Yan V Sun1,2, Scott M Damrauer3, Qin Hui1, Themistocles L Assimes4, Yuk-Lam Ho5, Pradeep Natarajan6, Derek Klarin7, Jie Huang5, Julie Lynch8,9, Scott L DuVall9,10, Saiju Pyarajan5, Jacqueline P Honerlaw5, J Michael Gaziano5,11, Kelly Cho5,11, Daniel J Rader12, Christopher J O'Donnell5,13, Philip S Tsao4, Peter W F Wilson14. 1. Department of Epidemiology, Emory University Rollins School of Public Health. 2. Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA. 3. Corporal Michael Crescenz VA Medical Center,University of Pennsylvania, Philadelphia, PA. 4. VA Palo Alto Health Care System, Department of Medicine, Stanford University School of Medicine, Stanford, CA. 5. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston. 6. Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA. Department of Medicine, Harvard Medical School, Program in Medical & Population Genetics, Broad Institute of Harvard & MIT, Cambridge. 7. Massachusetts General Hospital, Boston, MA, Broad Institute of Harvard & MIT, Cambridge. 8. University of Massachusetts College of Nursing & Health Sciences, Boston, MA. 9. Department of Veterans Affairs Salt Lake City Health Care System. 10. University of Utah, School of Medicine, Salt Lake City, UT. 11. Department of Medicine, Brigham and Women's Hospital, Boston, MA. 12. Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA. 13. Harvard Medical School, Boston, MA. 14. Atlanta VA Medical Center and Emory Clinical Cardiovascular Research Institute, Atlanta, GA.
Abstract
Background: Familial hypercholesterolemia (FH) is characterized by inherited high levels of low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Over a thousand low-frequency variants in LDLR, APOB and PCSK9 have been implicated in FH but few have been examined at the population level. We aim to estimate the phenotypic effects of a subset of FH variants on LDL-C and clinical outcomes among 331,107 multi-ethnic participants. Methods: We examined the individual and collective association between putatively pathogenic FH variants included on the MVP biobank array and the maximum LDL-C level over an interval of 15 years (maxLDL). We assessed the collective effect on clinical outcomes by leveraging data from 61.7 million clinical encounters. Results: We found 8 out of 16 putatively pathogenic FH variants with ≥30 observed carriers to be significantly associated with elevated maxLDL (9.4-80.2 mg/dL). Phenotypic effects were similar for European and African Americans despite substantial differences in carrier frequencies. Based on observed effects on maxLDL, we identified a total of 748 carriers (1:443) who had elevated maxLDL (36.5±1.4 mg/dL, p=1.2×10-152), and higher prevalence of clinical diagnoses related to hypercholesterolemia and CHD in a phenome-wide scan. Adjusted for maxLDL, FH variants collectively associated with higher prevalence of CHD (odds ratio, 1.59 [95% CI 1.36-1.86], p=1.1×10-8) but not peripheral artery disease. Conclusions: The distribution and phenotypic effects of putatively pathogenic FH variants were heterogeneous within and across variants. More robust evidence of genotype-phenotype associations of FH variants in multi-ethnic populations is needed to accurately infer at-risk individuals from genetic screening.
Background: Familial hypercholesterolemia (FH) is characterized by inherited high levels of low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Over a thousand low-frequency variants in LDLR, APOB and PCSK9 have been implicated in FH but few have been examined at the population level. We aim to estimate the phenotypic effects of a subset of FH variants on LDL-C and clinical outcomes among 331,107 multi-ethnic participants. Methods: We examined the individual and collective association between putatively pathogenic FH variants included on the MVP biobank array and the maximum LDL-C level over an interval of 15 years (maxLDL). We assessed the collective effect on clinical outcomes by leveraging data from 61.7 million clinical encounters. Results: We found 8 out of 16 putatively pathogenic FH variants with ≥30 observed carriers to be significantly associated with elevated maxLDL (9.4-80.2 mg/dL). Phenotypic effects were similar for European and African Americans despite substantial differences in carrier frequencies. Based on observed effects on maxLDL, we identified a total of 748 carriers (1:443) who had elevated maxLDL (36.5±1.4 mg/dL, p=1.2×10-152), and higher prevalence of clinical diagnoses related to hypercholesterolemia and CHD in a phenome-wide scan. Adjusted for maxLDL, FH variants collectively associated with higher prevalence of CHD (odds ratio, 1.59 [95% CI 1.36-1.86], p=1.1×10-8) but not peripheral artery disease. Conclusions: The distribution and phenotypic effects of putatively pathogenic FH variants were heterogeneous within and across variants. More robust evidence of genotype-phenotype associations of FH variants in multi-ethnic populations is needed to accurately infer at-risk individuals from genetic screening.
Entities:
Keywords:
Association Studies; Cardiovascular Disease; Genetic; Lipids and Cholesterol; coronary heart disease; familial hypercholesterolemia; low-density lipoprotein cholesterol; race and ethnicity
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