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Background <p>Kawasaki disease (KD) is a vasculitis of unknown etiology. Oxidative stress is hypothesized to play a key role in KD pathogenesis. However, the specific genes and mechanisms underlying this association remain unclear.</p> Methods <p>In this study, we employed a two-step strategy combining SMR screening and differential expression gene (DEG) validation to identify oxidative stress-related genes associated with KD. First, we used the Mendelian randomization approach (SMR) to assess causal associations between genes and KD, integrating data from genome-wide association studies (GWAS), blood methylation quantitative trait loci (mQTLs), expression QTLs (eQTLs), and proteomic QTLs (pQTLs) obtained from public databases. Subsequently, we validated the candidate genes through DEG analysis in two independent KD patient cohorts (GSE68004 and GSE100154).</p> Results <p>Integrated analysis identified <i>SLC9A1</i> and <i>RPS6KA1</i> as candidate risk loci. Genetically predicted upregulation of <i>SLC9A1</i> expression (OR = 7.25, <i>P</i> = 0.02) and RPS6KA1 protein abundance (OR = 2.82, <i>P</i> = 0.01) was causally associated with increased KD risk. These findings were validated in clinical cohorts, where both genes were consistently upregulated in KD patients across GSE68004 and GSE100154 (all <i>P</i> &lt; 0.05), aligning with SMR predictions. Additionally, <i>APRT</i> emerged as a multi-omics candidate, demonstrating consistent causal evidence across mQTL, eQTL, and pQTL layers, supported by downregulation in the GSE68004 cohort.</p> Conclusions <p>This study highlights prioritized <i>SLC9A1</i> and <i>RPS6KA1</i> as potential causal drivers of KD, and highlighted <i>APRT</i> as a potential multi-layer regulatory target. These findings provide genetic evidence linking oxidative stress pathways to KD pathogenesis, offering novel targets for therapeutic intervention.</p> Clinical trial number <p>Not applicable.</p>

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Oxidative stress-related genes in Kawasaki disease: a multi-omics Mendelian randomization study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Jingwei Sun,
  • Nan Dong,
  • Dong Qi,
  • Mengjin Wang,
  • Quming Zhao

摘要

Background

Kawasaki disease (KD) is a vasculitis of unknown etiology. Oxidative stress is hypothesized to play a key role in KD pathogenesis. However, the specific genes and mechanisms underlying this association remain unclear.

Methods

In this study, we employed a two-step strategy combining SMR screening and differential expression gene (DEG) validation to identify oxidative stress-related genes associated with KD. First, we used the Mendelian randomization approach (SMR) to assess causal associations between genes and KD, integrating data from genome-wide association studies (GWAS), blood methylation quantitative trait loci (mQTLs), expression QTLs (eQTLs), and proteomic QTLs (pQTLs) obtained from public databases. Subsequently, we validated the candidate genes through DEG analysis in two independent KD patient cohorts (GSE68004 and GSE100154).

Results

Integrated analysis identified SLC9A1 and RPS6KA1 as candidate risk loci. Genetically predicted upregulation of SLC9A1 expression (OR = 7.25, P = 0.02) and RPS6KA1 protein abundance (OR = 2.82, P = 0.01) was causally associated with increased KD risk. These findings were validated in clinical cohorts, where both genes were consistently upregulated in KD patients across GSE68004 and GSE100154 (all P < 0.05), aligning with SMR predictions. Additionally, APRT emerged as a multi-omics candidate, demonstrating consistent causal evidence across mQTL, eQTL, and pQTL layers, supported by downregulation in the GSE68004 cohort.

Conclusions

This study highlights prioritized SLC9A1 and RPS6KA1 as potential causal drivers of KD, and highlighted APRT as a potential multi-layer regulatory target. These findings provide genetic evidence linking oxidative stress pathways to KD pathogenesis, offering novel targets for therapeutic intervention.

Clinical trial number

Not applicable.