Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease

Abstract

Background: Familial sitosterolemia is a rare, recessive 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 ATPbinding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes, and have substantially elevated plasma sitosterol and 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 nine 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=29,361) 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 less than 0.1% in ABCG5 or ABCG8. Results:In sitosterolemia families, seven pedigrees harbored causative LoF variants in ABCG5 and two 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 to non-carriers. Within the large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 were approximately 0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (24.7 mg/dL; 95% confidence interval [CI] 14 to 35; P=1.1x10 -6 ), and were at two-fold increased risk of CAD (odds ratio 2.06, 95% CI 1.27 to 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 a LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a two-fold increase in risk of CAD.ATVB, PROCARDIS, OHS, PROMIS, Leicester, Lubeck was supported by 5U54HG003067 to SG. The ATVB Study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Università 2010-2012 Area 1-Strategic Programmes-Regione Emilia-Romagna. Funding for the ESP-EOMI was provided by RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). Exome sequencing was performed through RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO).

Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia

“…More comprehensive sequencing or array strategies for characterizing FH beyond targeted sequencing of candidate genes may allow improved clinical risk prediction and identify genetic diagnoses for individuals that have alternative or atypical explanation for an FH-like phenotype such as polygenic hypercholesterolemia, elevated lipoprotein(a), 34 or atypical variants (eg, ABCG5 37 ). This work demonstrates that genetic testing beyond the common candidate gene analysis of LDLR , APOB , and PCSK9 may provide insights relevant to the clinical heterogeneity of FH.…”

Beyond the Usual Suspects: Expanding on Mutations and Detection for Familial Hypercholesterolemia

“…Patients with sitosterolemia can present with xanthomas and premature CAD, characteristics that closely mimic the clinical FH phenotype [56]. Studies by Tada et al and Nomura et al suggest that heterozygous pathogenic variants in the ABCG5/ABCG8 can worsen the clinical expression of FH in terms of additional elevation of LDL-C levels and cardiovascular risk [57,58]. Recently, we have also addressed this issue and could not confirm these findings [41].…”

Low-Density Lipoprotein Cholesterol Level cannot be too Low: Considerations from Clinical Trials, Human Genetics, and Biology

“…On the other hand, loss of function mutation(s) in apolipoprotein B ( APOB ) gene (namely, FHBL) are robustly associated with reduced LDL cholesterol level and ASCVD risk. The same situations are applicable to ATP-binding cassette sub-family G member 5 ( ABCG5 ) (both elevated) 24 ) , angiopoietin-like 3 ( ANGPTL3 ) (both reduced) 22 ) , and PCSK9 (both reduced) 23 ) . It is interesting to note that LDL cholesterol levels are positively associated with ASCVD regardless of genes and diseases.…”