Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program
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. ,   On behalf of the VA Million Veteran Program*, 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 
Published: December 2018

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.