Background: Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry.
Methods: We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization-phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants.
Results: In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA-odds ratio and 95% CI for coronary heart disease 1.28 (1.16-1.41); cerebrovascular disease 1.14 (1.07-1.21); peripheral artery disease 1.22 (1.11-1.34); abdominal aortic aneurysm 1.28 (1.17-1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99-1.24) and cerebrovascular disease 1.06 (0.99-1.14) but similar for peripheral artery disease 1.16 (1.01-1.33) and abdominal aortic aneurysm 1.34 (1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10-1.62), mitral valve disorders 1.18 (1.09-1.27), congestive heart failure 1.12 (1.05-1.19), and chronic kidney disease 1.07 (1.01-1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94-1.25), mitral valve disorders 1.02 (0.89-1.16), congestive heart failure 1.02 (0.95-1.10), or chronic kidney disease 1.05 (0.99-1.12). Mendelian randomization-phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension.
Conclusions: Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.
Keywords: Mendelian randomization analysis; atherosclerosis; cardiovascular disease; heart failure; lipoprotein.