Proteome-wide Mendelian randomization identifies potential therapeutic targets for nonalcoholic fatty liver diseases

作者全名：Li, Junhang; Ma, Xiang; Yin, Cuihua

作者地址：[Li, Junhang; Yin, Cuihua] Dali Prefecture Third Peoples Hosp, Dept Ultrasonog, Dali, Yunnan, Peoples R China; [Ma, Xiang] Chongqing Med Univ, Chongqing, Peoples R China

通信作者：Yin, CH (通讯作者)，Dali Prefecture Third Peoples Hosp, Dept Ultrasonog, Dali, Yunnan, Peoples R China.

来源：SCIENTIFIC REPORTS

ESI学科分类：Multidisciplinary

WOS号：WOS:001230489600003

JCR分区：Q1

影响因子：3.8

年份：2024

卷号：14

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Nonalcoholic fatty liver disease; Mendelian randomization; Protein; Therapeutic target; Phewas

摘要：Nonalcoholic fatty liver disease (NAFLD) is the predominant cause of liver pathology. Current evidence highlights plasma proteins as potential therapeutic targets. However, their mechanistic roles in NAFLD remain unclear. This study investigated the involvement of specific plasma proteins and intermediate risk factors in NAFLD progression. Two-sample Mendelian randomization (MR) analysis was conducted to examine the association between plasma proteins and NAFLD. Colocalization analysis determined the shared causal variants between the identified proteins and NAFLD. The MR analysis was applied separately to proteins, risk factors, and NAFLD. Mediator shares were computed by detecting the correlations among these elements. Phenome-wide association studies (phewas) were utilized to assess the safety implications of targeting these proteins. Among 1,834 cis-protein quantitative trait loci (cis-pQTLs), after-FDR correction revealed correlations between the plasma levels of four gene-predicted proteins (CSPG3, CILP2, Apo-E, and GCKR) and NAFLD. Colocalization analysis indicated shared causal variants for CSPG3 and GCKR in NAFLD (posterior probability > 0.8). Out of the 22 risk factors screened for MR analysis, only 8 showed associations with NAFLD (p <= 0.05), while 4 linked to CSPG3 and GCKR. The mediator shares for these associations were calculated separately. Additionally, reverse MR analysis was performed on the pQTLs, risk factors, and NAFLD, which exhibited a causal relationship with forward MR analysis. Finally, phewas summarized the potential side effects of associated-targeting proteins, including CSPG3 and GCKR. Our research emphasized the potential therapeutic targets for NAFLD and provided modifiable risk factors for preventing NAFLD.

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