Association of Genetic Variants with Lipoprotein Levels and Cardiovascular Risk

Association of Genetic Variants with Lipoprotein Levels and Cardiovascular Risk
Joelle Ayoub, Pharm.D., Coborn’s Pharmacy-CHI St. Gabriel’s Health Family Medical Center

Background: Many studies have shown that a reduction in low-density lipoprotein cholesterol (LDL-C) is associated with lower risk of cardiovascular disease. It has been suggested that the reduction of cardiovascular risk is proportional to the reduction in LDL-C. However, cholesteryl ester transfer protein (CETP) inhibitors have not been shown to follow this pattern. These medications increase high-density lipoprotein cholesterol (HDL-C) and lower LDL-C, yet studies show no change in the reduction of risk of cardiovascular events. This raises question that the reduction in cardiovascular risk by lowering LDL-C may be dependent on the mechanism of which LDL-C is lowered.

Objective: This study was designed to evaluate the association between lower levels of LDL-C and the risk of cardiovascular events due to genetic variants that code for the target of CETP inhibitors in comparison to the gene code targets of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Study Design: The study was divided into three separate parts, each with its own objectives that contributed to the final conclusion. The first was a mendelian randomization study of 14 cohort or case-control studies (n=102,837) evaluating the association between CETP variants in genes that encode targets of CETP inhibitors, statins, ezetimibe and PCSK9 inhibitors, changes in LDL-C and apolipoprotein B (apoB) levels, and risk of cardiovascular events.

The second part was another mendelian randomization of the same studies which measured combined exposure to CETP and HMG-coA reductase (HMGCR) variants to evaluate changes in lipid and lipoprotein levels, and risk of cardiovascular events. This combination was compared to both HMGCR variants and CETP variants alone to determine if CETP effects on lipid changes are modified by HMGCR inhibition.

The third part of the study included external replication and validation analyses from a total of 48 studies from the coronary artery disease genome meta-analysis plus the coronary artery disease genetics consortium (n=184,305). This study compared variants and changes in LDL-C and apoB levels to assess if risk of cardiovascular events was dependent on the type of cholesterol particle carried.

CETP genetic scores were calculated by the sum of effects on HDL-C for all genetic variants included. Linear regression was utilized to determine the difference between biomarkers, and logistic regression was utilized to determine the associated risk with cardiovascular events. Analysis was performed separately for each study and then mendelian randomization estimates were obtained to determine the correlation between variants.

Results: The results of the first portion of the study showed participants with higher CETP scores had lower mean CETP activity, resulting in 4.62 mg/dL higher mean HDL-C, 2.15 mg/dL lower mean LDL-C, 1.39 mg/dL lower apoB, and a corresponding lower risk of cardiovascular events (OR 0.964 [95% CI 0.955-0.983] p<0.001).

The results of the second part of the study showed that scores above the median for both CETP and HMGCR variants (analogous to combination therapy with CETP inhibitor and a statin), resulted in a 4.81 mg/dL increase in HDL-C, 2.21 mg/dL decrease in LDL-C, 2.06 mg/dL decrease in apoB, and an overall statistically significant reduction in cardiovascular events (OR 0.946 [95% CI, 0.921-0.972], p<0.001) compared to when both CETP and HMGCR scores below the median. When above median CETP and HMGCR scores were compared to below median CETP and above median HMGCR scores, there was a 4.42 increase in HDL-C, 2.08 decrease in LDL-C, 0.59 decrease in apoB, and no significant difference in cardiovascular events (OR, 0.985 [95% CI, 0.959-1.012]; p=0.26).

In the external validation analyses in the third part of the study, 21 genetic variants were identified that had a discordonate reduction in LDL-C and apoB levels, compared to 36 variants that have shown to lower LDL-C and apoB proportionally. The genetic score consisting of the 21 variants was associated with a smaller risk reduction of coronary heart disease (CHD) per 10 mg/dL decrease in LDL-C compared to the risk reduced when including all 36 variants with the same lowering of LDL-C (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847];P = 2.9 × 10−8 fordifference). The effect of a 10 mg/dL decrease in apoB on CHD in the 21 variants versus the 36 variants was not significantly different (OR, 0.772 [95% CI, 0.701- 0.844] vs 0.788 [95% CI, 0.769-0.807]; P = 0.79 for difference).

Conclusions: The study determined genetic variants targeting CETP inhibitors were associated with higher HDL-C levels and concordant reductions in LDL-C and apoB levels, corresponding to a lower risk of cardiovascular events. The analysis suggests that the clinical benefit of lowering LDL-C is dependent on the mechanism in which LDL-C is lowered. The benefit of lowering LDL-C corresponds to the absolute reduction in concentration of apoB containing particles. Therapies such as statins, ezetimibe, and PCSK9 inhibitors that lower LDL-C by reducing the circulating LDL particles, should reduce the risk of cardiovascular events proportional to the absolute reduction in LDL-C, or apoB levels. In contrast, therapies that lower LDL-C without reducing apoB levels will have a decrease in cardiovascular risk proportional to the change in apoB level, not LDL-C.

Key Point: The clinical benefit of lowering LDL-C levels is likely dependent on the reduction in apoB containing lipoprotein particles. 

References:
Ference BA, Kastelien JJP, Ginsberg HN, et al. Association of Genetic Variants Related to CETP Inhibitors and Statins with Lipoprotein Levels and Cardiovascular Risk. JAMA. 2017;318(10):947-956.