Low-density Lipoprotein Cholesterol Response Research Articles

Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents.

Current statin guidelines in Europe and Canada advocate achieving a fixed LDL target or the attainment of a ≥50% reduction in low-density lipoprotein cholesterol (LDLC), while current US guidelines advocate the use of statin therapies that reduce LDLC by <50% (moderate intensity) or ≥50% (high intensity). Data are limited, however, linking the achievement of these % reduction thresholds to subsequent cardiovascular outcomes particularly for contemporary high-intensity regimens. In a randomized trial of 17 082 initially healthy men and women with median baseline LDLC of 108 mg/dL (interquartile range 94-119), we (i) used waterfall plots to assess the variability in LDLC response to rosuvastatin 20 mg daily and (ii) evaluated the impact of reaching ≥50% reductions in LDLC on risk of developing the first cardiovascular events. Among rosuvastatin allocated participants, 3640 individuals (46.3%) experienced an LDLC reduction ≥50%; 3365 individuals (42.8%) experienced an LDLC reduction >0 but <50%; and 851 individuals (10.8%) experienced no reduction or an increase in LDLC compared with baseline. These % LDLC reductions directly related to the risks of first cardiovascular events; at trial completion, incidence rates for the primary endpoint were 11.2, 9.2, 6.7, and 4.8 per 1000 person-years for those in the placebo, no LDLC reduction, LDLC reduction <50%, and LDLC reduction ≥50% groups, respectively. Compared with placebo, the multivariable adjusted hazard ratios for sequentially greater on-treatment per cent reductions in LDLC were 0.91 (95%CI 0.54-1.53), 0.61 (95%CI 0.44-0.83), and 0.43 (95%CI 0.30-0.60) (P < 0.00001). Similar relationships between % reduction and clinical outcomes were observed in analyses focusing on non-HDLC or apolipoprotein B. As documented for low- and moderate-intensity regimens, variability in % LDLC reduction following high-intensity statin therapy is wide yet the magnitude of this % reduction directly relates to efficacy. These data support guideline approaches that incorporate % reduction targets for statin therapy as well as absolute targets, and might provide a structure for the allocation of emerging adjunctive lipid-lowering therapies such as PCSK9 inhibitors should these agents prove broadly effective for cardiovascular event reduction.

The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy.

Statins (HMG-CoA reductase inhibitors) lower low-density lipoprotein cholesterol (LDL-C) and prevent cardiovascular disease. However, there is wide individual variation in LDL-C response. Drugs targeting proprotein convertase subtilin/kexin type 9 (PCSK9) lower LDL-C and will be used with statins. PCSK9 mediates the degradation of LDL receptors (LDLRs). Therefore, a greater LDL-C response to statins would be expected in individuals with PCSK9 loss-of-function (LOF) variants because LDLR degradation is reduced. To examine this hypothesis, the effect of 11 PCSK9 functional variants on statin response was determined in 669 African Americans. One LOF variant, rs11591147 (p.R46L) was significantly associated with LDL-C response to statin (P=0.002). In the three carriers, there was a 55.6% greater LDL-C reduction compared with non-carriers. Another functional variant, rs28362261 (p.N425S), was marginally associated with statin response (P=0.0064).The effect of rs11591147 was present in individuals of European ancestry (N=2388, P=0.054). The therapeutic effect of statins may be modified by genetic variation in PCSK9.

Meta-analysis of genome-wide association studies to assess C-reactive protein response to statin therapy

BackgroundWe have recently shown that the C-reactive protein (CRP) response to statin therapy is highly variable, with 45% of people on atorvastatin having no decrease in CRP. Whether there is any genetic component to this variability is unclear. We sought to identify genetic determinants and quantify the single nucleotide polymorphism based heritability of CRP response to statins. MethodsIn a meta-analysis of genome-wide association studies, we included datasets from both randomised controlled trials and observational studies. There were about 10 000 statin-treated individuals overall, grouped into a first discovery stage (from the CARDS trial and PROSPER, PARC, and FSH studies) and a second replication stage (from the JUPITER trial). CRP response was modelled as log(CRP follow-up/CRP baseline) adjusted for baseline CRP and other covariates. Genome-complex trait analysis (GCTA) was used to identify the narrow-sense heritability of CRP response. FindingsThe study consisted of about 5300 statin users in the discovery cohort and 4000 statin users as replication cohort. On the GCTA analysis narrow-sense heritability (h2) for CRP response was 0·19 (SE 0·24) and was higher than that reported for LDL cholesterol response to statin therapy 0·05 (SE 0·14). Preliminary results of the genome-wide association meta-analysis identified three loci that achieved genome-wide statistical significance: APOE, rs429358 (p=7·91E–10); RP11-458D21.5, rs184819447 (p=2·32E–9); MYT1L, rs79020661 (p=3·21E–8). Other than APOE none of these was associated with LDL response to statin therapy or baseline CRP. InterpretationThese data are consistent with statin-induced change in CRP having a mechanism distinct from LDL cholesterol change. We identified several loci associated with CRP-response to statin therapy and they need to be investigated further by additional replication analysis. FundingHD is funded by a National Institute for Health Research Clinical Academic Fellowship.

Seventeen years of statin pharmacogenetics: a systematic review.

We evaluated the evidence of pharmacogenetic associations with statins in a systematic review. Two separate outcomes were considered of interest: modification of low-density lipoprotein cholesterol (LDL-C) response and modification of risk for cardiovascular events. In candidate gene studies, 141 loci were claimed to be associated with LDL-C response. Only 5% of these associations were positively replicated. In addition, six genome-wide association studies of LDL-C response identified common SNPs in APOE, LPA, SLCO1B1, SORT1 and ABCG2 at genome-wide significance. None of the investigated SNPs consistently affected the risk reduction for cardiovascular events. Only five genetic loci were consistently associated with LDL-C response. However, as effect sizes are modest, there is no evidence for the value of genetic testing in clinical practice.

Adherence to standard-dose or low-dose statin treatment and low-density lipoprotein cholesterol response in type 2 diabetes patients

Objective:To determine the association between adherence, dose and low-density lipoprotein (LDL) cholesterol response in patients with type 2 diabetes initiating statin treatment.Research design and methods:This cohort study was performed using data for 2007–2012 from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database. The association between adherence to a standard-dose statin and LDL cholesterol response was assessed using linear regression, adjusting for covariates. The effect of low-dose versus standard-dose was assessed in a propensity-score matched cohort. Adherence rates, defined as the proportion of days covered (PDC), were estimated between statin initiation and LDL outcome measurement.Main outcome measure:LDL cholesterol level at follow-up.Results:The effect of adherence on LDL cholesterol response, measured in 2160 patients, was dependent on the baseline LDL cholesterol level. For patients with a baseline LDL cholesterol of 3.7 mmol/l and an adherence rate of 80%, a 40% reduction in LDL cholesterol was predicted. In the matched sample of 1144 patients, the treatment dose showed a difference in impact on the outcome for adherence rates higher than 50%. It was estimated that a patient with a baseline LDL cholesterol of 3.7 mmol/l will need an adherence rate of at least 76% on low-dose and 63% on standard-dose treatment to reach the LDL cholesterol target of 2.5 mmol/l.Limitations:Adherence was measured as the PDC, which is known to overestimate actual adherence. Also, we were not able to adjust for lifestyle factors.Conclusions:We determined the concurrent effect of treatment adherence and dose on LDL cholesterol outcomes. Given the adherence levels seen in clinical practice, diabetes patients initiating statin treatment are at high risk of not reaching the recommended cholesterol target, especially when they start on a low-dose statin.

CYP7A1-rs3808607and APOEisoform associate with LDL cholesterol lowering after plant sterol consumption in a randomized clinical trial

The benefits of plant sterols (PSs) for cholesterol lowering are hampered by large heterogeneity across individuals, potentially because of genetic polymorphisms. We investigated the impact of candidate genetic variations on cholesterol response to PSs in a trial that recruited individuals with high or low endogenous cholesterol synthesis, estimated by lathosterol to cholesterol (L:C) ratio. Mildly hypercholesterolemic adults preselected as possessing either high endogenous cholesterol synthesis (n = 24; mean ± SEM: L:C ratio = 2.03 ± 0.39 μmol/mmol) or low endogenous cholesterol synthesis (n = 39; mean ± SEM: L:C ratio = 0.99 ± 0.28 μmol/mmol) consumed 2 g PS/d or a placebo for 28 d by using a dual-center, single-blind, randomized crossover design. Cholesterol synthesis and change in cholesterol absorption were measured with stable isotopic tracers. Candidate single-nucleotide polymorphisms and apolipoprotein E (APOE) isoform were assessed by TaqMan genotyping assay. The cholesterol fractional synthesis rate was higher (P < 0.001) in participants with high endogenous cholesterol synthesis (mean ± SEM: placebo: 9.16% ± 0.47%; PSs: 9.74% ± 0.47%) than in participants with low endogenous cholesterol synthesis (mean ± SEM placebo: 5.72% ± 0.43%; PS: 7.10% ± 0.43%). Low-density lipoprotein (LDL) cholesterol lowering in response to PSs was associated with individuals' genotypes. Cholesterol 7 alpha-hydroxylase (CYP7A1-rs3808607) T/T homozygotes showed no LDL cholesterol lowering (mean ± SEM: -0.05 ± 0.07 mmol/L, P = 0.9999, n = 20), whereas the presence of the G-allele associated with LDL cholesterol response in a dose-dependent fashion (mean ± SEM G/T: -0.22 ± 0.06 mmol/L, P = 0.0006, n = 35; G/G: -0.46 ± 0.12 mmol/L, P = 0.0009, n = 8). Similarly, APOE ɛ3 carriers (mean ± SEM: -0.13 ± 0.05 mmol/L, P = 0.0370, n = 40) responded less than APOE ɛ4 carriers (mean ± SEM: -0.31 ± 0.07 mmol/L, P < 0.0001, n = 23). Moreover, genoset CYP7A1-rs3808607 T/T/APOE ɛ3 was associated with nonresponsiveness (mean ± SEM: +0.09 ± 0.08 mmol/L, P = 0.9999, n = 14). rs5882 in cholesteryl ester transfer protein (CETP) and rs4148217 in ATP-binding cassette subfamily G member 8 (ABCG8) did not associate with LDL cholesterol lowering. Cholesterol absorption decreased as a result of PS consumption, but this decrease was not related to circulating LDL cholesterol concentrations, cholesterol synthesis phenotype, or genotypes. CYP7A1-rs3808607 and APOE isoform are associated with the extent of reduction in circulating LDL cholesterol in response to PS consumption and could serve as potential predictive genetic markers to identify individuals who would derive maximum LDL cholesterol lowering with PS consumption. The trial was registered at clinicaltrials.gov as NCT01131832.

Differential Lipid Response to Statins Is Associated With Variants in the BUD13-APOA5 Gene Region.

Genetic variants within the BUD13-APOA5 gene region are known to be associated with high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels. Recent studies suggest that single nucleotide polymorphisms (SNPs) within this region affect HDL-C response to statin-fibrate combination therapy and low-density lipoprotein cholesterol (LDL-C) response to statin therapy. We hypothesized that SNPs within the BUD13-APOA5 region are associated with TG, HDL-C, and LDL-C response to statin therapy. We examined 1520 observations for 1086 patients from the Personalized Medicine Research Project, a large biorepository at the Marshfield Clinic Research Foundation, who had received statin therapy and been previously genotyped for polymorphisms in the 11q23 chromosomal region. A significant differential response to statin therapy was observed for 3 SNPs. The minor allele at rs11605293 significantly attenuated TG-lowering response to pravastatin (P = 0.000159), whereas the minor allele at rs12806755 was associated with a similar response to lovastatin (P = 0.000192). Genotypes at rs947990 significantly attenuated LDL-C reduction to atorvastatin therapy (P = 0.000668) with some patients with the minor allele having LDL-C increase after therapy. No SNPs within the BUD13-APOA5 region were associated with a significant effect on HDL-C reduction in response to statin therapy. In conclusion, this study suggests that common SNPs within the BUD13-APOA5 can affect TG and LDL-C response to statin therapy in a North American population.

Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial.

Aims/hypothesisWe investigated whether atorvastatin 10 mg daily lowered C-reactive protein (CRP) and whether the effects of atorvastatin on cardiovascular disease (CVD) varied by achieved levels of CRP and LDL-cholesterol.MethodsCRP levels were measured at baseline and 1 year after randomisation to atorvastatin in 2,322 patients with type 2 diabetes (40–75 years, 69% males) in a secondary analysis of the Collaborative Atorvastatin Diabetes Study, a randomised placebo-controlled trial. We used Cox regression models to test the effects on subsequent CVD events (n = 147) of CRP and LDL-cholesterol lowering at 1 year.ResultsAfter 1 year, the atorvastatin arm showed a net CRP lowering of 32% (95% CI −40%, −22%) compared with placebo. The CRP response was highly variable, with 45% of those on atorvastatin having no decrease in CRP (median [interquartile range, IQR] per cent change −9.8% [−57%, 115%]). The LDL-cholesterol response was less variable, with a median (IQR) within-person per cent change of −41% (−51%, −31%). Baseline CRP did not predict CVD over 3.8 years of follow-up (HRper SD log 0.89 [95% CI 0.75, 1.06]), whereas baseline LDL-cholesterol predicted CVD (HRper SD 1.21 [95% CI 1.02, 1.44]), as did on-treatment LDL-cholesterol. There was no significant difference in the reduction in CVD by atorvastatin, with above median (HR 0.57) or below median (HR 0.52) change in CRP or change in LDL-cholesterol (HR 0.61 vs 0.50).Conclusions/interpretationCRP was not a strong predictor of CVD. Statin efficacy did not vary with achieved CRP despite considerable variability in CRP response. The use of CRP as an indicator of efficacy of statin therapy on CVD risk in patients with type 2 diabetes is not supported by these data.Trial registration NCT00327418Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3586-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

The rs13064411 polymorphism in the WDR52 gene, associated with PCSK9 levels, modifies statin-induced changes in serum total and LDL cholesterol levels.

Recently, the minor allele of the rs13064411A>G polymorphism in the WD repeat domain 52 (WDR52) gene was associated with increased statin-induced proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and with LDL cholesterol response to statins. PCSK9 promotes LDL receptor degradation, leading to increased serum LDL cholesterol. We investigated whether the polymorphism was associated with cholesterol response to statins. We identified 1105 current, 322 past, and 4831 never statin users during follow-up in the prospective population-based Rotterdam Study. The mean delta total, LDL, and HDL cholesterol levels between current and no current statin users with the same number of minor alleles were analyzed using random-effect repeated measurements. We adjusted for age, sex, number of cholesterol measurements, and follow-up time. Compared with no users with the same genotype, current statin users carrying a minor allele showed a statistically significantly lower delta total and LDL cholesterol compared with reference homozygous major allele carriers [total: Δ=0.551 mmol/l (AG+GG) vs. Δ=0.732 mmol/l (AA), Pinteraction: 5.2×10(-7); LDL: Δ=0.566 mmol/l (AG+GG) vs. Δ=0.720 mmol/l (AA), Pinteraction: 1.8×10(-5)]. The effect was stronger in women (Pinteraction: 2.0×10(-5) for LDL cholesterol, 8.0×10(-6) for total cholesterol) and in high-dose users (defined daily doses>1.00) (Pinteraction: 7.0×10(-5) for LDL cholesterol, Pinteraction: 0.081 for total cholesterol). The polymorphism was not associated with HDL cholesterol in current statin users, or with total, LDL and HDL cholesterol in never statin users. The minor G allele of the rs13064411 polymorphism, associated with statin-induced PCSK9-levels, was associated with a decreased LDL-lowering and total cholesterol-lowering response to statins.

Effects of exercise accumulation on plasma lipids and lipoproteins.

Debate exists as to whether improvements in some cardiometabolic risk factors following exercise training result more from the last session of, or from an accumulation of, exercise sessions. This study was designed to compare the effect of a single exercise session with 3 consecutive days of exercise on triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C). Twelve young adult (aged 22.5±2.5 years), overweight (body mass index=29.7±4 kg·m(-2)), sedentary, black (n=5) and white (n=7) men (n=6) and women (n=6) completed, in random order, a single treadmill exercise session at 60% maximal oxygen uptake for 90 min (1EX), accumulated exercise sessions (same as for 1EX) for 3 consecutive days (3EX), and a control protocol (no exercise for 6 days). Plasma samples were collected from baseline through 24, 48, and 72 h postexercise. Significant treatment-by-time interactions (p<0.05) existed in HDL-C and LDL-C. Postexercise responses of HDL-C differed at 48 h (1EX: -3.6, 3EX: +3.7 mg·dL(-1)) and 72 h (1EX: -1.7, 3EX: +3.2 mg·dL(-1)). LDL-C responses differed at 48 h (1EX: -16, 3EX: +6 mg·dL(-1)). Although not statistically significant, TG concentrations decreased by 29% at 24 h after 3EX, compared with -7% after 1EX. An inverse relationship between baseline and postexercise reduction in TG was present with 3EX (r=-0.655; p<0.05). In conclusion, 3EX increased HDL-C and decreased TG more than 1EX, while the decrease in LDL-C after 1EX was suppressed. Blood lipid panel changes may be due to more accumulated effects over time rather than just a result of the most recent exercise session.

Determinants of Bezafibrate-induced Improvements in LDL Cholesterol in Dyslipidemic Patients with Diabetes.

Our previous "J-BENEFIT (Japan BEzafibrate cliNical EFfectIveness and Tolerability)" study demonstrated that bezafibrate improves blood lipid profiles and glucose control in dyslipidemic patients with diabetes. However, bezafibrate did not significantly improve low-density lipoprotein cholesterol (LDL-C), although some patients showed decreases while others showed increases in the LDL-C levels. Therefore, a subgroup analysis of the J-BENEFIT study was conducted to identify factors influencing the bezafibrate-induced changes in the LDL-C levels. Of the 3,316 patients in the J-BENEFIT study, 2,116 not treated with other lipid-lowering drugs were enrolled in the current study, and the effects of 24-week treatment with bezafibrate on the LDL-C levels were analyzed. A reduction in the LDL-C level of ≥ 25% occurred in 253 patients, and a logistic-regression analysis was used to identify factors associated with this improvement. Among the 2,116 overall patients, bezafibrate treatment significantly increased the LDL-C levels from 123.9±36.7 to 125.7±31.3 mg/dL. The subanalysis showed that the treatment responses varied according to the baseline LDL-C level, with significant decreases in the ≥ 160 and ≥ 140-＜160 mg/dL groups, no significant decrease in the ≥ 120-＜140 mg/dL group and a significant increase in the ＜120 mg/dL group. A multivariate logistic-regression analysis of the data for the patients with an LDL-C of ≥ 25% identified a female sex, the use of anti-hypertensive and hypoglycemic agents and a high baseline LDL-C level to be significant determinants of the LDL-C response to bezafibrate. Our results showed that treatment with bezafibrate improves the LDL-C levels and lipid profiles in dyslipidemic diabetic patients, especially women, subjects co-treated with anti-hypertensive or hypoglycemic agents and those with high baseline LDL-C levels.

Pharmacogenomics of statin therapy: any new insights in efficacy or safety?

To examine the current evidence concerning the effects of genetic variation on statin-related low-density lipoprotein cholesterol reductions, clinical efficacy, and adverse events and the relevance for patient care. Recent years have seen the emergence of large-scale genetic experiments, including genome-wide association studies and candidate gene studies, exploring the impact of common genetic variation on patient response to statins. These studies have built on previous smaller scale evidence, providing improved statistical power and enhanced ability to explore the genome. Current evidence suggests that common genetic variants do not alter low-density lipoprotein cholesterol response by more than a few percent, or materially alter the effect of statin on vascular risk reduction, and therefore that patients benefit from statins independent of common genetic variation. However, knowledge of SLCO1B1 genotypes is believed to have clinical utility for predicting myopathy risk and ensuring that statins are prescribed as safely as possible. Furthermore, new hypothesis-generating studies, such as those associating GATM with myopathy risk, offer potential insights for the future. Common genetic variation does not appear to be an important determinant of statin response, with the exception of SLCO1B1 and risk of myopathy. Future studies will help to determine the impact of low-frequency and rare genetic variation on statin response.

Abstract 18986: Low Density Lipoprotein Cholesterol Response and Statin Persistence among Patients with High Coronary Heart Disease Risk Initiating Treatment

The 2013 American College of Cardiology/American Heart Association cholesterol treatment guideline recommends monitoring percent reduction in low density lipoprotein cholesterol (LDL-C) among patients initiating statins as an indication of response and adherence. We examined LDL-C reduction and statin persistence among high risk patients initiating statins in a real-world setting. This retrospective cohort study included 1,066 Kaiser Permanente Georgia members with a history of coronary heart disease or risk equivalent(s) initiating statins in 2011. Percent change in LDL-C was defined using measurements before and 60-450 days after statin initiation. Statin persistence was defined by proportion of days covered and categorized as high (≥80%), intermediate (50-79%), and low (&lt;50%). Overall, 58.4% of patients failed to achieve a ≥30% LDL-C reduction after statin initiation. The prevalence of high, intermediate and low statin persistence was 41.3%, 23.2%, and 35.6%, respectively. Of patients with high persistence, 42.3% did not achieve a ≥30% reduction in LDL-C compared with 54.7%, and 79.7% of those with intermediate and low statin persistence, respectively. After multivariable adjustment and compared to high persistence, the risk ratio for a low LDL-C reduction was 1.31 (95%CI: 1.13,1.52) for intermediate persistence and 1.88 (95%CI: 1.67,2.11), for low persistence. Women and African-Americans were less likely to have high persistence while having cardiologist follow-up visits was associated with high persistence. Also, after multivariable adjustment, patients with an LDL-C ≥ 100 mg/dL versus &lt; 100 mg/dL were less likely, while those initiating therapy with pravastatin were more likely to have a ≥30% reduction in LDL-C. In a real-world setting, many patients initiating statins did not achieve a 30% or larger LDL-C reduction. These data support the ACC/AHA recommendation to monitor LDL-C response among patients initiating statins.

How effective are the ESC/EAS and 2013 ACC/AHA guidelines in treating dyslipidemia? Lessons from a lipid clinic

Objective:There is a paucity of data regarding the attainment of lipid-lowering treatment goals according to the recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The aim of the present study was to assess how applicable these 2013 recommendations are in the setting of an Outpatient University Hospital Lipid Clinic.Methods:This was a retrospective (from 1999 to 2013) observational study including 1000 consecutive adults treated for hyperlipidemia and followed up for ≥3 years. Comparisons for the applicability of current European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) and recent ACC/AHA guidelines were performed.Results:Achievement rates of low density lipoprotein cholesterol (LDL-C) targets set by ESC/EAS were 21%, 44% and 62% among patients at very high, high and moderate cardiovascular risk, respectively, receiving statin monotherapy. Among individuals on high-intensity statins only 47% achieved the anticipated ≥50% LDL-C reduction, i.e. the ACC/AHA target. The corresponding rate was significantly greater among those on statin + ezetimibe (76%, p < 0.05). Likewise, higher rates of LDL-C target attainment according to ESC/EAS guidelines were observed in patients on statin + ezetimibe compared with statin monotherapy (37, 50 and 71% for the three risk groups, p < 0.05 for the very high risk group).Conclusion:The application of the ACC/AHA guidelines may be associated with undertreatment of high risk patients due to suboptimal LDL-C response to high-intensity statins in clinical practice. Adding ezetimibe substantially increases the rate of the ESC/EAS LDL-C target achievement together with the rate of LDL-C lowering response suggested by the ACC/AHA.

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

The MYLIP p.N342S polymorphism is associated with response to lipid-lowering therapy in Brazilian patients with familial hypercholesterolemia.

A previous study reported that the myosin regulatory light chain interacting protein (MYLIP) might serve as a novel therapeutic class for treating dyslipidemia. It contributes to variations in the levels of circulating low-density lipoprotein cholesterol (LDL-C), promoting the degradation of LDL-LDLR, thus limiting absorption. The effect of genetic variation in the MYLIP gene in a disease scenario characterized by mutations in the LDLR gene has not been previously evaluated. The aim of this study was to assess the effect of the p.N342S variant on the response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia (FH). A total of 156 patients with heterozygous FH were followed up for 12 months and received lipid-lowering therapy (different doses of atorvastatin with the addition of ezetimibe in over half the patients of each genotype group). Cholesterol data were assessed, and analysis of the MYLIP rs9370867 (p.N342S) genotypes was carried out by melting curve analysis. Baseline total cholesterol and baseline LDL-C levels were not different between genotypes. After 1 year of treatment, LDL-C responses (expressed as mg/dl and as %) were significantly different among genotypes (AA: -79±68 and -39±27, GA: -60±79 and -27±32, and GG: -30±83 and -15±38; P=0.02 and 0.005, respectively). In addition, FH patients carrying the AA genotype were more likely to achieve LDL-C levels of less than 130 mg/dl after 1 year of treatment (75.0%) compared with patients with the GG and GA genotypes (34.5 and 34.8%, respectively; P=0.001). Our study indicates that MYLIP p.N342S might be a pharmacogenetic marker for lipid-lowering therapy in patients with FH.

The importance of considering low-density lipoprotein cholesterol response as well as cardiovascular risk in deciding who can benefit from statin therapy.

The importance of considering low-density lipoprotein cholesterol response as well as cardiovascular risk in deciding who can benefit from statin therapy.

The impact of routine next generation sequencing testing for familial hypercholesterolaemia – 5 months service experience

The impact of routine next generation sequencing testing for familial hypercholesterolaemia – 5 months service experience

Prediction of LDL cholesterol response to statin using transcriptomic and genetic variation.

BackgroundStatins are widely prescribed for lowering LDL-cholesterol (LDLC) levels and risk of cardiovascular disease. There is, however, substantial inter-individual variation in the magnitude of statin-induced LDLC reduction. To date, analysis of individual DNA sequence variants has explained only a small proportion of this variability. The present study was aimed at assessing whether transcriptomic analyses could be used to identify additional genetic contributions to inter-individual differences in statin efficacy.ResultsUsing expression array data from immortalized lymphoblastoid cell lines derived from 372 participants of the Cholesterol and Pharmacogenetics clinical trial, we identify 100 signature genes differentiating high versus low statin responders. A radial-basis support vector machine prediction model of these signature genes explains 12.3% of the variance in statin-mediated LDLC change. Addition of SNPs either associated with expression levels of the signature genes (eQTLs) or previously reported to be associated with statin response in genome-wide association studies results in a combined model that predicts 15.0% of the variance. Notably, a model of the signature gene associated eQTLs alone explains up to 17.2% of the variance in the tails of a separate subset of the Cholesterol and Pharmacogenetics population. Furthermore, using a support vector machine classification model, we classify the most extreme 15% of high and low responders with high accuracy.ConclusionsThese results demonstrate that transcriptomic information can explain a substantial proportion of the variance in LDLC response to statin treatment, and suggest that this may provide a framework for identifying novel pathways that influence cholesterol metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0460-9) contains supplementary material, which is available to authorized users.

The importance of considering LDL cholesterol response as well as cardiovascular risk in deciding who can benefit from statin therapy.

Guidelines seeking to deploy statin treatment rely heavily on the use of estimates of absolute cardiovascular disease (CVD) risk as an arbiter of who should receive statins. We question whether this is an effective strategy unless the LDL-cholesterol (LDL-C) response is also considered. Recently, meta-analyses of randomized clinical trials of statins have revealed that CVD risk decreases linearly by 22% for each 1 mmol/l reduction in LDL-C. Calculation of the number needed to treat with statins to prevent one CVD event using both the pretreatment absolute CVD risk and the LDL-C response that can be achieved is thus possible. Application of this evidence reveals that many people (including younger ones) with high LDL-C levels can benefit more than people currently receiving statin treatment solely on the basis of their absolute CVD risk, whereas others at higher CVD risk, but with lower LDL-C, will derive little benefit. This does not seem to have been adequately considered in recent clinical guidelines. A simple additional mathematical step in risk assessment to take account of the LDL-C response to statins and provide knowledge of number needed to treat would greatly improve individual management, cost-effectiveness and the population impact of statins.