GENETICALLY PREDICTED LIPOPROTEIN(A) IS ASSOCIATED WITH CORONARY ARTERY PLAQUE SEVERITY INDEPENDENT OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL

Therapeutic Area

ASCVD/CVD Risk Factors

Background

Elevated Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease, but mechanisms are debated. The role of Lp(a) in atherogenesis has been questioned by prior small studies showing a lack of association with markers of atherosclerosis, including carotid intima media thickness and coronary artery calcification. Some have hypothesized that the association between Lp(a) and atherosclerosis may depend on low-density lipoprotein cholesterol (LDL-C).

Methods

We examined participants of the Million Veteran Program who have undergone an invasive angiogram. The primary exposure was genetically predicted Lp(a), estimated by a validated polygenic score consisting of 43 single nucleotide variants at the LPA locus. The primary outcome was coronary artery plaque severity, categorized as normal, non-obstructive disease, 1-vessel disease, 2-vessel disease, and 3-vessel or left main disease. Multivariable multinomial regression was used to assess the association between genetically predicted Lp(a) and coronary plaque severity, independent of age, sex, LDL-C, lipid-lowering therapy, hypertension, diabetes, tobacco use, and genetic principal components. Similar logistic regression models were used to assess the overall risk for obstructive plaque. Odds ratios were calculated per 1 standard deviation increase in predicted Lp(a) and by comparing the top 20% to bottom 80%.

Results

Among 18,927 adults of genetically inferred European ancestry (mean age 66 years; 96.8% male), we observed significant associations between genetically predicted Lp(a) and all categories of obstructive plaque. The association was borderline significant for non-obstructive plaque. We observed a consistent pattern of increasing effect sizes for increasingly severe categories of atherosclerosis (Figure [A]). Participants with genetically predicted high Lp(a) were at significantly increased risk for obstructive plaque across LDL-C levels (Figure [B]).

Conclusions

Genetically predicted Lp(a) is positively associated with coronary plaque severity independent of LDL-C, consistent with Lp(a) promoting atherogenesis. However, Lp(a) may contribute more to plaque progression towards obstructive disease than to plaque initiation. Our findings suggest that Lp(a) reduction could protect against the development of obstructive coronary plaque beyond what might be achieved by LDL-C reduction alone.