	rs11759846	-0.326 3	0.026 6	A	G	150.45
	rs11878153	0.111 6	0.022 1	A	G	25.50
	rs12047801	0.078 3	0.017 1	T	C	20.96
	rs16886503	0.243 8	0.052 4	A	T	21.64
	rs4767214	0.062 0	0.013 0	T	C	22.74
	rs523604	0.075 4	0.014 2	A	G	28.19
	rs61098036	-0.085 6	0.018 7	A	G	20.95
	rs7138689	0.096 1	0.020 8	T	G	21.34
caspase-8	rs1032417	-0.085 8	0.016 5	C	G	27.04
	rs1034059	0.068 1	0.014 5	A	G	22.05
	rs111764025	0.109 5	0.023 8	C	G	21.16
	rs11695193	-0.080 6	0.016 2	A	T	24.75
	rs11709039	0.078 1	0.016 8	T	C	21.61
	rs137887001	0.231 8	0.048 6	C	G	22.75
	rs140844269	-0.361 5	0.077 6	C	G	21.70
	rs148608719	0.347 4	0.068 3	A	G	25.87
	rs187405204	0.419 5	0.091 2	T	C	21.16
	rs34154371	-0.201 6	0.042 2	T	C	22.82
	rs56328050	-0.198 7	0.017 3	C	G	131.90
	rs73306603	0.204 4	0.041 2	T	C	24.61
	rs78449258	-0.200 1	0.042 8	A	G	21.85

炎症细胞因子	rsID	效应值	标准误	效应等位基因	其他等位基因	F值
IL22RA1	rs117263973	0.346 7	0.075 2	A	G	21.25
	rs12240324	0.220 3	0.047 0	A	G	21.97
	rs13257574	0.271 4	0.058 4	T	C	21.59
	rs1473089	0.267 9	0.056 1	A	C	22.80
	rs4811167	0.063 2	0.013 4	T	C	22.24
	rs56282088	0.281 5	0.057 1	A	G	24.30
	rs75590335	0.172 2	0.037 0	A	G	21.66
	rs78594373	-0.127 1	0.027 3	T	C	21.67
	rs79229049	-0.210 2	0.041 2	A	T	26.03
IL15RA	rs10125254	0.065 1	0.013 8	A	C	22.25
	rs117428573	-0.313 2	0.068 4	A	C	20.96
	rs117484888	0.379 4	0.079 9	A	G	22.54
	rs12570881	-0.086 7	0.017 4	A	T	24.82
	rs145793996	-0.227 8	0.049 2	A	G	21.43
	rs151041734	-0.382 5	0.074 6	T	C	26.29
	rs192538756	0.115 9	0.024 1	A	T	23.12
	rs200144408	-0.068 2	0.014 7	T	TG	21.52
	rs2228059	0.369 2	0.012 7	T	G	844.97
	rs2836464	0.079 6	0.016 9	A	G	22.18
	rs4459616	0.140 0	0.029 4	T	C	22.67
	rs6845172	0.077 8	0.016 2	C	G	23.06
	rs7898286	-0.196 7	0.013 5	T	G	212.26
IL-1α	rs10233998	0.131 0	0.028 6	T	G	20.98
	rs115602471	0.221 5	0.046 9	T	C	22.30
	rs117537822	0.217 6	0.043 9	T	C	24.56
	rs11759846	-0.326 3	0.026 6	A	G	150.45
	rs11878153	0.111 6	0.022 1	A	G	25.50
	rs12047801	0.078 3	0.017 1	T	C	20.96
	rs16886503	0.243 8	0.052 4	A	T	21.64
	rs4767214	0.062 0	0.013 0	T	C	22.74
	rs523604	0.075 4	0.014 2	A	G	28.19
	rs61098036	-0.085 6	0.018 7	A	G	20.95
	rs7138689	0.096 1	0.020 8	T	G	21.34
caspase-8	rs1032417	-0.085 8	0.016 5	C	G	27.04
	rs1034059	0.068 1	0.014 5	A	G	22.05
	rs111764025	0.109 5	0.023 8	C	G	21.16
	rs11695193	-0.080 6	0.016 2	A	T	24.75
	rs11709039	0.078 1	0.016 8	T	C	21.61
	rs137887001	0.231 8	0.048 6	C	G	22.75
	rs140844269	-0.361 5	0.077 6	C	G	21.70
	rs148608719	0.347 4	0.068 3	A	G	25.87
	rs187405204	0.419 5	0.091 2	T	C	21.16
	rs34154371	-0.201 6	0.042 2	T	C	22.82
	rs56328050	-0.198 7	0.017 3	C	G	131.90
	rs73306603	0.204 4	0.041 2	T	C	24.61
	rs78449258	-0.200 1	0.042 8	A	G	21.85

暴露	方法	Cochran's Q检验值	异质性检验(P)	多效性检验(P)
IL22RA1	MR-Egger	6.66	0.465	0.065
IL22RA1	IVW	11.42	0.179	0.065
IL15RA	MR-Egger	10.12	0.519	0.679
IL15RA	IVW	10.30	0.589	0.679
IL-1α	MR-Egger	6.05	0.735	0.251
IL-1α	IVW	7.56	0.672	0.251
caspase-8	MR-Egger	10.43	0.493	0.893
caspase-8	IVW	10.44	0.577	0.893

暴露	方法	Cochran's Q检验值	异质性检验(P)	多效性检验(P)
IL22RA1	MR-Egger	6.66	0.465	0.065
IL22RA1	IVW	11.42	0.179	0.065
IL15RA	MR-Egger	10.12	0.519	0.679
IL15RA	IVW	10.30	0.589	0.679
IL-1α	MR-Egger	6.05	0.735	0.251
IL-1α	IVW	7.56	0.672	0.251
caspase-8	MR-Egger	10.43	0.493	0.893
caspase-8	IVW	10.44	0.577	0.893

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