Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease

Helgadóttir, Anna; Þorleifsson, Guðmar; Alexandersson, Kristjan F.; Tragante, Vinicius; Þorsteinsdóttir, Margrét; Eiríksson, Finnur Freyr; Grétarsdóttir, Sólveig; Björnsson, Eyþór; Magnusson, Olafur T; Sveinbjörnsson, Garðar; Jónsdóttir, Ingileif; Steinthórsdóttir, Valgerður; Ferkingstad, Egil; Jensson, Brynjar O.; Stefánsson, Hreinn; Ólafsson, Ísleifur; Christensen, Alex Hørby; Torp‐Pedersen, Christian; Køber, Lars; Pedersen, Ole Birger; Erikstrup, Christian; Sørensen, Erik; Brunak, Søren; Banasik, Karina; Hansen, Thomas Folkmann; Nyegaard, Mette; Eyjolfssson, Gudmundur I; Sigurðardóttir, Ólöf; Thorarinsson, Bjorn; Matthíasson, Stefán E.; Steingrímsdóttir, Þóra; Bjõrnsson, Einar; Daníelsen, Ragnar; Asselbergs, Folkert W.; Arnar, Davíð O.; Ullum, Henrik; Bundgaard, Henning; Sulem, Patrick; Þorsteinsdóttir, Unnur; Þorgeirsson, Guðmundur; Hólm, Hilma; Guðbjartsson, Daníel F.; Stefánsson, Kári

doi:10.1093/eurheartj/ehaa531

Cited by 65 publications

(57 citation statements)

References 31 publications

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“…Given the roles of G5G8 in opposing dietary sterol accumulation and biliary cholesterol secretion, it is unsurprising that both rare and common variants have been associated with plasma cholesterol, non-cholesterol sterols, low-density lipoprotein cholesterol (LDL-C), and atherosclerotic and gallbladder disease across a large number of studies and populations ([ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ], incomplete list). Other associations are intriguing and include insulin resistance (G8:D19H) and type 2 diabetes (G5:G604E, G8:Y54C) and its renal complications (G8:T400K) [ 81 , 82 , 83 ].…”

Section: Beyond Phytosterolsmentioning

confidence: 99%

“…Studies among hypercholesterolemic subjects suggest sitosterolemia is significantly underdiagnosed [ 143 , 144 ]. Genome and exome sequence analysis of large populations indicates that carriers of loss of function mutations are far more common than previously thought and are at an elevated risk of coronary artery disease [ 72 , 80 ]. Exome sequence analysis of over 60,000 individuals across multiple populations reveals 57 and 58 predicted loss of function alleles for ABCG5 and ABCG8 , respectively ( (accessed on 3 January 2021) v2.1.1) [ 145 ].…”

Section: Sitosterolemia And/or Familial Hypercholesterolemiamentioning

confidence: 99%

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Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8

Williams

Segard

Graf

2021

IJMS

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Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty years since its discovery. The genomic era has revealed that there are far more carriers of loss of function mutations and likely pathogenic variants of ABCG5 ABCG8 than previously thought. The impact of these variants on G5G8 structure and activity are largely unknown. We propose a classification system for ABCG5 ABCG8 mutants based on previously published systems for diseases caused by defects in ABC transporters. This system establishes a framework for the comprehensive analysis of disease-associated variants and their impact on G5G8 structure–function.

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Section: Beyond Phytosterolsmentioning

confidence: 99%

Section: Sitosterolemia And/or Familial Hypercholesterolemiamentioning

confidence: 99%

Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8

Williams

Segard

Graf

2021

IJMS

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“…So werden in der aktuellen Fassung Phytosterine aufgrund ihrer geringen, bis zu 10 % LDL-C senkenden Wirkung empfohlen. Aktuell publizierte genetische Analysen zeigen, dass Phytosterine "per se" atherogen sind [15]; ob eine vergleichsweise geringe LDL-C-Senkung durch Phytosterine daher den potenziell schädlichen Effekt nivelliert, ist offen [16,17].…”

Section: Lipoprotein(a)unclassified

Therapieempfehlungen bei Fettstoffwechselstörungen: Die neue Leitlinie von 2019

Vogt¹,

Weingärtner²

2021

Dtsch Med Wochenschr

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The updated guidelines for the management of dyslipidaemias 2019 sticks to the concept of individual risk-based intervention strategies, but intensifies LDL-C goals. Next to the established SCORE system non-invasive imaging techniques such as coronary CT or ultrasound of carotid or femoral arteries are now recommended for improved risk stratification. Screening for lipoprotein(a) identifies persons at higher cardiovascular risk. Non-statin trials with ezetimibe and PSCK9-inhibitors demonstrated further relative risk reduction for cardiovascular events. Cardiovascular risk reduction depends on the absolute lowering of LDL-C, duration of therapy and the individual cardiovascular risk. For patients at very high risk the new LDL-C goal is < 1.4 mmol/l (55 mg/dl) and reduction of ≥ 50 % from baseline. The overall aim is to reduce “cholesterol life years”.

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“…Quality control of the CHB data set has been described in detail previously. [20] In brief, samples with non-European genetic ancestry, individuals with sex chromosome aneuploidies or mismatch between inferred sex and sex chromosome count, or outliers for heterozygosity were excluded. The genotyped data were long-range phased using Eagle2 [21] and imputed using a reference panel backbone consisting of whole-genome sequence data from 8,429 Danes along with 7,146 samples from Northwestern Europe.…”

Section: Genotyping and Imputationmentioning

confidence: 99%

Common variants near the bradykinin receptor B₂gene are associated with angioedema induced by angiotensin-converting-enzyme inhibitor treatment - a genome wide association study

Ghouse

Ahlberg

Andreasen

et al. 2020

Preprint

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ObjectiveAngioedema is a rare, but potentially life-threatening adverse reaction, associated with angiotensin-converting-enzyme inhibitors (ACEi). Identification of potential genetic factors related to this adverse event may help identify at-risk patients.Design, Setting and ParticipantsA genome-wide association study (GWAS) involving patients of European descent, all taking ACEi was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as persons with an angioedema event and a filled prescription for an ACEi 180 days prior to the event. Controls were defined as persons with continuous treatment with ACEi without any history of angioedema. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were computed for angioedema risk by logistic mixed model regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis model.ExposureSingle-nucleotide polymorphisms associated with ACEi-associated angioedema.Main outcomeHospital record of angioedema.ResultsThe discovery cohort consisted of 462 cases and 53,391 ACEi-treated controls. The replication cohort consisted of 144 cases and 1,345 ACEi-treated controls. In the discovery cohort, we identified one locus, residing at chromosome 14q32.2, that was associated with angioedema at the genome-wide significance level of P <5 × 10−8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR 1.62; 95 % CI 1.38 to 1.90; P = 4.3 × 10−9). This variant was validated in our replication cohort with similar direction and effect size (OR 1.60; 95 % CI 1.13 to 2.25; P = 7.2 × 10−3). We found that carriers of the risk allele had significantly lower systolic (−0.46 mmHg per T allele; 95 % CI −0.83 to −0.10; P = 0.013) and diastolic blood pressure (−0.26 mmHg per T allele; 95 % CI −0.46 to −0.05; P = 0.013).ConclusionIn this GWAS, involving individuals treated with ACEi, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with ACEi-related angioedema. BDKRB2 genotype-directed therapy may aid in improving safety in evidence-based clinical decision-making.

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Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease

Cited by 65 publications

References 31 publications

Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8

Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8

Therapieempfehlungen bei Fettstoffwechselstörungen: Die neue Leitlinie von 2019

Common variants near the bradykinin receptor B₂gene are associated with angioedema induced by angiotensin-converting-enzyme inhibitor treatment - a genome wide association study

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Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease

Cited by 65 publications

References 31 publications

Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8

Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8

Therapieempfehlungen bei Fettstoffwechselstörungen: Die neue Leitlinie von 2019

Common variants near the bradykinin receptor B2gene are associated with angioedema induced by angiotensin-converting-enzyme inhibitor treatment - a genome wide association study

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Common variants near the bradykinin receptor B₂gene are associated with angioedema induced by angiotensin-converting-enzyme inhibitor treatment - a genome wide association study