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Effect of genetic variant (rs11887534) in ABCG8 gene in coronary artery disease and response to atorvastatin therapy.

ABSTRACT: ATP-binding cassette transporter ABCG8 plays an important role in excretion of cholesterol from liver. Common genetic polymorphisms in ABCG8 gene may genetically predispose an individual to coronary artery disease (CAD) along with response to atorvastatin therapy. Thus, we aimed to examine the role of ABCG8 D19H polymorphism (rs11887534) in susceptibility to CAD and its influence on atorvastatin response.The study included 213 CAD patients and 220 controls. Genotyping of ABCG8 D19H polymorphism was done by PCR-RFLP.Our results showed that ABCG8 'H' allele was conferring significant risk for CAD in a dominant model (OR=2.54; p=0.014). This increased risk for CAD was more pronounced in males (OR=2.69; p=0.030). No correlation of ABCG8 genotypes with the risk factors (diabetes, hypertension and smoking) of CAD was observed. On atorvastatin treatment there was a significant decrease in the LDL-C levels (p=0.021). However, stepwise multiple regression analysis showed that this decease was not associated with ABCG8 genetic variant (p=0.845). Observed determinants of variation in interindividual response to atorvastatin therapy were pre-treatment LDL-C (p= 0.024) and TC (p=0.017).Although the genetic variant 19H of ABCG8 confers risk for CAD in North Indian population, it is not associated with interindividual response to atorvastatin therapy.

SUBMITTER: Srivastava A

PROVIDER: S-EPMC3833422 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Effect of genetic variant (rs11887534) in ABCG8 gene in coronary artery disease and response to atorvastatin therapy.

Srivastava Anshika A Garg Naveen N Srivastava Anvesha A Srivastava Kshitij K Mittal Balraj B

Disease markers 20100101 5

<h4>Background</h4>ATP-binding cassette transporter ABCG8 plays an important role in excretion of cholesterol from liver. Common genetic polymorphisms in ABCG8 gene may genetically predispose an individual to coronary artery disease (CAD) along with response to atorvastatin therapy. Thus, we aimed to examine the role of ABCG8 D19H polymorphism (rs11887534) in susceptibility to CAD and its influence on atorvastatin response.<h4>Methodology</h4>The study included 213 CAD patients and 220 controls. ...[more]

PMID: 20592455

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Project description:Objective- Genome-wide association studies have revealed a robust association between genetic variation on chromosome 15q26.1 and coronary artery disease (CAD) susceptibility; however, the underlying biological mechanism is still unknown. The lead CAD-associated genetic variant (rs17514846) at this locus resides in the FURIN gene. In advanced atherosclerotic plaques, furin is expressed primarily in macrophages. We investigated whether this CAD-associated variant alters FURIN expression and whether furin affects monocyte/macrophage behavior. Approach and Results- A quantitative reverse transcription polymerase chain reaction analysis showed that leukocytes from individuals carrying the CAD risk allele (A) of rs17514846 had increased FURIN expression. A chromatin immunoprecipitation assay revealed higher RNA polymerase II occupancy in the FURIN gene in mononuclear cells of individuals carrying this allele. A reporter gene assay in transiently transfected monocytes/macrophages indicated that the CAD risk allele had higher transcriptional activity than the nonrisk allele (C). An analysis of isogenic monocyte cell lines created by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that isogenic cells with the A/A genotype for rs17514846 had higher FURIN expression levels than the isogenic cells with the C/C genotype. An electrophoretic mobility shift assay exhibited preferential binding of a nuclear protein to the risk allele. Studies of monocytes/macrophages with lentivirus-mediated furin overexpression or shRNA (short hairpin RNA)-induced furin knockdown showed that furin overexpression promoted monocyte/macrophage migration, increased proliferation, and reduced apoptosis whereas furin knockdown had the opposite effects. Conclusions- Our study shows that the CAD-associated genetic variant increases FURIN expression and that furin promotes monocyte/macrophage migration and proliferation while inhibiting apoptosis, providing a biological mechanism for the association between variation at the chromosome 15q26.1 locus and CAD risk.

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Effect of genetic variant (rs11887534) in ABCG8 gene in coronary artery disease and response to atorvastatin therapy.

Publications

Effect of genetic variant (rs11887534) in ABCG8 gene in coronary artery disease and response to atorvastatin therapy.

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