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Background <p>High LDL-cholesterol (LDL-C) is a well-known risk factor for coronary artery disease (CAD). <i>PCSK9</i>,<i> HMGCR</i>,<i> NPC1L1</i>,<i> ACLY</i>, and <i>LDLR</i> gene have been reported as lipid lowering drug genes related to LDL-C lowering. However relevant Asian studies were rare.</p> Methods <p>We examined the causality between LDL-c drug target genes and CAD using Korean and Japanese data using the two sample Mendelian Randomization (MR) method. We conducted two-sample MR analysis of LDL-c lowering drug target genes (7 Single-nucleotide polymorphisms (SNP) in <i>PCSK9</i>, 6 SNPs in <i>HMGCR</i>, 5 SNPs in <i>NPC1L1</i>, 9 SNPs in <i>ACLY</i>, 3 SNPs in <i>LDLR</i>) and CAD. We used summary statistics data from the Korean Genome Epidemiology Study (KOGES) for LDL-C data, and Biobank of Japan (BBJ) for CAD data.</p> Results <p>For every 10&#xa0;mg/dl decrease in LDL-C determined by four significant SNPs in the <i>PCSK9</i> gene, the risk of CAD decreased by approximately 20% (OR = 0.80, 95% CI: 0.75–0.86). The risk of CAD decreased by 10% for every 10&#xa0;mg/dl decrease in LDL-C due to the six significant SNPs in the <i>HMGCR</i> gene (OR = 0.90, 95% CI: 0.86–0.94). Due to the two significant SNPs in the gene <i>LDLR</i>, the risk of CAD decreased by approximately 26% for every 10&#xa0;mg/dl decrease in LDL-C (OR = 0.74, 95% CI: 0.66–0.82). The combined effect on CAD showed the largest effect size for the PCSK9 gene and LDLR gene, and the reduced CAD risk induced by these two genes together was OR = 0.78 (95%CI, 0.74–0.83). Finally, the combined effect of all three genes (PCSK9, HMGCR, and LDLR) was OR = 0.85 (95%CI, 0.79–0.91).</p> Conclusion <p>LDL-C reduction estimated by SNPs in LDL-C lowering drug target genes significantly reduced the risk of CAD. We found the potential of using of proxy research design for clinical trials using LDL-C lowering drugs.</p>

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Causal relationship between drug target genes of LDL-cholesterol and coronary artery disease: drug target Mendelian randomization study

  • 期刊论文

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  • 发表日期：

    2025年3月13日

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  • Yongho Jee,
  • Jong Won Shin,
  • Mikyung Ryu,
  • Tae-Jin Song

摘要

Background

High LDL-cholesterol (LDL-C) is a well-known risk factor for coronary artery disease (CAD). PCSK9, HMGCR, NPC1L1, ACLY, and LDLR gene have been reported as lipid lowering drug genes related to LDL-C lowering. However relevant Asian studies were rare.

Methods

We examined the causality between LDL-c drug target genes and CAD using Korean and Japanese data using the two sample Mendelian Randomization (MR) method. We conducted two-sample MR analysis of LDL-c lowering drug target genes (7 Single-nucleotide polymorphisms (SNP) in PCSK9, 6 SNPs in HMGCR, 5 SNPs in NPC1L1, 9 SNPs in ACLY, 3 SNPs in LDLR) and CAD. We used summary statistics data from the Korean Genome Epidemiology Study (KOGES) for LDL-C data, and Biobank of Japan (BBJ) for CAD data.

Results

For every 10 mg/dl decrease in LDL-C determined by four significant SNPs in the PCSK9 gene, the risk of CAD decreased by approximately 20% (OR = 0.80, 95% CI: 0.75–0.86). The risk of CAD decreased by 10% for every 10 mg/dl decrease in LDL-C due to the six significant SNPs in the HMGCR gene (OR = 0.90, 95% CI: 0.86–0.94). Due to the two significant SNPs in the gene LDLR, the risk of CAD decreased by approximately 26% for every 10 mg/dl decrease in LDL-C (OR = 0.74, 95% CI: 0.66–0.82). The combined effect on CAD showed the largest effect size for the PCSK9 gene and LDLR gene, and the reduced CAD risk induced by these two genes together was OR = 0.78 (95%CI, 0.74–0.83). Finally, the combined effect of all three genes (PCSK9, HMGCR, and LDLR) was OR = 0.85 (95%CI, 0.79–0.91).

Conclusion

LDL-C reduction estimated by SNPs in LDL-C lowering drug target genes significantly reduced the risk of CAD. We found the potential of using of proxy research design for clinical trials using LDL-C lowering drugs.