Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol

Yiyi Zhang; Jacqueline S. Dron; Brandon K. Bellows; Amit V. Khera; Junxiu Liu; Pallavi P. Balte; Elizabeth C. Oelsner; Sami Samir Amr; Matthew S. Lebo; Anna Nagy; Gina M. Peloso; Pradeep Natarajan; Jerome I. Rotter; Cristen Willer; Eric Boerwinkle; Christie M. Ballantyne; Pamela L. Lutsey; Myriam Fornage; Donald M. Lloyd-Jones; Lifang Hou; Bruce M. Psaty; Joshua C. Bis; James S. Floyd; Ramachandran S. Vasan; Nancy L. Heard-Costa; April P. Carson; Michael E. Hall; Stephen S. Rich; Xiuqing Guo; Dhruv S. Kazi; Sarah D. de Ferranti; Andrew E. Moran

doi:10.1001/jamacardio.2023.5366

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February 1, 2024

Important paper that shows why genetic testing for FH variants is clinically of low value

James Stein, MD | UW-Madison

This is really important work. It confirms the low prevalence of FH variants among people with elevated LDL-C (over 190 mg/dl) and clarifies that the CVD risk increase associated with a variant is due to long-term exposure to high LDL-C (LDL-cholesterol-years, like "pack-years"). Based on this and previous reports, it is very hard to believe that genetic testing will be useful until it becomes much less expensive and more easy to perform in a clinical setting. But even then, with only 2.5% prevalence in people with LDL-C>=190 mg/dL (who need to be treated anyway) and 0.3% prevalence in people with LDL-C of 130-189 - it's a lot of testing for a very small yield. Did the authors look at how knowing a test result could improve discrimination or reclassification of risks? Then there is the poor man's genetic test: the electronic medical record, which allows the clinician and patient to see 10, 20, or even more years of lipid panels with a click of button, which is instantaneous and free. Though less precise, it's pretty easy to identify a patient with lifelong high LDL-C (or non-HDL-C) values. With a limited health care budget, genetic testing for FH variants seems to be low value. But work like this is really important and I appreciate seeing it done so well. Thanks for advancing our understanding - Jim

CONFLICT OF INTEREST: None Reported

Original Investigation

January 31, 2024

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol

驰颈测颈听窜丑补苍驳,听笔丑顿¹; Jacqueline S.听Dron,听PhD^2,3; Brandon K.听Bellows,听PharmD, MS¹; et al Amit V.听Khera,听MD, MSc^2,4,5; 闯耻苍虫颈耻听尝颈耻,听笔丑顿⁶; Pallavi P.听Balte,听PhD¹; Elizabeth C.听Oelsner,听MD¹; Sami Samir听Amr,听PhD^7,8; Matthew S.听Lebo,听PhD^7,8; 础苍苍补听狈补驳测,听惭厂⁸; Gina M.听Peloso,听PhD⁹; Pradeep听Natarajan,听MD, MMSc^2,4,10; Jerome I.听Rotter,听MD¹¹; 颁谤颈蝉迟别苍听奥颈濒濒别谤,听笔丑顿^12,13,14; 贰谤颈肠听叠辞别谤飞颈苍办濒别,听笔丑顿¹⁵; Christie M.听Ballantyne,听MD¹⁶; Pamela L.听Lutsey,听PhD¹⁷; 惭测谤颈补尘听贵辞谤苍补驳别,听笔丑顿¹⁸; Donald M.听Lloyd-Jones,听MD, ScM¹⁹; Lifang听Hou,听MD, PhD¹⁹; Bruce M.听Psaty,听MD, PhD^20,21,22; Joshua C.听Bis,听PhD²⁰; James S.听Floyd,听MD, MS^20,21; Ramachandran S.听Vasan,听MD^23,24,25; Nancy L.听Heard-Costa,听PhD, MPH²⁶; April P.听Carson,听PhD²⁷; Michael E.听Hall,听MD, MS²⁷; Stephen S.听Rich,听PhD²⁸; 齿颈耻辩颈苍驳听骋耻辞,听笔丑顿¹¹; Dhruv S.听Kazi,听MD, MSc^4,29; Sarah D.听de Ferranti,听MD, MPH^30,31; Andrew E.听Moran,听MD, MPH¹

Author Affiliations Article Information

¹Division of General Medicine, Columbia University, New York, New York
²Cardiovascular Disease Initiative, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge
³Center for Genomic Medicine, Massachusetts General Hospital, Boston
⁴Department of Medicine, Harvard Medical School, Boston, Massachusetts
⁵Division of Cardiology, Brigham and Women鈥檚 Hospital, Boston, Massachusetts
⁶Department of Population Health Science and Policy, Icahn School of Medicine, Mount Sinai, New York, New York
⁷Department of Pathology, Brigham and Women鈥檚 Hospital, Harvard Medical School, Boston, Massachusetts
⁸Laboratory for Molecular Medicine, Personalized Medicine, Mass General Brigham, Cambridge, Massachusetts
⁹Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
¹⁰Department of Medicine, Massachusetts General Hospital, Boston
¹¹The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
¹²Department of Internal Medicine, University of Michigan, Ann Arbor
¹³Department of Human Genetics, University of Michigan, Ann Arbor
¹⁴Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor
¹⁵Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston
¹⁶Department of Medicine, Baylor College of Medicine, Houston, Texas
¹⁷Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis
¹⁸The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston
¹⁹Northwestern University, Chicago, Illinois
²⁰Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
²¹Department of Epidemiology, University of Washington, Seattle
²²Department of Health Systems and Population Health, University of Washington, Seattle
²³The Framingham Heart Study, Framingham, Massachusetts
²⁴Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts
²⁵Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
²⁶Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts
²⁷Department of Medicine, University of Mississippi Medical Center, Jackson
²⁸Center for Public Health Genomics, University of Virginia, Charlottesville
²⁹Richard A. and Susan F. Smith Center for Outcomes Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts
³⁰Department of Cardiology, Boston Children鈥檚 Hospital, Boston, Massachusetts
³¹Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

JAMA Cardiol. 2024;9(3):263-271. doi:10.1001/jamacardio.2023.5366

Key Points

Question听 How do familial hypercholesterolemia (FH) genetic variants modify coronary heart disease (CHD) risk among adults with moderate (LDL-C 130-189 mg/dL) and severe (LDL-C鈮�190 mg/dL) hypercholesterolemia?

Findings听 In this pooled cohort study of 21鈥�426 participants followed up with for a median of 18 years, FH variants were associated with a 2-fold higher CHD risk, even among individuals with moderately elevated LDL-C. The increased CHD risk appeared to be largely explained by the substantially higher lifetime cumulative LDL-C exposure in those with an FH variant vs those without.

Meaning听 The findings suggest that genetic testing for FH may help refine risk stratification beyond LDL-C alone; clinical research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

Abstract

Importance听 Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.

Objective听 To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (鈮�190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.

Design, Setting, and Participants听 A total of 21鈥�426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.

Exposures听 LDL-C, cumulative past LDL-C, FH variant status.

Main Outcomes and Measures听 Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.

Results听 Of the 21鈥�426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12鈥�041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417鈥�000 carry an FH variant and were projected to experience more than 12鈥�000 excess CHD deaths in those with moderately elevated LDL-C and 15鈥�000 in those with severely elevated LDL-C compared with individuals without an FH variant.

Conclusions and Relevance听 In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

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Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol