Akihiro Nomura1,2, Connor A Emdin3,4,5, Amit V Khera3,4,5, Sekar Kathiresan3,4,5,6, Hong Hee Won7, Gina M Peloso8, Pradeep Natarajan3,4,5, Diego Ardissino9,10, John Danesh11,12,13, Heribert Schunkert14,15,16, Adolfo Correa17, Matthew J Bown18,19, Nilesh J Samani18,19, Jeanette Erdmann20, Ruth McPherson21, Hugh Watkins22,23, Danish Saleheen24, Roberto Elosua25,26,27, Masa-Aki Kawashiri1, Hayato Tada1, Namrata Gupta3, Svati H Shah28, Daniel J Rader29, Stacey Gabriel3. 1. Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Japan (A.N., M.K., H.T.). 2. Innovative Clinical Research Center, Kanazawa University, Japan (A.N.). 3. Center for Genomic Medicine (C.A.E., P.N., N.G., S.G., A.V.K., S.K.), Massachusetts General Hospital, Boston. 4. Department of Medicine (C.A.E., P.N., A.V.K., S.K.), Massachusetts General Hospital, Boston. 5. Cardiovascular Disease Initiative, Broad Institute, Cambridge, MA (C.A.E., P.N., A.V.K., S.K.). 6. Verve Therapeutics, Cambridge, MA (S.K.). 7. Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea (H.H.W.). 8. Department of Biostatistics, Boston University School of Public Health, Boston, MA (G.M.P.). 9. Cardiology, Azienda Ospedaliero-Universitaria di Parma, University of Parma, Italy (D.A.). 10. Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, Italy (D.A.). 11. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (J.D.), University of Cambridge, United Kingdom. 12. National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics (J.D.), University of Cambridge, United Kingdom. 13. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, United Kingdom (J.D.). 14. Department of Cardiology, Deutsches Herzzentrum München, Germany (H.S.). 15. Technische Universität München, Germany (H.S.). 16. Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany (H.S.). 17. Department of Medicine and Pediatrics, University of Mississippi Medical Center, Jackson, MS (A.C.). 18. Department of Cardiovascular Sciences, University of Leicester, United Kingdom (M.J.B., N.J.S.). 19. NIHR Leicester Biomedical Research Center, Glenfield Hospital, Leicester, United Kingdom (M.J.B., N.J.S.). 20. Institute for Cardiogenetics, University of Lübeck, German Research Center for Cardiovascular Research, Partner Site Hamburg/Lübeck/Kiel and University Heart Center Lübeck (J.E.). 21. University of Ottawa Heart Institute, Canada (R.M.). 22. Cardiovascular Medicine, Radcliffe Department of Medicine (H.W.), University of Oxford, United Kingdom. 23. Wellcome Trust Center for Human Genetics (H.W.), University of Oxford, United Kingdom. 24. Department of Biostatistics and Epidemiology, Perelman School of Medicine (D.S.), University of Pennsylvania, Philadelphia. 25. Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, Spain (R.E.). 26. CIBER Enfermedades Cardiovasculares, Barcelona, Spain (R.E.). 27. Facultat de Medicina, Universitat de Vic-Central de Cataluña, Spain (R.E.). 28. Division of Cardiology, Department of Medicine, Duke University, Durham, NC (S.H.S.). 29. Department of Genetics (D.J.R.), University of Pennsylvania, Philadelphia.
Abstract
BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8-as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in ABCG5 or ABCG8. RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in ABCG5 and 2 pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 was ≈0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; P=1.1×10-6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8-as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in ABCG5 or ABCG8. RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in ABCG5 and 2 pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 was ≈0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; P=1.1×10-6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
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