Two-sample bidirectional Mendelian randomization to analyze the causal relationship between blood metabolites and keloids
10.3760/cma.j.cn114453-20240306-00059
- VernacularTitle:两样本双向孟德尔随机化分析血液代谢物与瘢痕疙瘩的因果关系
- Author:
Qingyong CHEN
1
;
Liqiang LIN
;
Huaiqing LYU
;
Dongqing WANG
Author Information
1. 滨州医学院第二临床医学院耳鼻咽喉头颈外科，烟台 264003
- Keywords:
Keloid;
Blood metabolites;
Succinyl taurine;
Mendelian randomization;
Causality
- From:
Chinese Journal of Plastic Surgery
2024;40(9):1001-1010
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the causal relationship between blood metabolites and keloids.Methods:The study was a two-sample bidirectional Mendelian randomization (MR) analysis-based study. Blood metabolites of 7 824 adult volunteers and 8 299 participants and data related to 481 912 keloid patients were obtained from the genome-wide association studies (GWAS) Catalog database. Single nucleotide polymorphisms (SNPs) significantly associated with blood metabolites and keloids were screened for inclusion as instrumental variables in the MR analysis by setting a significance threshold of P<1.0×10 -5, chain imbalance analysis [ r2 = 0.001, kilobase pairs (kb) = 10, 000)], and the F statistic ( F≥10) . Five method of MR analysis, i.e., inverse variance weighting (IVW) as the main method and MR-Egger regression, weighted median, simple modeling, and weighted modeling as auxiliary method, were used to analyze the causal relationship between blood metabolites (exposure factors) and keloids (outcome variables) . Sensitivity analyses were performed on eligible blood metabolite SNPs to assess the reliability and stability of the findings: heterogeneity was assessed by Cochran Q-test and MR-Egger regression test, MR Egger intercept test to rule out horizontal pleiotropy, leave-one-out test to determine if the presence of a single SNP significantly affected the result of the MR analyses, MR-PRESSO method was used to test for outliers of SNPs, which were corrected by false discovery rate (FDR) (FDR <0.2) to control the false positive rate. Reverse MR analysis was performed with keloid as the exposure factor, and blood metabolites screened by the aforementioned MR analysis were used as outcome variables for effect analysis and sensitivity analysis. The data were analyzed using R 4.3.2 software and the TwoSampleMR program package therein, and the causal effect values of the MR analysis were expressed as the ratio ( OR) and 95% CI, with P<0.05 being considered as a statistically significant difference, i. e., the evidence of a potential causal effect was substantial. Forest plots, funnel plots, and scatter plots were constructed to visualize the result of MR analysis and sensitivity analysis. Results:A total of 1 400 blood metabolites with 34 843 SNPs were obtained from the GWAS Catalog database, all of which were consistent with the hypothesis that genetic variants are closely associated with exposure factors; a total of 24 197 210 SNPs were obtained from the keloid dataset. IVW analysis revealed that one blood metabolite, succinyl taurine (16 ∶ 1n-7), had 28 SNPs with keloid with a causal relationship ( OR=1.13, 95% CI 1.06-1.19, P<0.001, FDR=0.070) ; MR-Egger regression method ( OR = 1.11, 95% CI 1.04-1.19, P=0.005), weighted median method ( OR = 1.11, 95% CI 1.02-1.20, P=0.014) and weighted modeling method ( OR=1.12, 95% CI 1.04 to 1.20, P=0.004) analyses also showed that succinyl taurine (16 ∶ 1n-7) was a risk factor for keloid disease; the result of the simple modeling method only showed that the causal relationship between succinyl taurine (16 ∶ 1n-7) and keloid disease was not significant ( OR=1.10, 95% CI 0.85-1.41, P=0.485) . MR overall analysis showed a significant positive causal relationship between succinyl taurine (16 ∶ 1n-7) and keloid, i.e., elevated levels of succinyl taurine (16 ∶ 1n-7) were associated with an increased risk of keloid disease. Cochran Q-test ( Q = 26.98, P=0.465), MR-Egger regression test ( Q = 26.65, P = 0.428), MR-Egger intercept test ( P = 0.574), and MR-PRESSO composite test ( P=0.569) showed that there was no heterogeneity and horizontal pleiotropy among SNPs ( P>0.05) ; the leave-one-out test confirmed that individual SNPs did not have a significant effect on the overall result, indicating that the result had reliability and stability. The inverse MR analysis suggested that there was no causal relationship between keloid on succinyl taurine (16 ∶ 1n-7) (IVW: OR=0.98, 95% CI 0.93-1.04, P=0.490) . Conclusions:There is a significant positive causal relationship between the blood metabolite succinyl taurine (16 ∶ 1n-7) and keloids, and succinyl taurine (16 ∶ 1n-7) is a risk factor for keloid disease.
