Causal association between plasma phosphatidylethanolamine and risk of colorectal adenocarcinoma: a two-sample Mendelian randomization study

doi:10.3969/j.issn.1674-8115.2025.05.009

Abstract

Abstract:

Objective ·To employ the two-sample Mendelian randomization (TSMR) method, using genetic variants as instrumental variables, to investigate the causal relationship between phosphatidylethanolamine (PE) and the risk of colorectal adenocarcinoma. Methods ·The single-nucleotide polymorphism (SNP) data associated with PE and colorectal adenocarcinoma were obtained from the Medical Research Council Integrative Epidemiology Unit (MRC IEU) at the University of Bristol and the Finnish Biobank, respectively. A secondary data analysis was conducted using summary statistics from genome-wide association studies (GWAS), and genetic loci strongly associated with PE were selected as instrumental variables. Four Mendelian randomization (MR) methods, inverse-variance weighted (IVW) method, MR-Egger regression, weighted median (WME) method, and weighted mode (WM) method, were employed to assess the causal effect. The IVW method was used as the primary statistical approach, while MR-Egger, WME, and WM served as supplementary methods. Rigorous assessments for robustness included MR-Egger regression, MR-PRESSO global tests for horizontal pleiotropy, and Cochran′s Q test to evaluate heterogeneity. Results ·Ten instrumental variables were selected, and the Steiger test indicated that all PE-associated SNPs exhibited a consistent direction of causal effect on colorectal cancer. Among the 10 SNPs, rs102275 and rs9393903 showed the strongest positive associations with colorectal adenocarcinoma risk, with effect sizes of 0.45 (P=8.01×10^-5) and 0.82 (P=2.31×10^-2), respectively. Consistent findings from MR analyses demonstrated that PE elevated the risk of colorectal adenocarcinoma across all four methods. In the IVW analysis, the OR was 1.36 (95%CI 1.17‒1.59, P=7.24×10^-5). In the MR-Egger regression, the OR was 1.44 (95%CI 0.97‒2.14, P=1.12×10^-1). In the WEM analysis, the OR was 1.33 (95%CI 1.07‒1.65, P=8.81×10^-3). In the WM analysis, the OR was 1.41 (95%CI 1.12‒1.77, P=1.70×10^-2). Cochran′s Q test revealed no heterogeneity among the effect estimates of the 10 SNPs on colorectal adenocarcinoma. Both MR-Egger regression intercept and MR-PRESSO test indicated no evidence of horizontal pleiotropy among the SNPs. Leave-one-out analysis showed overlapping confidence intervals after excluding any single SNP, indicating that the results were not sensitive to individual SNPs and were highly robust. Conclusions ·There is a causal association between circulating PE levels and the risk of colorectal adenocarcinoma. A genetically predicted increase of one standard deviation in plasma PE levels is associated with a 1.36-fold higher risk of developing colorectal adenocarcinoma (95%CI 1.17‒1.59, P=7.24×10^-5).

Key words: colorectal adenocarcinoma, phosphatidylethanolamine, two-sample mendelian randomization, causal association, genome-wide association study

CLC Number:

R735.3

XU Ling, HUANGFU Yuchan, SHEN Lisong, MA Yanhui. Causal association between plasma phosphatidylethanolamine and risk of colorectal adenocarcinoma: a two-sample Mendelian randomization study[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(5): 605-613.

Figures/Tables 6

TrendMD

References 47

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SNP	Chr	Position	Effect allele	Other allele	EAF	β	SE	P value	Nearby gene	R²	F value	SteigerP value
rs102275	11	61790331	C	T	0.35	-0.18	0.01	4.40×10^-66	TMEM258	0.020 9	202.64	8.47×10^-57
rs10781444	9	77534256	C	T	0.80	0.06	0.01	3.10×10^-6	GNA14	0.001 6	14.69	1.48×10^-5
rs1087299	4	184305068	C	T	0.33	0.05	0.01	5.41×10^-6	MYL12BP2	0.001 5	14.17	9.06×10^-6
rs11254897	10	6942964	G	A	0.06	0.09	0.02	6.40×10^-6	LOC105376387	0.001 5	13.79	3.20×10^-5
rs1532085	15	58391167	G	A	0.61	-0.11	0.01	3.01×10^-27	ALDH1A2	0.008 4	79.73	2.58×10^-25
rs17395349	2	132439386	A	G	0.05	-0.11	0.02	2.00×10^-6	GPR39	0.001 6	15.38	7.45×10^-6
rs1800588	15	58431476	T	C	0.22	0.14	0.01	1.10×10^-31	LIPC	0.009 8	94.84	9.27×10^-30
rs75933914	1	51296770	A	G	0.03	0.13	0.03	8.70×10^-6	TTC39A LOC124904177	0.001 4	13.63	4.65×10^-5
rs7655751	4	148712269	T	C	0.21	-0.06	0.01	8.30×10^-7	LOC107986195	0.001 9	16.86	4.04×10^-6
rs9393903	6	11042676	A	G	0.23	0.08	0.01	4.00×10^-12	ELOVL2	0.003 5	33.24	3.13×10^-10

SNP	Chr	Position	Effect allele	Other allele	EAF	β	SE	P value	Nearby gene	R²	F value	SteigerP value
rs102275	11	61790331	C	T	0.35	-0.18	0.01	4.40×10^-66	TMEM258	0.020 9	202.64	8.47×10^-57
rs10781444	9	77534256	C	T	0.80	0.06	0.01	3.10×10^-6	GNA14	0.001 6	14.69	1.48×10^-5
rs1087299	4	184305068	C	T	0.33	0.05	0.01	5.41×10^-6	MYL12BP2	0.001 5	14.17	9.06×10^-6
rs11254897	10	6942964	G	A	0.06	0.09	0.02	6.40×10^-6	LOC105376387	0.001 5	13.79	3.20×10^-5
rs1532085	15	58391167	G	A	0.61	-0.11	0.01	3.01×10^-27	ALDH1A2	0.008 4	79.73	2.58×10^-25
rs17395349	2	132439386	A	G	0.05	-0.11	0.02	2.00×10^-6	GPR39	0.001 6	15.38	7.45×10^-6
rs1800588	15	58431476	T	C	0.22	0.14	0.01	1.10×10^-31	LIPC	0.009 8	94.84	9.27×10^-30
rs75933914	1	51296770	A	G	0.03	0.13	0.03	8.70×10^-6	TTC39A LOC124904177	0.001 4	13.63	4.65×10^-5
rs7655751	4	148712269	T	C	0.21	-0.06	0.01	8.30×10^-7	LOC107986195	0.001 9	16.86	4.04×10^-6
rs9393903	6	11042676	A	G	0.23	0.08	0.01	4.00×10^-12	ELOVL2	0.003 5	33.24	3.13×10^-10

SNP	β	SE	P value
rs102275	0.45	0.11	8.01×10^-5
rs10781444	0.47	0.44	2.89×10^-1
rs1087299	-0.01	0.44	9.87×10^-1
rs11254897	0.51	0.43	2.42×10^-1
rs1532085	0.13	0.18	4.70×10^-1
rs17395349	-0.41	0.53	4.42×10^-1
rs1800588	0.07	0.16	6.48×10^-1
rs75933914	0.77	0.61	2.01×10^-1
rs7655751	0.48	0.50	3.34×10^-1
rs9393903	0.82	0.36	2.31×10^-2
All IVW	0.31	0.08	7.24×10^-5
All MR-Egger	0.36	0.20	1.12×10^-1

SNP	β	SE	P value
rs102275	0.45	0.11	8.01×10^-5
rs10781444	0.47	0.44	2.89×10^-1
rs1087299	-0.01	0.44	9.87×10^-1
rs11254897	0.51	0.43	2.42×10^-1
rs1532085	0.13	0.18	4.70×10^-1
rs17395349	-0.41	0.53	4.42×10^-1
rs1800588	0.07	0.16	6.48×10^-1
rs75933914	0.77	0.61	2.01×10^-1
rs7655751	0.48	0.50	3.34×10^-1
rs9393903	0.82	0.36	2.31×10^-2
All IVW	0.31	0.08	7.24×10^-5
All MR-Egger	0.36	0.20	1.12×10^-1

Outcome	MR method	OR (95%CI)	P value	P value (Cochran′s Q)
Colorectal adenocarcinoma	IVW	1.36 (1.17‒1.59)	7.24×10^-5	0.363
Colorectal adenocarcinoma	MR-Egger	1.44 (0.97‒2.14)	1.12×10^-1	0.283
Colorectal adenocarcinoma	WME	1.33 (1.07‒1.65)	8.81×10^-3	‒
Colorectal adenocarcinoma	WM	1.41 (1.12‒1.77)	1.70×10^-2	‒