Details

Autor(en) / Beteiligte

• Nomura, Akihiro
• Emdin, Connor A
• Won, Hong Hee
• Peloso, Gina M
• Natarajan, Pradeep
• Ardissino, Diego
• Danesh, John
• Schunkert, Heribert
• Correa, Adolfo
• Bown, Matthew J
• Samani, Nilesh J
• Erdmann, Jeanette
• McPherson, Ruth
• Watkins, Hugh
• Saleheen, Danish
• Elosua, Roberto
• Kawashiri, Masa-Aki
• Tada, Hayato
• Gupta, Namrata
• Shah, Svati H
• Rader, Daniel J
• Gabriel, Stacey
• Khera, Amit V
• Kathiresan, Sekar

Titel

Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease

Ist Teil von

• Circulation. Genomic and precision medicine, 2020-10, Vol.13 (5), p.417-423

Ort / Verlag

United States

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in or . In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of 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 and in was ≈0.1% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; =1.1×10 ) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.