Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation Concordance With Clinical Outcomes
2016 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 9, no 4, 340-348 p.Article in journal (Refereed) Published
Background-Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation. Methods and Results-Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo. Conclusions-Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309.
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS , 2016. Vol. 9, no 4, 340-348 p.
reactive protein; cholesterol efflux; dalcetrapib; HDL; pharmacogenetics
Cardiac and Cardiovascular Systems
IdentifiersURN: urn:nbn:se:liu:diva-131911DOI: 10.1161/CIRCGENETICS.116.001405ISI: 000382234000005PubMedID: 27418594OAI: oai:DiVA.org:liu-131911DiVA: diva2:1034846
Funding Agencies|F. Hoffmann-La Roche2016-10-132016-10-112017-04-24