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Causal relationship between drug target genes of LDL-cholesterol and coronary artery disease: drug target Mendelian
Yongho Jee1, Jong Won Shin2, Mikyung Ryu3
1Advanced Biomedical Research Institute, Ewha Womans University Seoul Hospital, Seoul, Republic of Korea.
Insights
High LDL-cholesterol (LDL-C) is a risk factor for coronary artery disease (CAD). Genetic analysis in Asian populations confirms that targeting LDL-C lowering genes like PCSK9 and LDLR significantly reduces CAD risk, supporting clinical trial designs.
Area of Science:
- Genetics
- Cardiovascular Disease Epidemiology
- Pharmacogenomics
Background:
- Elevated LDL-cholesterol (LDL-C) is a primary risk factor for coronary artery disease (CAD).
- Genes such as PCSK9, HMGCR, NPC1L1, ACLY, and LDLR are implicated in LDL-C regulation and are targets for lipid-lowering drugs.
- There is a scarcity of relevant studies focusing on Asian populations.
Purpose of the Study:
- To investigate the causal relationship between LDL-C lowering drug target genes and CAD risk.
- To analyze genetic data from Korean and Japanese populations to assess this relationship.
- To provide evidence supporting the use of genetic data as a proxy for clinical trials involving lipid-lowering drugs.
Main Methods:
- Utilized a two-sample Mendelian Randomization (MR) approach.
- Analyzed summary statistics from the Korean Genome Epidemiology Study (KOGES) for LDL-C data and the Biobank of Japan (BBJ) for CAD data.
- Examined single-nucleotide polymorphisms (SNPs) in PCSK9, HMGCR, NPC1L1, ACLY, and LDLR genes.
Main Results:
- A decrease in LDL-C levels, driven by specific SNPs in PCSK9, HMGCR, and LDLR genes, was significantly associated with reduced CAD risk.
- PCSK9 and LDLR showed the largest effect sizes, with combined SNPs reducing CAD risk by approximately 22%.
- The combined effect of PCSK9, HMGCR, and LDLR SNPs demonstrated a significant reduction in CAD risk.
Conclusions:
- Genetic evidence supports that LDL-C reduction through the identified drug target genes significantly lowers CAD risk.
- The findings suggest the utility of a proxy research design, leveraging genetic data, for future clinical trials on LDL-C lowering drugs.
- This study highlights the importance of genetic associations in understanding CAD etiology in Asian populations.
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.
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