Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy

Kim, Seung Hyun; Ye, Y. M.; Lee, H. Y.; Sin, H. J.; Park, Hae‐Sim

doi:10.1111/j.1365-2710.2010.01196.x

Cited by 48 publications

(49 citation statements)

References 17 publications

(28 reference statements)

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“…These dalcetrapib-associated changes were statistically significant albeit small and were in the direction opposite to that expected: patients with the homozygous genotype for the major allele (eg, GG homozygotes for rs1967309) and hence exposed to a higher risk of cardiovascular events and progression of carotid atherosclerosis had mild decreases in body-mass index, weight and those plasma lipid fractions. Whether this counterintuitive finding is related to altered β-adrenergic signaling 15 or to other factors will need further investigations to elucidate the reasons for the increased cardiovascular risk incurred by this subset of patients when treated with dalcetrapib. Dalcetrapib has been shown to increase cellular cholesterol efflux in patients with coronary artery disease.…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphisms in the ADCY9 gene have been shown to affect individual response to inhaled therapy in patients with asthma. 15 Recently, another ADCY9 gene polymorphism was shown to be associated with bodymass index and clinical classes of obesity. 16 In our study, polymorphisms in the ADCY9 gene influenced responses to dalcetrapib in terms of body mass index, weight, plasma LDL-cholesterol, LDL/HDL cholesterol ratio, and triglycerides (Figures VI and VII in the Data Supplement).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib

Tardif

Rhéaume

Perreault

et al. 2015

Circ Cardiovasc Genet

166

132

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H igh-density lipoprotein (HDL)-based therapies have yielded disappointing results, [1][2][3][4] which have led to questioning of the HDL hypothesis. Cholesteryl ester transfer protein mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, such as low-density lipoproteins (LDLs).5 Torcetrapib, the first cholesteryl ester transfer protein inhibitor to be evaluated in a large clinical trial, caused excess morbidity and mortality despite increasing HDL-cholesterol levels by ≈70% although elevations of aldosterone levels and blood pressure observed in some patients may have contributed to the negative findings.3 Dalcetrapib is another cholesteryl ester transfer protein inhibitor that raises HDL-cholesterol levels by ≈30%, without effects on circulating neurohormones. 6 The dal-OUTCOMES trial was designed to test whether dalcetrapib could modify cardiovascular risk in patients with a recent acute coronary syndrome. Background-Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile. Methods and Results-We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10 -8 ), with 8 polymorphisms providing P<10 -6 in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r 2 =0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10 -8 ; hazard ratio, 0.67; 95% confidence interval, 0.58-0.78). Conclusions-The Tardif et al Pharmacogenomic Determinants of Dalcetrapib 373Dalcetrapib failed to improve clinical outcomes among the 15 871 patients of the dal-OUTCOMES study, with no subgroups defined by baseline clinical or biochemical characteristics appearing to benefit from therapy. 4 These results are ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic Determinants of the Cardiovascular Effects of Dalcetrapib

Tardif

Rhéaume

Perreault

et al. 2015

Circ Cardiovasc Genet

166

132

View full text Add to dashboard Cite

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“…It was speculated that it contributes to treatment of patients with mild to moderate asthma [94]. However, the relationship between ADCY9 and miR-210 in lung cancer has not been examined.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

Cen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Since the function of microRNA (miR)-210 in non-small cell lung cancer (NSCLC) remains unclear, we aimed to explore the clinical significance of miR-210 in NSCLC. Methods: NSCLC-related data from 1673 samples on Gene Expression Omnibus and 1090 samples on The Cancer Genome Atlas were obtained and analyzed. The expression level of miR-210 was validated via real-time quantitative PCR analysis with 125 paired clinical samples. A meta-analysis was performed to generate a comprehensive understanding of miR-210 expression and its clinical significance in NSCLC. In addition, bioinformatics analysis was also conducted to reveal the potential underlying mechanism of miR-210 action in NSCLC. Results: miR-210 expression was consistently elevated in NSCLC solid tissue samples. However, its expression was controversial in easily obtained body fluids (i.e., blood, plasma, and serum). Moreover, an overall pooled meta-analysis implied a comparatively higher level of miR-210 expression in NSCLC cancerous tissue than in normal control tissue (P < 0.001). In addition, a meta-analysis of outcome revealed a significant diagnostic capacity of miR-210 in NSCLC by detecting its expression in serum and sputum (area under the summary receiver operating characteristic curve 0.82 and 0.81, respectively). miR-210 overexpression was associated with poor progression-free survival (PFS) in NSCLC and was negatively related to overall survival and disease-free survival. Bioinformatic gene enrichment and annotation analyses showed that the target genes of miR-210 were greatly enriched in cell adhesion and plasma membrane, and three pathways were considered to be the main functional circuits of miR-210: renin secretion, the cGMP-PKG signaling pathway, and cell adhesion molecules. Conclusion: In NSCLC, miR-210 expression was elevated and overexpression indicated poor PFS. Expression level of miR-210 in serum and sputum showed significant diagnostic value for NSCLC.

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“…Finally, association of AC9 with Yotiao and certain potassium channels in heart may point to a role in cardiac repolarization and certain forms of long-QT syndrome (Li et al, 2012). ADCY9 gene polymorphisms are linked to different diseases including asthma (Small et al, 2003;Kim et al, 2011b), pancreatic cancer (Lee Pharmacological Modulation of Mammalian Adenylyl Cyclases and Gyu Song, 2015), mood disorders (Toyota et al, 2002), body weight (Berndt et al, 2013), and susceptibility to malaria (Manjurano et al, 2012;Maiga et al, 2013). ADCY9 gene polymorphisms determine the efficacy of dalcetrapib, increasing high-density lipoprotein, on atherosclerosis (Tardif et al, 2015).…”

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confidence: 99%