Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. (December 2018)

• Record Type: Journal Article
• Authors: Sun, Yan V.; Damrauer, Scott M.; Hui, Qin; Assimes, Themistocles L.; Ho, Yuk-Lam; Natarajan, Pradeep; Klarin, Derek; Huang, Jie; Lynch, Julie; DuVall, Scott L.; Pyarajan, Saiju; Honerlaw, Jacqueline P.; Gaziano, J. Michael; Cho, Kelly; Rader, Daniel J.; O'Donnell, Christopher J.; Tsao, Philip S.; Wilson, Peter W. F.; Ramoni, Rachel; Breeling, Jim; Chang, Kyong-Mi; Huang, Grant; Muralidhar, Sumitra; Muralidhar, Sumitra; Moser, Jennifer; Whitbourne, Stacey B.; Brewer, Jessica V.; Concato, John; Warren, Stuart; Argyres, Dean P.; Stephens, Brady; Brophy, Mary T.; Humphries, Donald E.; Do, Nhan; Shayan, Shahpoor; Nguyen, Xuan-Mai T.; Hauser, Elizabeth; Sun, Yan; Zhao, Hongyu; Wilson, Peter; McArdle, Rachel; Dellitalia, Louis; Harley, John; Whittle, Jeffrey; Beckham, Jean; Wells, John; Gutierrez, Salvador; Gibson, Gretchen; Kaminsky, Laurence; Villareal, Gerardo; Kinlay, Scott; Xu, Junzhe; Hamner, Mark; Haddock, Kathlyn Sue; Bhushan, Sujata; Iruvanti, Pran; Godschalk, Michael; Ballas, Zuhair; Buford, Malcolm; Mastorides, Stephen; Klein, Jon; Ratcliffe, Nora; Florez, Hermes; Swann, Alan; Murdoch, Maureen; Sriram, Peruvemba; Yeh, Shing Shing; Washburn, Ronald; Jhala, Darshana; Aguayo, Samuel; Cohen, David; Sharma, Satish; Callaghan, John; Oursler, Kris Ann; Whooley, Mary; Ahuja, Sunil; Gutierrez, Amparo; Schifman, Ronald; Greco, Jennifer; Rauchman, Michael; Servatius, Richard; Oehlert, Mary; Wallbom, Agnes; Fernando, Ronald; Morgan, Timothy; Stapley, Todd; Sherman, Scott; Anderson, Gwenevere; Tsao, Philip; Sonel, Elif; Boyko, Edward; Meyer, Laurence; Gupta, Samir; Fayad, Joseph; Hung, Adriana; Lichy, Jack; Hurley, Robin; Robey, Brooks; Striker, Robert;
• Is Part Of: Circulation. Volume 11:Number 12(2018)
• Publication Date: 2018-12
• Subjects: atherosclerosis -- coronary disease -- familial hypercholesterolemia -- genetic testing -- pathogenicity -- PheWAS; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.118.002192
• Languages: English
• ISSNs: 2574-8300

Abstract

Abstract : 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. Abstract : Supplemental Digital Content is available in the text.