%0 Journal Article %J PLoS One %D 2019 %T Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. %A Floyd, James S %A Bloch, Katarzyna M %A Brody, Jennifer A %A Maroteau, Cyrielle %A Siddiqui, Moneeza K %A Gregory, Richard %A Carr, Daniel F %A Molokhia, Mariam %A Liu, Xiaoming %A Bis, Joshua C %A Ahmed, Ammar %A Liu, Xuan %A Hallberg, Pär %A Yue, Qun-Ying %A Magnusson, Patrik K E %A Brisson, Diane %A Wiggins, Kerri L %A Morrison, Alanna C %A Khoury, Etienne %A McKeigue, Paul %A Stricker, Bruno H %A Lapeyre-Mestre, Maryse %A Heckbert, Susan R %A Gallagher, Arlene M %A Chinoy, Hector %A Richard A Gibbs %A Bondon-Guitton, Emmanuelle %A Tracy, Russell %A Eric Boerwinkle %A Gaudet, Daniel %A Conforti, Anita %A van Staa, Tjeerd %A Sitlani, Colleen M %A Rice, Kenneth M %A Maitland-van der Zee, Anke-Hilse %A Wadelius, Mia %A Morris, Andrew P %A Pirmohamed, Munir %A Palmer, Colin A N %A Psaty, Bruce M %A Alfirevic, Ana %K Genome-Wide Association Study %K High-Throughput Nucleotide Sequencing %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Muscle, Skeletal %K Rhabdomyolysis %K Whole Genome Sequencing %X

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.

METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.

CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

%B PLoS One %V 14 %P e0218115 %8 2019 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/31242253?dopt=Abstract %R 10.1371/journal.pone.0218115 %0 Journal Article %J Am Heart J %D 2007 %T Absence of an interaction between the angiotensin-converting enzyme insertion-deletion polymorphism and pravastatin on cardiovascular disease in high-risk hypertensive patients: the Genetics of Hypertension-Associated Treatment (GenHAT) study. %A Maitland-van der Zee, Anke-Hilse %A Boerwinkle, Eric %A Arnett, Donna K %A Davis, Barry R %A Leiendecker-Foster, Catherine %A Miller, Michael B %A Klungel, Olaf H %A Ford, Charles E %A Eckfeldt, John H %K Aged %K Antihypertensive Agents %K Coronary Disease %K Female %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Hypertension %K Male %K Middle Aged %K Myocardial Infarction %K Peptidyl-Dipeptidase A %K Pharmacogenetics %K Polymorphism, Genetic %K Pravastatin %K Proportional Hazards Models %K Randomized Controlled Trials as Topic %K Risk Assessment %X

BACKGROUND: The aim of this study was to determine whether the angiotensin-converting enzyme (ACE) insertion-deletion (ID) polymorphism interacts with pravastatin to modify the risk of coronary heart disease (CHD) and other cardiovascular end points in a large clinical trial.

METHODS: GenHAT is an ancillary study of the ALLHAT. The ACE ID genotyped population in the lipid-lowering arm of ALLHAT included 9467 participants randomly assigned to pravastatin (n = 4741) or to usual care (n = 4726). The efficacy of pravastatin in reducing the risk of primary outcome (all-cause mortality) and secondary outcomes (fatal CHD and nonfatal myocardial infarction, cardiovascular disease [CVD] mortality, CHD, stroke, other CVD, non-CVD mortality, stroke, and heart failure) was compared between the genotype strata (dominant model ID + II vs DD, additive model II vs ID vs DD), by examining an interaction term in a Cox proportional hazards model.

RESULTS: The relative risk of fatal CHD and nonfatal myocardial infarction among subjects randomized to pravastatin compared with subjects randomized to usual care was similar in subjects with the II genotype (hazard ratio [HR] 0.84, 95% CI 0.59-1.18), the ID genotype (HR 0.84, 95% CI 0.68-1.03), and the DD genotype (HR 0.99, 95% CI 0.77-1.27).

CONCLUSIONS: We found no evidence that the ACE ID genotype was a major modifier of the efficacy of pravastatin in reducing the risk of cardiovascular events.

%B Am Heart J %V 153 %P 54-8 %8 2007 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17174637?dopt=Abstract %R 10.1016/j.ahj.2006.10.019 %0 Journal Article %J Curr Atheroscler Rep %D 2005 %T Pharmacogenetics of response to statins: where do we stand? %A Maitland-van der Zee, Anke-Hilse %A Eric Boerwinkle %K Carrier Proteins %K Cholesterol Ester Transfer Proteins %K Cholesterol, LDL %K Coronary Artery Disease %K Glycoproteins %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Hypercholesterolemia %K Pharmacogenetics %K Polymorphism, Genetic %X

Cardiovascular disease is one of the leading causes of death, especially in developed countries. Blood cholesterol lowering by way of statin therapy is a common risk-lowering therapy. The risk reduction for coronary artery disease for patients using statins is 27%. These reductions, however, are average effects for all patients included in the trials. There is notable interindividual variation in response to statins, and the origins of this variation are poorly understood. Pharmacogenetics seeks to determine the role of genetic factors in variation of drug response. In patients with primary hypercholesterolemia, 23 studies have examined the effects of genetic polymorphisms at 20 different loci on the lipid response to statin treatment, and 18 studies examined genetic polymorphisms involved in the benefits of statin therapy in the prevention of cardiovascular disease. Even though many studies have been performed, few results have been replicated. It is our contention that larger sample sizes and consideration of multiple genes are needed in the field of pharmacogenetics of statin response.

%B Curr Atheroscler Rep %V 7 %P 204-8 %8 2005 May %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/15811254?dopt=Abstract %R 10.1007/s11883-005-0007-3