Two-sample bidirectional Mendelian randomization analysis of 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
- Publication Type:Journal Article
- Keywords:
Keloid;
Blood metabolites;
Succinyl taurine;
Mendelian randomization;
Causality
- From:
Chinese Journal of Plastic Surgery
2024;40(12):1331-1340
- 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. Data on blood metabolites were collected from 7 824 adult volunteers and 8 299 participants, alongside information related to 481 912 keloid patients obtained from the genome-wide association studies (GWAS) 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 methods of MR analysis were employed: inverse variance weighting (IVW) as the primary method, and MR-Egger regression, weighted median, simple modeling, and weighted modeling as auxiliary methods. These analyses aimed to determine 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 was utilized to rule out horizontal pleiotropy, while the leave-one-out test determined whether the presence of a single SNP significantly affected the results of the MR analyses. The MR-PRESSO method was used to identify outliers among 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, using the blood metabolites identified in the previous MR analysis as outcome variables for effect and sensitivity analyses. The data were analyzed using R version 4.3.2 and the TwoSampleMR package, with the causal effect values of the MR analysis expressed as odds ratio ( OR) and 95% confidence intervals ( CI). A P-value <0.05 was considered statistically significant, indicating substantial evidence of a potential causal effect. Forest plots, funnel plots, and scatter plots were constructed to visualize the results of the MR analysis and sensitivity analyses. Results:A total of 1 400 blood metabolites with 34 843 SNPs were obtained from the GWAS database, all of which support the hypothesis that genetic variants were closely associated with exposure factors. Additionally, 24 197 210 SNPs were obtained from the keloid dataset. The IVW analysis revealed that one blood metabolite, succinyl taurine (16∶1n-7) with 28 SNPs, was linked to keloid disease, demonstrating a causal relationship (O R=1.13, 95% CI 1.06-1.19, P<0.001, FDR=0.07). Further analyses using the MR-Egger regression method ( OR=1.11, 95% CI 1.04-1.19, P=0.005), the weighted median method ( OR=1.11, 95% CI 1.02-1.20, P=0.014) and weighted modeling method ( OR=1.12, 95% CI 1.04-1.20, P=0.004) also indicated that succinyl taurine (16∶1n-7) was a risk factor for keloid disease. However, the results from 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, suggesting that elevated levels of succinyl taurine (16∶1n-7) were associated with an increased risk of keloid disease. The 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) indicated no heterogeneity or 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 results, indicating the reliability and stability of the findings. 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). Conclusion: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.
