Xu Dongrui, Yang Xiaoyi, Wu Wenjuan, Yang Jiankang
School of Basic Medical Sciences, Dali University, Dali, Yunnan, People's Republic of China.
Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.
J Inflamm Res. 2024 Jul 9;17:4431-4441. doi: 10.2147/JIR.S463450. eCollection 2024.
Despite the availability of numerous therapies, the treatment of acne vulgaris remains challenging. Novel drug targets for acne vulgaris are still needed.
We conducted a Mendelian randomization analysis to explore possible drug targets for acne vulgaris. We utilized summary statistics obtained from the dataset of acne vulgaris, including 399,413 individuals of European ancestry. We gathered genetic instruments for 566 plasma proteins from genome-wide association studies. In order to strengthen the findings from Mendelian randomization, various methods were employed, including bidirectional Mendelian randomization analysis, Bayesian co-localization, phenotype scanning, and single-cell analysis. These methods facilitated the identification of reverse causality, the search for reported variant-trait associations, and the determination of the cell types that is the primary source of protein. Furthermore, using the plasma proteins in the deCODE cohort, we conducted a replication of the Mendelian randomization analysis as an external validation.
At the significance level of Bonferroni (P < 8.83×10), a protein-acne pair was discovered through Mendelian randomization analysis. In plasma, increasing TIMP4 (OR = 1.15; 95% CI, 1.09-1.21; P = 1.01×10) increased the risk of acne vulgaris. The absence of reverse causality was observed in the TIMP4 protein. According to Bayesian co-localization analysis, TIMP4 shared the same variant with acne vulgaris (PPH4 = 0.93). TIMP4 was replicated in deCODE cohort (OR = 1.17; 95% CI, 1.10-1.24; P = 1.48×10). Single-cell analysis revealed that TIMP4 was predominantly detected in myeloid cells in blood, and was detected in almost all cell types in skin tissue.
The integrative analysis revealed that the level of plasma TIMP4 has a direct influence on the risk of developing acne vulgaris. This implies that TIMP4 protein could serve as a potential target for the development of drugs aimed at treating acne vulgaris.
尽管有多种治疗方法可用，但寻常痤疮的治疗仍然具有挑战性。仍然需要针对寻常痤疮的新型药物靶点。
我们进行了孟德尔随机化分析，以探索寻常痤疮可能的药物靶点。我们利用从寻常痤疮数据集获得的汇总统计数据，其中包括399413名欧洲血统的个体。我们从全基因组关联研究中收集了566种血浆蛋白的遗传工具。为了加强孟德尔随机化的研究结果，采用了多种方法，包括双向孟德尔随机化分析、贝叶斯共定位、表型扫描和单细胞分析。这些方法有助于识别反向因果关系、寻找已报道的变异-性状关联以及确定作为蛋白质主要来源的细胞类型。此外，利用deCODE队列中的血浆蛋白，我们进行了孟德尔随机化分析的重复实验作为外部验证。
在Bonferroni显著性水平（P < 8.83×10）下，通过孟德尔随机化分析发现了一对蛋白质-痤疮关系。在血浆中，TIMP4水平升高（比值比 = 1.15；95%置信区间，1.09 - 1.21；P = 1.01×10）会增加寻常痤疮的风险。在TIMP4蛋白中未观察到反向因果关系。根据贝叶斯共定位分析，TIMP4与寻常痤疮共享相同的变异（后验概率 = 0.93）。TIMP4在deCODE队列中得到了重复验证（比值比 = 1.17；95%置信区间，1.10 - 1.24；P = 1.48×10）。单细胞分析显示，TIMP4主要在血液中的髓细胞中检测到，并且在皮肤组织的几乎所有细胞类型中都能检测到。
综合分析表明，血浆TIMP4水平对寻常痤疮的发病风险有直接影响。这意味着TIMP4蛋白可能成为开发治疗寻常痤疮药物的潜在靶点。
