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Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program

2018; Wolters Kluwer; Volume: 11; Issue: 12 Linguagem: Inglês

10.1161/circgen.118.002192

2574-8300

Yan V. Sun, Scott M. Damrauer, Qin Hui, Themistocles L. Assimes, Yuk‐Lam Ho, Pradeep Natarajan, Derek Klarin, Jie Huang, Julie A. Lynch, Scott L. DuVall, Saiju Pyarajan, Jacqueline Honerlaw, J. Michael Gaziano, Kelly Cho, Daniel J. Rader, Christopher J. O’Donnell, Philip S. Tsao, Peter W.F. Wilson, Rachel Ramoni, Jim Breeling, Kyong–Mi Chang, Grant D. Huang, Sumitra Muralidhar, Sumitra Muralidhar, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, John Concato, Stuart Warren, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Xuan‐Mai T. Nguyen, Elizabeth R. Hauser, Yan V. Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis J. Dell’Italia, John B. Harley, Jeff Whittle, Jean C. Beckham, John M. Wells, Salvador Gutierrez, Gretchen Gibson, Laurence S. Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark B. Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair K. Ballas, Malcolm Buford, Stephen Mastorides, Jon B. Klein, Nora Ratcliffe, Hermes Flórez, Alan C. Swann, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Ronald G. Washburn, Darshana Jhala, Samuel M. Aguayo, David Cohen, Satish Sharma, John T. Callaghan, Kris Ann Oursler, Mary A. Whooley, Sunil K. Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard J. Servatius, Mary E. Oehlert, Agnes Wallbom, Ronald Fernando, Timothy R. Morgan, Todd Stapley, Scott E. Sherman, Gwenevere Anderson, Philip S. Tsao, Elif Sonel, Edward J. Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana M. Hung, Jack Lichy, Robin A. Hurley, R. Brooks Robey, Rob Striker,

Genetic Associations and Epidemiology

Background: Familial hypercholesterolemia (FH) is characterized by inherited high levels of LDL-C (low-density lipoprotein cholesterol) and premature coronary heart disease. 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 multiethnic participants. Methods: We examined the individual and collective association between putatively pathogenic FH variants included on the Million Veteran Program 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 Americans 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 coronary heart disease in a phenome-wide scan. Adjusted for maxLDL, FH variants collectively associated with higher prevalence of coronary heart disease (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 multiethnic populations is needed to accurately infer at-risk individuals from genetic screening.