Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels

Abstract

Background: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation.

Objectives: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD.

Methods: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD.

Results: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk.

Conclusions: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.

Keywords: coronary heart disease; genetics; phenome-wide association study; single nucleotide polymorphism.

FIGURE 1. Study Design

This study included 1 primary and 2 secondary analyses to estimate the effect of a lipoprotein(a) (Lp[a]) on a range of outcomes. ARIC = Atherosclerosis Risk in Communities; CARDIoGRAM = Coronary ARtery DIsease Genome wide Replication and Meta-analysis; CHARGE-HF = Cohorts for Heart and Aging Research in Genomic Epidemiology – Heart Failure Consortium; CKDGen = Chronic Kidney Disease Genetics Consortium; DIAGRAM = DIAbetes Genetics Replication And Meta-analysis; DNA = deoxyribonucleic acid; GIANT = Genetic Investigation of ANthropometric Traits; GLGC = Global Lipids Genetics Consortium; MAGIC = Meta-Analyses of Glucose and Insulin-related traits Consortium; MIGen = Myocardial Infarction Genetics.

FIGURE 2. Associations of Genetically Lowered Lp(a) With a Range of Diseases

While 1 SD genetically lowered Lp(a) level was significantly associated with reduced risk of coronary heart disease, stroke, aortic stenosis, heart failure, chronic kidney disease, and peripheral vascular disease, there was no significant association seen for 3 other cardiometabolic disorders as well as 28 other diseases. COPD = chronic obstructive pulmonary disease; OR = odds ratio; other abbreviations as in Figure 1.

FIGURE 3. Association of Genetically Lowered Lp(a) (1 SD Decrease) with Cardiometabolic Quantitative Traits

Genetically lowered Lp(a) was associated with reductions in total and low-density lipoprotein (LDL) cholesterol as well as improved kidney function. There were no other significant associations seen between 1 SD decrease in Lp(a) and other traits measured. BMI = body mass index; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; HbA_1c = glycosylated hemoglobin; HDL = high-density lipoprotein; SBP = systolic blood pressure; SNP = single nucleotide polymorphism; other abbreviations as in Figures 1 and 2.

FIGURE 4. Effect of LPA Variants on Lp(a) and CHD

Logistic regression was used to test the association of coronary heart disease (CHD) as an outcome and DNA sequence variant as a predictor, adjusting for sex and principal components of ancestry, with additional adjustment for array type and age in UK Biobank. The impact of LPA variation on CHD risk is directly proportional to its effect on circulating Lp(a) levels. Abbreviations as in Figure 1.

CENTRAL ILLUSTRATION. Impact of Genetically Mediated Lp(a) Reduction (1 SD) on Disease Risk

This study to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma lipoprotein (Lp) (a) and risk for coronary heart disease. Estimates were derived in UK Biobank using logistic regression, adjusted for age, sex, 10 principal components and array type, with the exception of chronic kidney disease (CKD), which was derived using summary statistics from CKDGen. One SD genetically lowered Lp(a) level was associated with reduced risk of 5 cardiometabolic diseases. Although the estimate for CKD did not reach Bonferroni adjusted significance, it was included as a significant outcome as the underlying trait (estimated glomerular filtration rate) was significantly associated with Lp(a) (p = 2 × 10⁻⁵). OR = odds ratio.