ABSTRACT
Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.
Subject(s)
Black People/genetics , Genetic Predisposition to Disease , Genome, Human/genetics , Genomics , Female , Gene Frequency/genetics , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide/genetics , Uganda/epidemiology , Whole Genome SequencingABSTRACT
HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.
Subject(s)
DNA Helicases , DNA-Binding Proteins , Genetic Variation , HIV Infections , HIV-1 , Viral Load , Humans , Cell Line , DNA Helicases/genetics , DNA Helicases/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , HIV Infections/genetics , HIV-1/growth & development , HIV-1/physiology , Viral Load/genetics , Africa , Chromosomes, Human, Pair 1/genetics , Alleles , RNA, Long Noncoding/genetics , Virus ReplicationABSTRACT
MOTIVATION: Interpreting genetic variation in noncoding regions of the genome is an important challenge for personal genome analysis. One mechanism by which noncoding single nucleotide variants (SNVs) influence downstream phenotypes is through the regulation of gene expression. Methods to predict whether or not individual SNVs are likely to regulate gene expression would aid interpretation of variants of unknown significance identified in whole-genome sequencing studies. RESULTS: We developed FIRE (Functional Inference of Regulators of Expression), a tool to score both noncoding and coding SNVs based on their potential to regulate the expression levels of nearby genes. FIRE consists of 23 random forests trained to recognize SNVs in cis-expression quantitative trait loci (cis-eQTLs) using a set of 92 genomic annotations as predictive features. FIRE scores discriminate cis-eQTL SNVs from non-eQTL SNVs in the training set with a cross-validated area under the receiver operating characteristic curve (AUC) of 0.807, and discriminate cis-eQTL SNVs shared across six populations of different ancestry from non-eQTL SNVs with an AUC of 0.939. FIRE scores are also predictive of cis-eQTL SNVs across a variety of tissue types. AVAILABILITY AND IMPLEMENTATION: FIRE scores for genome-wide SNVs in hg19/GRCh37 are available for download at https://sites.google.com/site/fireregulatoryvariation/. CONTACT: nilah@stanford.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Gene Expression Regulation , Genetic Variation , Software , Genomics , Humans , Quantitative Trait LociABSTRACT
BACKGROUND: The gastrointestinal (GI) microbiome is recognized for potential clinical relevance in inflammatory bowel disease (IBD). Data suggest that there is a disease-dependent loss of microbial diversity in IBD. Trimethylamine-N-oxide (TMAO) is generated by GI anaerobes through the digestion of dietary phosphatidylcholine and carnitine in a microbial-mammalian co-metabolic pathway. IBD-related changes in the gut microbiome may result in disease-specific changes in TMAO plasma concentrations. AIM: To determine whether TMAO plasma levels in IBD are altered compared to controls and whether they correlate with disease presence or activity. METHODS: Liquid chromatography-tandem mass spectrometry was used to measure TMAO, choline, and carnitine plasma levels in 479 subjects (373 non-IBD controls, 106 IBD). Subjects were also genotyped for the flavin monooxygenase (FMO)3 variants, E158K and E308G. RESULTS: Plasma TMAO levels were 2.27 µM lower in the IBD population compared to the control population (p = 0.0001). Lower TMAO levels were similarly seen in active ulcerative colitis (UC) (1.56 µM) versus inactive disease (3.40 µM) (p = 0.002). No difference was seen in active Crohn's disease (CD) versus inactive CD. No intergroup variation existed in plasma TMAO levels based on FMO3 genotype. Choline levels were higher in IBD, while carnitine levels were similar between the two groups, suggesting that lower TMAO levels in IBD were not due to dietary differences. CONCLUSIONS: Decreased TMAO levels are seen in IBD compared to a non-IBD population. These data suggest that TMAO may have potential as a biomarker to support IBD diagnosis as well as to assess disease activity in UC.
Subject(s)
Inflammatory Bowel Diseases/blood , Inflammatory Bowel Diseases/diagnosis , Methylamines/blood , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Case-Control Studies , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
AIMS: It is thought that clopidogrel bioactivation and antiplatelet response are related to cytochrome P450 2C19 (CYP2C19). However, a recent study challenged this notion by proposing CYP2C19 as wholly irrelevant, while identifying paraoxonase-1 (PON1) and its Q192R polymorphism as the major driver of clopidogrel bioactivation and efficacy. The aim of this study was to systematically elucidate the mechanism and relative contribution of PON1 in comparison to CYP2C19 to clopidogrel bioactivation and antiplatelet response. METHODS AND RESULTS: First, the influence of CYP2C19 and PON1 polymorphisms and plasma paraoxonase activity on clopidogrel active metabolite (H4) levels and antiplatelet response was assessed in a cohort of healthy subjects (n = 21) after administration of a single 75 mg dose of clopidogrel. There was a remarkably good correlation between H4 AUC (0-8 h) and antiplatelet response (r2 = 0.78). Furthermore, CYP2C19 but not PON1 genotype was predictive of H4 levels and antiplatelet response. There was no correlation between plasma paraoxonase activity and H4 levels. Secondly, metabolic profiling of clopidogrel in vitro confirmed the role of CYP2C19 in bioactivating clopidogrel to H4. However, heterologous expression of PON1 in cell-based systems revealed that PON1 cannot generate H4, but mediates the formation of another thiol metabolite, termed Endo. Importantly, Endo plasma levels in humans are nearly 20-fold lower than H4 and was not associated with any antiplatelet response. CONCLUSION: Our results demonstrate that PON1 does not mediate clopidogrel active metabolite formation or antiplatelet action, while CYP2C19 activity and genotype remains a predictor of clopidogrel pharmacokinetics and antiplatelet response.
Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Aryldialkylphosphatase/genetics , Platelet Aggregation Inhibitors/pharmacology , Polymorphism, Genetic/genetics , Ticlopidine/analogs & derivatives , Adolescent , Adult , Area Under Curve , Biotransformation/drug effects , Clopidogrel , Cytochrome P-450 CYP2C19 , Cytochrome P-450 CYP3A/drug effects , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Midazolam/pharmacokinetics , Midazolam/pharmacology , Middle Aged , Platelet Aggregation/drug effects , Platelet Aggregation/genetics , Platelet Aggregation Inhibitors/pharmacokinetics , Ticlopidine/pharmacokinetics , Ticlopidine/pharmacology , Young AdultABSTRACT
Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.
ABSTRACT
The human organic anion-transporting polypeptides OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are liver-enriched membrane transporters of major importance to hepatic uptake of numerous endogenous compounds, including bile acids, steroid conjugates, hormones, and drugs, including the 3-hydroxy-3-methylglutaryl Co-A reductase inhibitor (statin) family of cholesterol-lowering compounds. Despite their remarkable substrate overlap, there are notable exceptions: in particular, the gastrointestinal peptide hormone cholecystokinin-8 (CCK-8) is a high affinity substrate for OATP1B3 but not OATP1B1. We utilized homologous recombination of linear DNA by E. coli to generate a library of cDNA containing monomer size chimeric OATP1B1-1B3 and OATP1B3-1B1 transporters with randomly distributed chimeric junctions to identify three discrete regions of the transporter involved in conferring CCK-8 transport activity. Site-directed mutagenesis of three key residues in OATP1B1 transmembrane helices 1 and 10, and extracellular loop 6, to the corresponding residues in OATP1B3, resulted in a gain of CCK-8 transport by OATP1B1. The residues appear specific to CCK-8, as the mutations did not affect transport of the shared OATP1B substrate atorvastatin or the OATP1B1-specific substrate estrone sulfate. Regions involved in gain of CCK-8 transport by OATP1B1, when mapped to the crystal structures of bacterial transporters from the major facilitator superfamily, are positioned to suggest these regions could readily interact with drug substrates. Accordingly, our data provide new insight into the molecular determinants of the substrate specificity of these hepatic uptake transporters with relevance to targeted drug design and prediction of drug-drug interactions.
Subject(s)
Amino Acids/metabolism , Organic Anion Transporters, Sodium-Independent/chemistry , Organic Anion Transporters, Sodium-Independent/metabolism , Organic Anion Transporters/chemistry , Organic Anion Transporters/metabolism , Amino Acids/chemistry , Amino Acids/genetics , Cholecystokinin/metabolism , Liver-Specific Organic Anion Transporter 1 , Mutagenesis, Site-Directed , Organic Anion Transporters/genetics , Organic Anion Transporters, Sodium-Independent/genetics , Peptide Fragments/metabolism , Solute Carrier Organic Anion Transporter Family Member 1B3 , Substrate SpecificityABSTRACT
Associations between genetic variation and traits are often in noncoding regions with strong linkage disequilibrium (LD), where a single causal variant is assumed to underlie the association. We applied a massively parallel reporter assay (MPRA) to functionally evaluate genetic variants in high, local LD for independent cis-expression quantitative trait loci (eQTL). We found that 17.7% of eQTLs exhibit more than one major allelic effect in tight LD. The detected regulatory variants were highly and specifically enriched for activating chromatin structures and allelic transcription factor binding. Integration of MPRA profiles with eQTL/complex trait colocalizations across 114 human traits and diseases identified causal variant sets demonstrating how genetic association signals can manifest through multiple, tightly linked causal variants.
Subject(s)
Genetic Variation , Linkage Disequilibrium , Multifactorial Inheritance , Quantitative Trait Loci , Alleles , Asthma/genetics , Chromatin/metabolism , Genetic Predisposition to Disease , Genome, Human , Genome-Wide Association Study , Haplotypes , Histone Code , Humans , Inflammatory Bowel Diseases/genetics , Multiple Sclerosis/genetics , Phenotype , Platelet Count , Transcription Factors/genetics , Transcription Factors/metabolism , Untranslated RegionsABSTRACT
Multidrug resistance protein 1 (MRP1/ABCC1) is a 190kDa member of the ATP-binding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively effluxing anticancer drugs. Knowledge of the atomic structure of MRP1 is needed to elucidate its transport mechanism, but only low resolution structural data are currently available. Consequently, comparative modeling has been used to generate models of human MRP1 based on the crystal structure of the ABC transporter Sav1866 from Staphylococcus aureus. In these Sav1866-based models, the arrangement of transmembrane helices differs strikingly from earlier models of MRP1 based on the structure of the bacterial lipid transporter MsbA, both with respect to packing of the twelve helices and their interactions with the nucleotide binding domains. The functional importance of Tyr324 in transmembrane helix 6 predicted to project into the substrate translocation pathway was investigated.
Subject(s)
Models, Molecular , Multidrug Resistance-Associated Proteins/chemistry , Bacterial Proteins/chemistry , Crystallography, X-Ray , Humans , Mutagenesis, Site-Directed , Protein Conformation , Staphylococcus aureus/chemistry , Structure-Activity Relationship , Tyrosine/genetics , Tyrosine/metabolismABSTRACT
Multidrug resistance proteins (MRPs) are members of the "C" branch of the ATP-binding cassette transporter superfamily. Human MRP1 transports a wide range of natural product drugs and structurally diverse conjugated and unconjugated organic anions. Its closest relative is MRP3. Despite their structural similarity, the homologs differ substantially in their substrate specificity. It is noteworthy that MRP1 transports glutathione (GSH) and GSH conjugates and displays GSH-stimulated transport of a number of unconjugated and conjugated compounds. In contrast, MRP3 does not transport GSH and is a poor transporter of GSH conjugates. However, both proteins transport glucuronide conjugates, such as 17beta-estradiol 17-(beta-D-glucuronide). We have constructed a series of MRP1/MRP3 hybrids and used them to identify a region of MRP1 that is critical for binding and transport of GSH conjugates such as leukotriene C(4) (LTC(4)). Substitution of this region encompassing transmembrane helices 8 and 9 and portions of cytoplasmic loops 4 and 5 of MRP1 with the equivalent region of MRP3 eliminated LTC(4) transport. Transport of other substrates was either unaffected or enhanced. We identified three residues in this region: Tyr(440), Ile(441), and Met(443), mutation of which differentially affected transport. It is noteworthy that substitution of Tyr(440) with Phe, as found in MRP3, reduced LTC(4) and GSH-stimulated estrone-3-sulfate transport without affecting transport of other substrates tested. The mutation increased the K(m) for LTC(4) 5-fold and substantially reduced photolabeling of MRP1 by both [3H]LTC(4) and the GSH derivative, azidophenacyl-[35S]GSH. These results suggest that Tyr(440) makes a major contribution to recognition of GSH and the GSH moiety of conjugates such as LTC(4).
Subject(s)
Multidrug Resistance-Associated Proteins/chemistry , Amino Acid Sequence , Amino Acid Substitution , Cell Line , Cell Membrane/metabolism , Cell Survival/drug effects , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/genetics , Estradiol/analogs & derivatives , Estradiol/metabolism , Estrone/analogs & derivatives , Estrone/metabolism , Etoposide/pharmacology , Glutathione/analogs & derivatives , Glutathione/chemistry , Glutathione/metabolism , Humans , Kinetics , Leukotriene C4/metabolism , Methotrexate/metabolism , Models, Molecular , Molecular Sequence Data , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Mutagenesis, Site-Directed , Protein Binding , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Substrate Specificity/genetics , Transfection , Vincristine/pharmacologySubject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Organic Anion Transporters, Sodium-Dependent/metabolism , Rosuvastatin Calcium/pharmacokinetics , Symporters/metabolism , Animals , HeLa Cells , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Liver/metabolism , Male , Mice , Mice, Knockout , Models, Animal , Organic Anion Transporters, Sodium-Dependent/genetics , Rosuvastatin Calcium/administration & dosage , Symporters/genetics , Tissue DistributionABSTRACT
Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support TH2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG1 and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology.
Subject(s)
Asthma/chemically induced , Asthma/metabolism , Mast Cells/physiology , Receptors, IgE/metabolism , Receptors, Tumor Necrosis Factor, Member 14/metabolism , Airway Remodeling , Animals , Antibodies , Antigens, Dermatophagoides/immunology , Antigens, Dermatophagoides/toxicity , Asthma/pathology , Bronchoalveolar Lavage Fluid/cytology , Female , Gene Expression Regulation/drug effects , Genotype , Immunoglobulin E , Immunoglobulin G , Mice , Mice, Knockout , Ovalbumin/immunology , Ovalbumin/toxicity , Receptors, IgE/genetics , Receptors, Tumor Necrosis Factor, Member 14/geneticsSubject(s)
Liver/drug effects , Liver/metabolism , Octamer Transcription Factor-1/genetics , Octamer Transcription Factor-1/metabolism , Organic Cation Transport Proteins/genetics , Organic Cation Transport Proteins/metabolism , Pharmacogenetics , Cholestasis/metabolism , Glucose/metabolism , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Hypoglycemic Agents/pharmacology , Liver/pathology , Metformin/pharmacology , Polymorphism, Genetic/genetics , RNA, Messenger/metabolismABSTRACT
BACKGROUND: Nondaily statin dosing is an alternative for patients unable to tolerate daily dosing. The higher potency and longer half-life of rosuvastatin lends itself to this regimen. The basis of this improved tolerability is not understood, but might be related to lower plasma drug concentrations. We examined the efficacy of nondaily rosuvastatin in previously statin-intolerant patients and determined plasma drug concentrations at various dose regimens. METHODS: A retrospective analysis at a specialty lipid clinic identified 58 patients eligible for evaluation after therapy with nondaily rosuvastatin. Plasma rosuvastatin levels were measured by liquid chromatography-mass spectrometry in 12 patients taking 10 mg nondaily rosuvastatin and in 11 and 12 age- and sex-matched patients taking 10 mg and 5 mg rosuvastatin daily, respectively. Whole body cholesterol synthesis was estimated from serum lathosterol measured by liquid chromatography-mass spectrometry. RESULTS: In patients with a previous history of statin intolerance, nondaily rosuvastatin (average of 29.4 mg per week) lowered low-density lipoprotein cholesterol by 34.4 ± 21.3% (P < 0.001). Serum lathosterol levels were significantly higher in patients on nondaily regimens, as expected. However, mean plasma rosuvastatin levels of patients taking 10 mg nondaily did not significantly differ from those taking 10 mg daily. CONCLUSIONS: In statin intolerant patients, nondaily rosuvastatin resulted in clinically relevant reductions in low-density lipoprotein cholesterol levels, with improved compliance. Whole body cholesterol synthesis was higher in patients taking nondaily rosuvastatin, but no differences in plasma drug concentrations were observed, suggesting that the improved tolerability was independent of plasma rosuvastatin levels.
Subject(s)
Cholesterol, LDL/blood , Cholesterol/blood , Fluorobenzenes/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Aged , Cholesterol, LDL/drug effects , Chromatography, Liquid , Drug Administration Schedule , Female , Fluorobenzenes/blood , Fluorobenzenes/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Mass Spectrometry , Middle Aged , Pyrimidines/blood , Pyrimidines/therapeutic use , Retrospective Studies , Rosuvastatin Calcium , Sulfonamides/blood , Sulfonamides/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Ezetimibe is typically administered at a dose of 10 mg daily, with few reports of use at other doses. We compared plasma concentrations of low-density lipoprotein (LDL) cholesterol and other lipid variables in patients with dyslipidemia who were receiving ezetimibe 10 mg and then 20 mg daily. METHODS: A retrospective chart review identified 27 patients who received ezetimibe 10 mg and then 20 mg daily at different times; 15 participants were receiving stable statin therapy and 12 were not receiving concomitant statins. Plasma concentrations of lipids, creatine kinase (CK), and aspartate transaminase (AST) were determined. Plasma concentrations of ezetimibe and ezetimibe glucuronide were measured in a second group of patients. RESULTS: Patients taking statins and ezetimibe 20 mg had further reductions in total and LDL cholesterol of 7.1% and 10.3%, respectively (both P < 0.05) than did those receiving the 10-mg dose. No difference between 20-mg and 10-mg dosing was seen among patients not receiving statins. Plasma concentrations of ezetimibe and its active metabolite were about 2-fold higher (P < 0.05) in patients taking ezetimibe 20 mg than in those receiving 10 mg daily. All patients tolerated ezetimibe 20 mg without side effects. CONCLUSIONS: Ezetimibe 20 mg daily reduced total and LDL cholesterol further in patients receiving statin therapy compared with 10 mg daily. Prospective studies are required to show whether the higher plasma levels of ezetimibe and its active metabolite in patients taking the 20-mg dose have any detrimental effects. Increasing the ezetimibe dose to 20 mg daily might be an interesting potential approach for patients who fail to reach lipid targets on ezetimibe 10 mg daily along with maximally tolerated doses of statin.
Subject(s)
Anticholesteremic Agents/administration & dosage , Azetidines/administration & dosage , Cholesterol, LDL/blood , Dyslipidemias/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Aged , Anticholesteremic Agents/blood , Aspartate Aminotransferases/blood , Azetidines/blood , Creatine Kinase/blood , Dose-Response Relationship, Drug , Ezetimibe , Female , Glucuronides/blood , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
BACKGROUND: A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. METHODS AND RESULTS: In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for sex, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (P<0.001) and ABCG2 c.421C>A (P<0.01) were important to rosuvastatin concentration (adjusted R(2)=0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (P<0.01) and c.521T>C (P<0.05) and 4ß-hydroxycholesterol, a CYP3A activity marker (adjusted R(2)=0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. CONCLUSIONS: Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine whether this approach reduces incidence of statin myopathy.