***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective —Although statins are efficacious for lowering low-density lipoprotein cholesterol , there is wide interindividual variation in response . We tested the extent to which combined effects of common alleles of LDLR and HMGCR can contribute to this variability . Methods and Results —Haplotypes in the LDLR 3′-untranslated region ( 3-UTR ) were tested for association with lipid-lowering response to simvastatin treatment in the Cholesterol and Pharmacogenetics trial ( 335 blacks and 609 whites ) . LDLR haplotype 5 ( LDLR L5 ) was associated with smaller simvastatin-induced  reductions in low-density lipoprotein cholesterol , total cholesterol , non-high-density lipoprotein cholesterol , and apolipoprotein B ( P=0.0002 to 0.03 ) in blacks but not whites . The combined presence of LDLR L5 and previously described HMGCR haplotypes in blacks was associated with significantly attenuated apolipoprotein B reduction ( −22.4±1.5 % , N=89 ) compared with both noncarriers ( −30.6±1.5 % , N=78 , P=0.0001 ) and carriers of either individual haplotype ( −28.2±1.1 % , N=158 , P=0.001 ) . We observed similar differences when measuring simvastatin-mediated induction of low-density lipoprotein receptor surface expression using lymphoblast cell lines ( P=0.03 ) . Conclusion —We have identified a common LDLR 3-UTR haplotype that is associated with attenuated lipid-lowering response to simvastatin treatment . Response was further reduced in individuals with both LDLR and previously described HMGCR haplotypes . Previously identified racial differences in statin efficacy were partially explained by the greater prevalence of these combined haplotypes in blacks In vitro data indicate that biotransformation of the synthetic 3‐hydroxy‐3‐methylglutaryl – coenzyme A reductase inhibitor fluvastatin is catalyzed by the cytochrome P450 ( CYP ) enzyme 2C9 . The consequences of CYP2C9 genetic polymorphisms on  fluvastatin pharmacokinetics and on its efficacy have not been investigated in humans thus far Background — Hypothesis-generating data raise the possibility that carriers of the kinesin-like protein 6 ( KIF6 ) 719 arginine ( Arg ) allele preferentially benefit from statin therapy , and , on this basis , a commercial assay for KIF6 has been developed . Methods and Results — In the recently completed JUPITER trial , men and women without prior cardiovascular disease or diabetes who had baseline low-density lipoprotein cholesterol < 130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L were r and omly allocated to rosuvastatin 20 mg daily or to placebo and followed for first major vascular events ( nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for unstable angina , arterial revascularization , or vascular death ) and for all-cause mortality . We evaluated the effect of polymorphism at rs20455 encoding the KIF6 719Arg allele on outcomes in this primary prevention trial , both among Caucasian participants and in the trial as a whole . Among 8781 Caucasian trial participants , we observed no increase in vascular event rates among carriers of the KIF6 719Arg allele as compared with noncarriers ( hazard ratio , 0.91 ; 95 % confidence interval , 0.66 to 1.26 ) nor any difference in percent low-density lipoprotein cholesterol reduction with rosuvastatin according to genotype ( −52 versus −52 mg/dL , P=0.11 ) . Rosuvastatin allocation was associated with an almost identical reduction in the trial primary end point among carriers ( hazard ratio , 0.61 ; 95 % confidence interval , 0.43 to 0.87 ) as among noncarriers ( hazard ratio , 0.59 ; 95 % confidence interval , 0.39 to 0.88 ) ( P-interaction=0.90 ) . Genotype had no impact  on rosuvastatin  efficacy in further analyses that included all-cause mortality , in analyses conducted in the total trial cohort that adjusted for race , or in analyses using generalized models of inheritance rather than recessive models . Conclusions — In the large primary prevention JUPITER trial , rosuvastatin was equally effective at reducing cardiovascular event rates among carriers and noncarriers of the KIF6 719Arg allele . Thus , at least for rosuvastatin , there appears to be no clinical utility to screening for KIF6 genotype as a method to determine vascular risk or to predict statin efficacy . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00239681 OBJECTIVE To investigate whether ScrF I polymorphism in the 2nd intron of the HMG-COA reductase gene ( HMGCR ) influences serum lipid levels and whether this polymorphism affects the efficiency of the cholesterol lowering HMG-CoA reductase inhibitor , simvastatin . METHODS One hundred sixty-eight patients with type 2 diabetes mellitus ( T2DM ) prospect ively received simvastatin as a single-agent therapy ( 20 mg day-1 p.o . ) for 12 weeks . Serum lipid levels were determined before and after simvastatin treatment . Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism ( PCR-RFLP ) . RESULTS Subjects with the AA homozygotes had significantly higher serum very low-density lipoprotein cholesterol ( VLDL-C ) levels than those with the aa homozygotes . In addition , in 168 patients with T2DM who took 20 mg simvastatin , the VLDL-C lowering effect by simvastatin in subjects with the aa homozygotes was significantly lower than in those with the Aa heterozygotes and AA homozygotes . CONCLUSIONS Simvastatin treatment significantly decreased plasma lipids in all patients ( P<0.01 ) . Importantly , we demonstrate that ScrF I polymorphism of the HMGCR gene in patients with T2DM groups is associated with significant elevation of serum VLDL-C levels . Subjects with the AA homozygotes had significantly higher serum high VLDL-C levels than those with the Aa heterozygotes and aa homozygotes ( AA : 2.18+/-0.51 ; Aa : 2.04+/-0.59 , aa : 1.86+/-0.43 , P<0.05 for comparison among three genotypes and P<0.01 for difference between AA and aa ) . Furthermore , this polymorphism tends to show an enhanced response to an HMG-CoA reductase inhibitor in terms of the cholesterol-lowering effect . In 168 patients with T2DM who took 20 mg simvastatin , the VLDL-C lowering effect by simvastatin in subjects with the AA homozygotes was significantly lower than in those with the Aa heterozygotes and aa homozygotes ( the reduction in serum VLDL-C levels ; 37.03+/-5.67 versus 28.97+/-4.96 , P<0.01 ; 34.62+/-5.87 versus 28.97+/-4.96 , P<0.05 ) . These results suggest that the HMGCR gene may serve as a modifier gene for hypercholesterolemia in Chinese diabetic patients We carried out a genome-wide association study ( GWAS ) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study ( CARDS ; n = 1,156 ) , the Anglo-Sc and inavian Cardiac Outcomes Trial ( ASCOT ; n = 895 ) , and the observational phase of ASCOT ( n = 651 ) , all of whom were prescribed atorvastatin 10 mg .  Following genome-wide imputation , we combined data from the three studies in a meta- analysis . We found associations of LDL-c response  to atorvastatin that reached genome-wide significance at rs10455872 ( P = 6.13 × 10−9 ) within the LPA gene and at two single nucleotide polymorphisms ( SNP ) within the APOE region ( rs445925 ; P = 2.22 × 10−16 and rs4420638 ; P = 1.01 × 10−11 ) that are proxies for the ε2 and ε4 variants , respectively , in APOE . The novel association with the LPA SNP was replicated in the PROspect i ve Study of Pravastatin in the Elderly at Risk ( PROSPER ) trial ( P = 0.009 ) . Using CARDS data , we further showed that atorvastatin therapy did not alter lipoprotein(a ) [ Lp(a ) ] and that Lp(a ) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels . However , statin therapy had a similar effect in reducing cardiovascular disease ( CVD ) in patients in the top quartile for serum Lp(a ) levels ( HR = 0.60 ) compared with those in the lower three quartiles ( HR = 0.66 ; P = 0.8 for interaction ) . The data emphasize that high Lp(a ) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response . Therefore , an apparently lower LDL-c response  to statin therapy may indicate a need for measurement of Lp(a ) . However , statin therapy seems beneficial even in those with high Lp(a ) BACKGROUND Although statin therapy is known to increase concentrations of PCSK9 , whether this effect is related to the magnitude of LDL reduction is uncertain . This study was undertaken to underst and the extent of this effect and examine the relationship between PCSK9 and LDL cholesterol ( LDL-C ) reduction . METHODS We measured plasma PCSK9 concentrations by ELISA at baseline and at 1 year in 500 men and 500 women participating in the Justification for Use of Statins in Prevention : an Intervention Trial Evaluating Rosuvastatin ( JUPITER ) trial that r and omly allocated participants to rosuvastatin 20 mg daily or placebo . We also evaluated rs11591147 , a single nucleotide polymorphism known to have an impact on plasma PCSK9 concentrations . RESULTS At baseline , median ( interquartile range ) PCSK9 concentrations were higher in women [ 73 ( 62 - 90 ) ] ng/mL than in men [ 69 ( 57 - 81 ) ng/mL ] ( P<0.005 ) . During 1 year , there was no change in PCSK9 concentrations in the placebo arm , suggesting stability in time . In contrast , the rosuvastatin increased PCSK9 by 35 % in women [ 101 ( 82 - 117 ) ng/mL ] and 28 % in men [ 89 ( 71 - 109 ) ng/mL ] ( P<0.0001 ) . Among those allocated to rosuvastatin , greater reductions in LDL-C were associated with greater increases in PCSK9 on both absolute and relative scales ( r=-0.15 , P<0.0005 ) . Furthermore PCSK9 ( rs11591147 ) did not alter the magnitude of LDL-C reduction associated with rosuvastatin use . CONCLUSIONS In this r and omized trial , rosuvastatin increased plasma concentration of PCSK9 in proportion to the magnitude of LDL-C reduction ; the LDL-C response to statin could not be inferred by PCSK9 concentrations Background Statins effectively lower total and plasma LDL-cholesterol , but the magnitude of decrease varies among individuals . To identify single nucleotide polymorphisms ( SNPs ) contributing to this variation , we performed a combined analysis of genome-wide association ( GWA ) results from three trials of statin efficacy . Methods and Principal Findings Bayesian and st and ard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol , total cholesterol , HDL-cholesterol , and triglyceride on a total of 3932 subjects using data from three studies : Cholesterol and Pharmacogenetics ( 40 mg/day simvastatin  , 6 weeks ) , Pravastatin/Inflammation CRP Evaluation (  40 mg/day pravastatin , 24 weeks ) , and Treating to New Targets ( 10 mg/day atorvastatin , 8 weeks ) . Genotype imputation was used to maximize genomic coverage and to combine information across studies . Phenotypes were normalized within each study to account for systematic differences among studies , and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies . Two SNP associations were assessed as having posterior probability greater than 50 % , indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response . SNP rs8014194 , located within the CLMN gene on chromosome 14 , was strongly associated with statin-mediated change in total cholesterol with an 84 % probability by Bayesian analysis , and 
    Output:
    
None of the investigated SNPs consistently affected the risk reduction for cardiovascular events .
However , as effect sizes are modest , there is no evidence for the value of genetic testing in clinical practice