Benjamin A Satterfield1, Ozan Dikilitas1, Maya S Safarova1, Shoa L Clarke2,3, Catherine Tcheandjieu2,3,4, Xiang Zhu2,5,6,7, Lisa Bastarache8, Eric B Larson9, Anne E Justice10, Ning Shang11, Elisabeth A Rosenthal12, Amy Sanghavi Shah13, Bahram Namjou-Khales14, Elaine M Urbina15, Wei-Qi Wei8, QiPing Feng16, Gail P Jarvik12, Scott J Hebbring17, Mariza de Andrade18, Teri A Manolio19, Themistocles L Assimes2, Iftikhar J Kullo1,20. 1. Department of Cardiovascular Medicine (B.A.S., O.D., M.S.S., I.J.K.), Mayo Clinic, Rochester, MN. 2. VA Palo Alto Health Care System, Palo Alto (S.L.C., C.T., X.Z., T.L.A.). 3. Division of Cardiovascular Medicine, Department of Medicine (S.L.C., C.T.). 4. Department of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA (C.T.). 5. Department of Statistics (X.Z.). 6. Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park (X.Z.). 7. Department of Statistics, Stanford University, CA (X.Z.). 8. Department of Biomedical Informatics, Vanderbilt University, Nashville, TN (L.B., W.-Q.W.). 9. Kaiser Permanente Washington Health Research Institutes, Seattle (E.B.L.). 10. Department of Population Health Sciences, Geisinger, Danville, PA (A.E.J.). 11. Department of Biomedical Informatics, Columbia University, New York, NY (N.S.). 12. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle (E.A.R., G.P.J.). 13. Division of Endocrinology (A.S.S.), Cincinnati Children's Hospital Medical Center & University of Cincinnati. 14. Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center & Department of Pediatrics, University of Cincinnati College of Medicine, OH (B.-N.K.). 15. Heart Institute (E.M.U.), Cincinnati Children's Hospital Medical Center & University of Cincinnati. 16. Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Q.F.). 17. Center for Precision Medicine, Marshfield Clinic Research Institute, WI (S.J.H.). 18. Department of Health Sciences Research (M.d.A.), Mayo Clinic, Rochester, MN. 19. Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, MD (T.A.M.). 20. Gonda Vascular Center (I.J.K.,), Mayo Clinic, Rochester, MN.
Abstract
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.
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.
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