Analysis of impact of type 1 diabetes on colorectal cancer by using two-sample Mendelian randomization

doi:10.3969/j.issn.1674-8115.2024.06.011

Abstract

Abstract:

Objective ·To investigate the potential causal relationship between type 1 diabetes and colorectal cancer by using Mendelian randomization (MR). Methods ·Two-sample bidirectional MR was used to investigate the causal relationship between type 1 diabetes and colorectal cancer. All research data were collected from the IEU Open GWAS Project database. The dataset of type 1 diabetes included 9 266 cases and 15 574 controls, with correlation analysis in 12 783 129 single nucleotide polymorphisms (SNPs); the dataset of colorectal cancer included 5 657 cases and 372 016 controls, with correlation analysis in 29 999 696 SNPs. The instrumental variables SNPs were screened. The results derived from the inverse-variance weighted (IVW) method were used as the main indicator of effect. The results derived from other four methods, namely MR-Egger regression, weighted median, simple mode, and weighted mode, were used as reference. Sensitivity was analyzed with the leave-one-out method. Heterogeneity was analyzed with Cochran's Q test by using both IVW and MR-Egger methods. Pleiotropy was analyzed with MR-pleiotropy function, and Steiger test was used for directional research. The colocation analysis was used to find out whether the causal relationship between type 1 diabetes and colorectal cancer was caused by the same SNP. The genetic correlation between 2 diseases was analyzed by using the linkage disequilibrium score regression (LDSC). All tests were analyzed by using R language software (version 4.3.1). Results ·After being screened, a total of 33 instrumental variables (SNPs) were used. The heterogeneity test results showed that there was heterogeneity among the SNPs (IVW and MR-Egger: P<0.05), so the effect evaluation was based on the results of the random effect model. MR analysis showed that type 1 diabetes had a significant causal effect on colorectal cancer (P<0.05) by using IVW, MR-Egger, weighted median and weighted mode. Sensitivity analysis showed that the results were stable. Pleiotropy was not detected in pleiotropy test (P>0.05). Steiger test showed that the effect of type 1 diabetes on colorectal cancer was not interfered with by the reverse effect. Reverse MR analysis showed no causal effect of colorectal cancer on type 1 diabetes (P>0.05). The results of colocalization analysis showed that the probability of H₄ hypothesis was 45.7%, and the causal relationship between the 2 diseases was not caused by the same SNP in the gene sequences. LDSC analysis demonstrated that there was no genetic correlation between the two diseases. Conclusion ·Type 1 diabetes may promote colorectal cancer, but colorectal cancer has no effect on type 1 diabetes.

Key words: colorectal cancer, type 1 diabetes, Mendelian randomization

CLC Number:

R735.3

YU Yang, MENG Dan, QIU Yiwen, YUAN Jian, ZHU Yingjie. Analysis of impact of type 1 diabetes on colorectal cancer by using two-sample Mendelian randomization[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024,(6): 755-761.

Figures/Tables 6

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References 27

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Exposure	Outcome	MR method	P value	OR (95%CI)
Type 1 diabetes	Colorectal cancer	IVW	0.003 4	1.000 7 (1.000 2‒1.001 1)
		MR-Egger	0.001 3	1.001 1 (1.000 5‒1.001 8)
		Weighted median	3.39×10^-5	1.001 0 (1.000 5‒1.001 4)
		Simple mode	0.671 9	1.000 3 (0.998 8‒1.001 9)
		Weighted mode	0.000 1	1.001 0 (1.000 6‒1.001 4)

Exposure	Outcome	MR method	P value	OR (95%CI)
Type 1 diabetes	Colorectal cancer	IVW	0.003 4	1.000 7 (1.000 2‒1.001 1)
		MR-Egger	0.001 3	1.001 1 (1.000 5‒1.001 8)
		Weighted median	3.39×10^-5	1.001 0 (1.000 5‒1.001 4)
		Simple mode	0.671 9	1.000 3 (0.998 8‒1.001 9)
		Weighted mode	0.000 1	1.001 0 (1.000 6‒1.001 4)

Exposure	Outcome	MR method	P value	OR (95%CI)
Colorectal cancer	Type 1 diabetes	IVW	0.373 2	0.013 8 (1.12×10^-6‒171.093 6)
		MR-Egger	0.643 6	0.000 3 (3.23×10^-18‒2.96×10^-10)
		Weighted median	0.273 9	0.000 8 (2.34×10^-9‒279.941 3)
		Simple mode	0.247 1	3.36×10^-6 (1.82×10^-14‒745.124 1)
		Weighted mode	0.266 8	4.42×10^-5 (4.18×10^-12‒426.783 2)

Exposure	Outcome	MR method	P value	OR (95%CI)
Colorectal cancer	Type 1 diabetes	IVW	0.373 2	0.013 8 (1.12×10^-6‒171.093 6)
		MR-Egger	0.643 6	0.000 3 (3.23×10^-18‒2.96×10^-10)
		Weighted median	0.273 9	0.000 8 (2.34×10^-9‒279.941 3)
		Simple mode	0.247 1	3.36×10^-6 (1.82×10^-14‒745.124 1)
		Weighted mode	0.266 8	4.42×10^-5 (4.18×10^-12‒426.783 2)

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