Identification of risk biomarkers of gallbladder cancer through plasma proteome-wide Mendelian randomization analysis

doi:10.3969/j.issn.1674-8115.2026.07.016

Abstract

Abstract:

Objective ·To systematically evaluate the potential causal associations between plasma protein levels and the risk of gallbladder cancer (GBC) through proteome-wide Mendelian randomization analysis. Methods ·GBC genome-wide association study (GWAS) summary data from Japan, Republic of Korea, Finland, and the UK were used for a multi-ethnic meta-analysis to obtain genetic effect estimates for GBC. Summary-level GWAS data of plasma proteomes from two large-scale proteomic studies (deCODE and UKBPPP) were used as exposure variables. A generalized summary-data-based Mendelian randomization (GSMR) analysis was performed to assess the causal associations between each plasma protein level and GBC risk, and significant associations were validated by two-sample Mendelian randomization (TSMR). Significant associations discovered between plasma proteins and GBC risk were also validated using colocalization analysis. Results ·GSMR analysis identified 56 plasma proteins significantly causally associated with GBC risk in the deCODE cohort (P_adj<0.001), of which 31 proteins were replicated in another independent proteomic cohort (UKBPPP). TSMR further confirmed two proteins with robust causal associations with GBC. Among these two proteins, higher plasma complement receptor 2 (CR2) levels were significantly associated with a reduced risk of GBC (OR=0.258, 95%CI 0.071‒0.935, P=0.039), whereas higher plasma neural cell adhesion molecule 1 (NCAM1) levels were associated with an increased risk of GBC (OR=2.306, 95%CI 1.432‒3.713, P<0.001). The Bayesian colocalization analysis showed strong colocalization between protein quantitative trait loci (pQTL) variants of CR2 and NCAM1 and GBC risk variants. Conclusion ·Two potential risk-related biomarkers for GBC, CR2, and NCAM1, were identified in the whole plasma proteome. The elevated CR2 level is linked to a lower risk of GBC, while the elevated NCAM1 level corresponds to a higher risk.

Key words: gallbladder cancer, Mendelian randomization analysis, proteomics, biomarker, complement receptor 2 (CR2), neural cell adhesion molecule 1 (NCAM1)

CLC Number:

R735.8

Tang Qiuyi, Dong Wenjun, Hu Chunnan, Gong Wei. Identification of risk biomarkers of gallbladder cancer through plasma proteome-wide Mendelian randomization analysis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(7): 972-980.

Figures/Tables 7

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References 29

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Phenotype	Region	Population	Case/n	Sample size/n	DOI
GBC	Japan	East Asia	41	907	10.1038/jhg.2012.9
GBC	Republic of Korea	East Asia	12	72 298	10.1016/j.xgen.2022.100189
GBC	Finland	Europe	84	259 667	10.1038/s41586-022-05473-8
GBC	The UK	Europe	289	400 583	10.5281/zenodo.8011558

Phenotype	Region	Population	Case/n	Sample size/n	DOI
GBC	Japan	East Asia	41	907	10.1038/jhg.2012.9
GBC	Republic of Korea	East Asia	12	72 298	10.1016/j.xgen.2022.100189
GBC	Finland	Europe	84	259 667	10.1038/s41586-022-05473-8
GBC	The UK	Europe	289	400 583	10.5281/zenodo.8011558

Gene	β	SE	P value	OR(95%CI)	SNP/n
CR2	-1.356	0.657	0.039	0.258 (0.071‒0.935)	4
NCAM1	0.836	0.243	<0.001	2.306 (1.432‒3.713)	4

Gene	β	SE	P value	OR(95%CI)	SNP/n
CR2	-1.356	0.657	0.039	0.258 (0.071‒0.935)	4
NCAM1	0.836	0.243	<0.001	2.306 (1.432‒3.713)	4

Analysis	Exposure	Source	Outcome	Estimate β	SE	OR(95%CI)	P value
TSMR	CR2	deCODE	GBC.UKB	-0.304	0.254	0.738 (0.449‒1.214)	0.231
TSMR	CR2	UKBPPP	GBC.UKB	-0.302	0.219	0.739 (0.481‒1.136)	0.168
TSMR	NCAM1	deCODE	GBC.UKB	0.617	0.253	1.853 (1.129‒3.043)	0.015
TSMR	NCAM1	UKBPPP	GBC.UKB	0.459	0.231	1.582 (1.006‒2.489)	0.047