Simon P.R. Romaine

The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are well established in the treatment of hypercholesterolaemia and the prevention of coronary artery disease. Despite this, there is wide inter-individual variability in response to statin therapy, in terms of both lipid-lowering and adverse drug reactions. The major site of statin action is within hepatocytes and recent interest has focussed on genetic variation in hepatic influx and efflux transporters for their potential to explain these differences. In this review we explore current literature regarding the pharmacokinetic and pharmacodynamic influence of the common c.388A>G and c.521T>C single-nucleotide polymorphisms (SNPs) within the solute carrier organic anion transporter 1B1 (SLCO1B1) gene, encoding the organic anion transporter polypeptide 1B1 (OATP1B1) influx transporter. We discuss their potential to predict the efficacy of statin therapy and the likelihood that patients will experience adverse effects.

Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study.

Background—Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results—The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). Conclusion—The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration—URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.

A sequence variant associated with sortilin-1 (SORT1) on 1p13.3 is independently associated with abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76-0.85, P = 7.2 × 10(-14)). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case-control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.

Multi-Ethnic Analysis of Lipid-Associated Loci: The NHLBI CARe Project

Background Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities. Methodology/Principal Findings We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed. Conclusions/Significance We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

A randomized, controlled trial of simvastatin versus rosuvastatin in patients with acute myocardial infarction: the Secondary Prevention of Acute Coronary Events – Reduction of Cholesterol to Key European Targets Trial

Aims We sought to evaluate reports that rosuvastatin 10 mg is a more efficacious treatment of hyperlipidaemia than is simvastatin 40 mg, hoping to assess this issue in the previously unstudied context of acute myocardial infarction. Methods and results The Secondary Prevention of Acute Coronary Events - Reduction of Cholesterol to Key European Targets (SPACE ROCKET) Trial was an investigator-led, open-label, blinded-endpoint, multicentre, randomized, controlled trial assessing the proportion of patients, at 3 months, achieving European Society of Cardiology 2003 (ESC-03) lipid targets of total cholesterol (TC) less than 4.5 mmol/l (174 mg/dl) or low-density lipoprotein cholesterol (LDLc) less than 2.5 mmol/l (97 mg/dl). Of 1263 patients randomized, 77.6% simvastatin versus 79.9% rosuvastatin achieved ESC-03 targets [odds ratio (OR): 1.16; 95% confidence interval (CI): 0.88–1.53; P = 0.29]. There were statistically significant differences for simvastatin versus rosuvastatin, respectively, for mean LDLc 2.03 mmol/l (78 mg/dl) versus 1.94 mmol/l (75 mg/dl; P =0.009) and also mean TC 3.88 mmol/l (150 mg/dl) versus 3.75 mmol/l (145 mg/dl; P =0.005). A post-hoc analysis showed higher achievement of the new ESC, American Heart Association and American College of Cardiology optimal lipid target of LDLc less than 1.81 mmol/l (70 mg/dl) with rosuvastatin (45.0%) compared with simvastatin (37.8%; OR: 1.37; 95% CI: 1.09–1.72; P = 0.007). The proportion of patients achieving the Fourth Joint Task Force European Guidelines (2007) of TC less than 4.0 mmol/l (155 mg/dl) and LDLc less than 2.0 mmol/l (77 mg/dl) was 38.7% for simvastatin 40 mg and 47.7% for rosuvastatin 10 mg (OR: 1.48; 95% CI: 1.18–1.86; P = 0.001). Conclusion We observed no superiority of either treatment for the ESC-03 lipid targets. Rosuvastatin 10 mg lowered mean cholesterol more effectively than simvastatin and achieved better results for the latest, more stringent, ESC target.

Signatures of miR-181a on renal transcriptome and blood pressure.

MicroRNA-181a binds to the 3′ untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure.

Change in serum lipids after acute coronary syndromes: secondary analysis of SPACE ROCKET study data and a comparative literature review.

BACKGROUND It has long been an accepted belief that serum cholesterol significantly falls after myocardial infarction and that a return to pre-event levels takes approximately 3 months. The magnitude and clinical significance of this fall has recently been challenged. METHODS In the Secondary Prevention of Acute Coronary Events-Reduction Of Cholesterol to Key European Targets (SPACE ROCKET) trial, we measured serum lipids of individuals on day 1 and between days 2 and 4 after acute myocardial infarction (AMI). Second, we performed a thorough literature review and compared all studies reporting data on absolute changes in lipids immediately after AMI, using weighted means. RESULTS Of 1263 SPACE ROCKET participants, 128 had paired lipid measurements where both samples had been measured using identical methods at baseline and on days 2-4 after AMI. The mean lowering in total cholesterol between day 1 and day 2-4 was 0.71 mmol/L (95% CI 0.58-0.84; P < 0.0001) and in triglycerides was 0.10 mmol/L (-0.14-0.33; P = 0.405). A total of 25 papers showing absolute lipid changes post-AMI were identified. The combined data demonstrated a mean fall in total cholesterol of 9% to 11% from baseline over days 3-14 post-AMI, whereas for triglycerides, there was a rise of 18% from baseline to between day 9 and 12 weeks. CONCLUSIONS After a secondary analysis of SPACE ROCKET data and a comparison of previously published data, we report a 10% fall in total cholesterol after AMI-a difference that is of high clinical significance. Consequently, measurement of serum lipids in patients with AMI should be performed within the first hours after presentation.

A multi-omics glimpse into the biology of arterial stiffness.

I t has long been recognized that the structure of arteries throughout the vascular tree is not uniform. Notably, the media of large proximal (central) vessels contains relatively much greater amounts of elastin and elastic lamellae than smaller, more distal (peripheral) arteries; the converse is true of vascular smooth muscle cells. Under physiological conditions, the greater elasticity of central arteries compared with more muscular peripheral arteries allows conversion of the pulsatile nature of ventricular ejection into a relatively steady flow of blood at the distal end of the arterial system, conferring protection from pulsatile energy [1,2]. Furthermore, these differences in impedance can generate partial wave reflections, which arrive in the aorta during diastole, boosting diastolic blood pressure and augmenting coronary perfusion pressure [3]. Arterial stiffness is a broad term used to describe loss of arterial compliance and changes in vessel wall properties [1]. Stiffening of central arteries impairs the above protective mechanisms and can in turn lead to damage of the microvascular beds within end organs [1,2] – the brain and kidneys are particularly susceptible as both are torrential circulations with minimal vascular resistance [4]. Furthermore, this decreased compliance causes reflected waves to arrive in the aorta prematurely, during systole, raising systolic blood pressure and perhaps more importantly, reducing diastolic blood pressure with a concomitant reduction in coronary perfusion pressures [3]. Although arterial stiffness can be assessed using a variety of techniques, carotid–femoral pulse wave velocity (cf-PWV) is the current ‘gold standard’ [5]. Measured noninvasively by transcutaneously recording pulse waves over the common carotid and femoral arteries, cf-PWV is assessed by measuring the pulse transit time and the distance travelled between the two recording sites [PWV

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial InfarctionClinical Perspective

Background—Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results—The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). Conclusion—The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration—URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial InfarctionClinical Perspective: The GEOSTAT-1 Study

Background—Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results—The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). Conclusion—The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration—URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.