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Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify novel lipid-associated genes and study the relationships between lipids, genotypes, gene expression and hundreds of complex human diseases from electronic Medical Records and Genomics (347 traits) and UK Biobank (549 traits) cohorts. Aside from 67 novel lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies.

Differential diagnosis of fevers?, Fever without localizing features?, Sepsis?, Cancer?, General rules of cancer management?, Rheumatoid arthritis?, Osteoarthritis?, Systemic lupus erythematosus?, Typhoid and paratyphoid fevers?, Rickettsioses?, Bartonella?, Ehrlichia?, Coxiella?, Relapsing fevers?, Leptospirosis?, Brucellosis?, Plague?, Melioidosis?, Anthrax?, African trypanosomiasis?, American trypanosomiasis?, Visceral leishmaniasis (kala-azar)?, Infectious mononucleosis?, Measles?, Arboviruses and zoonotic haemorrhagic fever viruses , Ebola and Marburg virus diseases, Crimean-Congo haemorrhagic fever, Rift Valley fever, Lassa fever, Hantavirus infections, Severe fever and thrombocytopenia, Zika virus, Japanese encephalitis , Dengue virus, Yellow fever, West Nile virus , Kyasanur Forest Disease, Chikungunya, Ross River fever, O'nyong nyong

Purpose Hydrocodone, codeine, oxycodone, and tramadol are frequently prescribed to adolescents for moderate pain related to minor trauma or dental, surgical, or medical procedures. Pharmacokinetic and pharmacodynamic differences between these opioids could affect their relative safety. We aimed to compare occurrence of opioid-related adverse events in adolescents without cancer or other severe conditions taking hydrocodone, codeine, oxycodone, and tramadol. Methods Retrospective cohort study of 201 940 Tennessee Medicaid enrollees 12 to 17 years of age without cancer, other severe conditions, or evidence of substance abuse with 529 731 filled prescriptions for study opioids. Adverse events were defined as an emergency department visit, hospital admission, or death related to opioid use, confirmed by medical record review. Serious events had opioid-related escalation of care, hospitalization, or death. Propensity-score adjusted hazard ratios (HRs) were calculated with hydrocodone as the reference category. Results The incidence of opioid-related adverse events per 10 000 person-years of opioid exposure was 97.5 for hydrocodone (127 events/13 026 person-years), 91.2 for codeine (58/6,359), 229.7 for oxycodone (43/1,872), and 317.7 for tramadol (47/1479). The HRs for tramadol in comparison with hydrocodone for all and serious events were 2.98 (2.03-4.39) and 2.94 (1.81-4.75), respectively. Increased risk for tramadol was consistently present when the adverse events were restricted to those with neurologic-respiratory depression/other symptoms of possible overdose. Conclusion In adolescents without cancer or other severe conditions prescribed short-acting opioids, the incidence of both all opioid-related adverse events and more serious events with opioid-related escalation of care, hospitalization, or death was consistently greater for tramadol than for hydrocodone.

Background Blood pressure visit-to-visit variability is a novel risk factor for deleterious long-term cardiac and renal outcomes in the general population. We hypothesized that patients with systemic lupus erythematosus (SLE) have greater blood pressure visit-to-visit variability than control subjects and that blood pressure visit-to-visit variability is associated with a higher comorbidity burden. Methods We studied 899 patients with SLE and 4172 matched controls using de-identified electronic health records from an academic medical center. We compared blood pressure visit-to-visit variability measures in patients with SLE and control subjects and examined the association between blood pressure visit-to-visit variability and patients’ characteristics. Results Patients with SLE had higher systolic blood pressure visit-to-visit variability 9.7% (7.8–11.8%) than the control group 9.2% (7.4–11.2%), P Conclusion Patients with SLE had higher blood pressure visit-to-visit variability than controls, and this increased blood pressure visit-to-visit variability was associated with greater Charlson comorbidity scores, several clinical characteristics and immunosuppressant medications. In particular, hydroxychloroquine prescription was associated with lower blood pressure visit-to-visit variability.

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q

Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).

Aim: Sympathetic activation suppresses insulin secretion via pancreatic ADRA2A. Because sympathetic activity and insulin demand increase during pregnancy, we tested the hypothesis that ADRA2A variants are associated with gestational diabetes (GDM). Patients & methods: Among Caucasian pregnant women without pre-existing diabetes, we genotyped 458 who had GDM and 1537 without GDM for seven ADRA2A variants. Results: rs1800038 (OR: 2.34; p = 0.020) and rs3750625 (OR: 1.56; p = 0.010) increased the risk of GDM, and rs11195418 decreased it (OR: 0.62; p = 0.025). The associations remained significant after adjustment for maternal age, maternal BMI, parity and a genetic risk score that included variants previously associated with Type 2 diabetes mellitus and GDM. Conclusion: ADRA2A genetic variation contributes independently to the risk of GDM in Caucasian women.

Objectives Sodium (Na+) is stored in the skin and muscle and plays an important role in immune regulation. In animal models, increased tissue Na+ is associated with activation of the immune system, and high salt intake exacerbates autoimmune disease and worsens hypertension. However, there is no information about tissue Na+ and human autoimmune disease. We hypothesized that muscle and skin Na+ content is (a) higher in patients with systemic lupus erythematosus (SLE) than in control subjects, and (b) associated with blood pressure, disease activity, and inflammation markers (interleukin (IL)-6, IL-10 and IL-17 A) in SLE. Methods Lower-leg skin and muscle Na+ content was measured in 23 patients with SLE and in 28 control subjects using 23Na+ magnetic resonance imaging. Demographic and clinical information was collected from interviews and chart review, and blood pressure was measured. Disease activity was assessed using the SLE Disease Activity Index (SLEDAI). Plasma inflammation markers were measured by multiplex immunoassay. Results Muscle Na+ content was higher in patients with SLE (18.8 (16.7–18.3) mmol/L) than in control subjects (15.8 (14.7–18.3) mmol/L; p + content was also higher in SLE patients than in controls, but this difference was not statistically significant. Among patients with SLE, muscle Na+ was associated with SLEDAI and higher concentrations of IL-10 after adjusting for age, race, and sex. Skin Na+ was significantly associated with systolic blood pressure, but this was attenuated after covariate adjustment. Conclusion Patients with SLE had higher muscle Na+ content than control subjects. In patients with SLE, higher muscle Na+ content was associated with higher disease activity and IL-10 concentrations.

Aims: To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response. Methods: We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia. Results: Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels. Conclusion: Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.

Sodium and potassium intake are modifiable determinants of hypertension in the general population but have not been studied in patients with systemic lupus erythematosus (SLE). We examined the relationship between urinary excretion of sodium and potassium, as an estimate of intake, and blood pressure in patients with SLE. We studied 178 SLE patients and 86 controls, matched for age, sex, and race. Urine sodium (Na+) and potassium (K+) were measured by flame photometry. Blood pressure was the average of two resting measurements. The associations between systolic (SBP) and diastolic blood pressures (DBP) and estimated 24-hour urinary Na+, K+, and Na+:K+ ratio were tested. The estimated mean 24-hour urinary K+ excretion was lower, and the Na+:K+ ratio was higher in patients with SLE than controls. There were no significant differences in the estimated 24-hour urinary Na+. In patients with SLE, a higher urinary Na+:K+ ratio was associated with higher SBP (β coefficient = 4.01, p = 0.023) and DBP (β coefficient = 4.41, p = 0.002) after adjusting for age, sex, and race. SLE patients had significantly lower estimated 24-hour urinary K+ and higher estimated 24-hour urinary Na+: K+ ratio than controls. The urinary Na+:K+ ratio was significantly associated with SBP and DBP.

The alpha1B (α1B)-adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean (95% confidence interval), 144 (69–299) ng ml−1) compared with 27 African-American non-carriers (208 (130–334) ng ml−1; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity.

Cellular microRNAs (miRNA) have proven to be critical regulators of inflammatory gene expression across many pathways within autoimmunity. Circulating miRNAs serve as a new class of disease biomarkers. Nevertheless, the functional roles of miRNAs, particularly extracellular miRNAs, in systemic lupus erythematosus (SLE) remain poorly understood. Therefore, we aimed to link changes in extracellular miRNAs to lymphocyte gene regulation and the pathophysiology of SLE. Here, we demonstrate that circulating miR-22-3p levels are associated with SLE, and miR-22-3p regulates T and B cell function and SLE-associated kidney disease. Based on high-throughput small RNA sequencing and real-time PCR, extracellular miR-22-3p levels were found to be significantly increased in whole plasma in human SLE subjects. To determine the functional impact of miR-22-3p in SLE, miR-22-3p loss-of-function studies were performed in a mouse model of SLE (B6.SLE1.2.3). We found that in vivo administration of locked-nucleic acid inhibitors of miR-22-3p (LNA-22) reduced lymphocyte accumulation in both the spleen and lymph nodes compared to LNA scramble (LNA-Scr) control-treated mice. Strikingly, LNA-22-3p treatments reduced kidney disease pathology and glomerular IgG deposition compared to LNA-Scr treatments in SLE mice. Moreover, miR-22-3p inhibition reduced the proportion of T effector memory IFN-γ producing CD4+ T cells, suggesting that miR-22-3p regulates Th1 T cell differentiation. We also found that miR-22 inhibition in mice reduced STAT1 phosphorylation in the kidney which was correlated with loss of IFN-γ production by splenic CD4+ T cells. In conclusion, our findings suggest that miR-22-3p is a critical regulator of SLE-associated CD4+ T cell immunity and kidney disease. These results provide therapeutic potential for limiting splenic Th1 signaling and preventing the progression of lupus nephritis.Key FindingsExtracellular miR-22-3p levels are significantly increased in plasma from human SLE subjects.Inhibition of miR-22-3p in vivo significantly reduced lymphocyte accumulation in both the spleen and lymph nodes in a mouse model of SLE, thus reducing splenomegaly and lymphadenopathy.miR-22-3p inhibition significantly reduced IFN-γ expression and secretion from splenic T cell subsets.Inhibition of miR-22-3p in vivo resulted in decreased IgG deposition in the kidney, decreased STAT1 phosphorylation, and decreased kidney disease in a mouse model of SLE.

Background Resistant hypertension (RHTN) is characterised by blood pressure that remains ≥140/90 mmHg despite concurrent use of 3 antihypertensive drugs. In the general population, RHTN is associated with a 47% increased risk of cardiovascular events. 1 Patients with systemic lupus erythematosus (SLE) have increased cardiovascular risk; however, no research has addressed the incidence, prevalence, or risk factors associated with RHTN in patients with SLE. Objectives To compare the risk of RHTN in patients with SLE and frequency-matched controls without SLE; to define factors associated with RHTN in patients with SLE. Methods We used a validated algorithm (94% PPV) to identify patients with SLE from the electronic health records (EHR) at an academic medical centre. 2 We established a control cohort matched by age, race, and sex with a 5:1 control-case ratio. Follow-up began at first ICD9 code for SLE (cases) or first ICD9 code (controls) and continued until RHTN diagnosis or last note. RHTN diagnosis required either the simultaneous use of 3 antihypertensive drugs and a mean blood pressure ≥140/90 mm Hg in the following 6 months, or the use of ≥4 antihypertensive drugs simultaneously. We used logistic regression and Cox proportional hazards (CPH) models to compare risk of RHTN between groups, with CPH performed on incident cases only. Results We studied 1044 patients with SLE and 5241 controls (median age 42, [31–54] 90% female and 70% Caucasian). Of the total cohort, RHTN developed in 106 SLE patients (10%) and 278 controls (4%). The incidence rate of RHTN was 14.7 cases/1000 person-years in SLE patients compared to 7.4 in controls [HR 1.66, 95% CI, 1.25–2.21] (figure 1). In logistic regression models, RHTN was associated with older age, black race, male gender and end stage renal disease (ESRD). Patients with SLE had a higher risk of RHTN when adjusted for age, sex, race, calendar year, and ESRD [HR 1.53, 1.15–2.05]. In an analysis among SLE patients, RHTN was associated with mortality in an unadjusted model [HR 3.38, 2.20–5.18]. This association remained when age, sex and race were added to the model [HR 2.58, 1.65–4.03], but when ESRD, calendar year and creatinine were included, the association was no longer significant [HR 1.51, 0.91–2.51]. Log rank test: p=0.000391 Conclusions Patients with SLE have a higher risk of RHTN compared to frequency-matched controls. RHTN is an important comorbiditiy for clinicans to recognise in SLE, as it is associated with a 3.3-fold higher risk of mortality. References [1] Muntner P, et al. Hypertension2014;64(5):1012–1021. [2] Barnado A, et al. Arthritis Care Res2017;69(5):687–693. Acknowledgements VUMC’s Synthetic Derivative supported by institutional funding and by the CTSA grant ULTR000445 from NCATS/NIH. CTSA awaUL1TR000445 from NCATS, The Rheumatology Research Foundation, Lupus Research Alliance and K-23 award from the NIAMS. Disclosure of Interest None declared

OBJECTIVE: Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) risk. In the general population, exercise improves several CV risk factors. In a cross-sectional study, we examined the hypothesis that more exercise is associated with protective traditional and non-traditional CV risk factor profile in patients with RA. METHODS: Patient-reported exercise outside of daily activities was quantified by time and metabolic equivalents per week (METmin/week) and CV risk factors including blood pressure, standard lipid profiles, lipoprotein particle concentrations (NMR spectroscopy), and vascular indices were measured in 165 patients with RA. The relationship between exercise and CV risk factors was assessed according to whether patients exercised or not, and after adjustment for age, race and sex. RESULTS: Over half (54%) of RA patients did not exercise. Among those who did exercise, median value for exercise duration was 113 minute/week [IQR: 60, 210], and exercise metabolic equivalent expenditure was 484 METmin/week [IQR: 258, 990]. Disease activity (measured by DAS28 score), C-reactive protein, waist-hip ratio, and prevalence of hypertension were lower in patients who exercised compared to those who did not (all P-values

PURPOSE OF REVIEW Patients with rheumatoid arthritis (RA) have accelerated atherosclerosis despite the appearance of having a less atherogenic lipid profile; however, lipoprotein function rather than concentration may be a better indicator of atherosclerotic risk. The purpose of this review is to summarize recent findings concerning HDL function in patients with RA. RECENT FINDINGS Two major activities of HDL, its antioxidant and cholesterol efflux functions have been examined in RA. HDL antioxidant capacity is inversely associated with inflammation and RA disease activity; however, there is no clear consensus if antioxidant capacity is altered significantly in RA compared with control study participants. Moreover, despite numerous studies there is no consensus whether HDL cholesterol efflux capacity is significantly altered in RA compared with control study participants or influenced by inflammation or disease activity. SUMMARY Additional studies will be valuable to consolidate existing data and find consensus. Moreover, studies evaluating the impact of various HDL functions on cardiovascular disease in RA are needed.

Background GlycA is a novel marker of systemic inflammation detected by nuclear magnetic resonance (NMR) spectroscopy. In the general population, GlycA is correlated with inflammatory markers such as C-reactive protein (CRP) and associated with coronary heart disease and diabetes. The utility of GlycA in patients with systemic lupus erythematosus (SLE) has not been defined. Therefore, we tested the hypothesis that GlycA concentrations are elevated in patients with SLE and associated with other markers of inflammation and coronary atherosclerosis. Methods We compared concentrations of GlycA, detected by NMR, in 116 patients with SLE and 84 control subjects frequency-matched for age, sex, and race. SLE disease activity index (SLEDAI) and the SLE Collaborating Clinics damage index (SLICC) were calculated. Acute phase reactants, a panel of cytokines, and a lipid panel were measured. Electron beam computer tomography (EBCT) was used to quantify coronary artery calcification, a measure of coronary artery atherosclerosis. Results Patients with SLE had higher concentrations of GlycA (398 (350–445)) than control subjects (339 (299–391)) µmol/L, p Conclusions Concentrations of GlycA are higher in patients with SLE than control subjects and associated with markers of inflammation but not with SLE disease activity or chronicity scores or coronary artery calcification.

Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).

Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype-directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).

This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

Purpose The opioid analgesic propoxyphene was withdrawn from the U.S. market in 2010, motivated by concerns regarding fatality in overdose and adverse cardiac effects, including prolongation of the QT interval. These concerns were based on case reports, summary vital statistics, and surrogate endpoint studies.

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with pCONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

Free fatty acids (FFAs) are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines promote lipolysis and increase FFAs, a cause of endothelial dysfunction and increased atherosclerosis risk. We hypothesized that increased inflammation is associated with increased FFAs, resulting in insulin resistance and atherosclerosis in patients with systemic lupus erythematosus (SLE). We measured clinical variables, serum FFAs, homeostasis model assessment for insulin resistance (HOMA), inflammatory cytokines, markers of endothelial activation, cholesterol concentrations and coronary artery calcium in 156 patients with SLE and 90 controls. We compared FFAs in patients with SLE and controls using Wilcoxon rank sum tests and further tested for the independent association between FFAs and disease status with adjustment for age, race and sex using multivariable regression models. We assessed the relationship between FFAs and continuous variables of interest using Spearman correlation and multivariable regression analysis. Levels of FFAs were higher in patients with SLE than controls (0.55 mmol/l (0.37–0.71) vs 0.44 mmol/l (0.32–0.60), P = 0.02). Levels of FFAs remained significantly higher among patients with SLE after adjustment for age, race and sex ( P = 0.03) but not after further adjustment for body mass index ( P = 0.13). FFA levels did not differ according to the usage of current immunosuppressive medications in univariate and adjusted analysis (all P > 0.05). Among patients with SLE, concentrations of FFAs were higher among those with metabolic syndrome compared to those without (0.66 mmol/l (0.46–0.81) vs 0.52 mmol/l (0.35–0.66), P 0.05) but were positively associated with levels of E-selectin (rho = 0.33, P =

Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized.We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients, who had been dosed to a steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked deidentified electronic medical record data. Genotyping included Affymetrix drug-metabolizing enzymes and transporters Plus (1936 polymorphisms), custom Sequenom Massarray iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration to dose ratio.In analyses, which adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration to dose ratio with CYP3A5 rs776746 (P=7.15×10), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1I2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement and 46% was explained by the model containing clinical covariates.This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

Women with systemic lupus erythematosus (SLE) have increased risk for coronary heart disease (CHD) which is underestimated by the Framingham risk score (FRS). We hypothesized that new risk scores that include inflammation or vascular age in the risk calculation would better identify women with SLE at risk for CHD, particularly in those with subclinical coronary atherosclerosis. We calculated the FRS and Reynolds risk score (RRS) in 121 women with SLE and 65 age-matched female controls; coronary age-modified risk scores (camFRS, camRRS) were calculated using coronary age derived from the coronary artery calcium (CAC) score. Risk scores were compared in SLE and controls, and in SLE patients with and without CAC. Although CAC was present in 21 SLE patients (17%) and four controls (6%) ( p = 0.033); the FRS, camFRS, RRS, and camRRS, did not differ significantly among SLE and controls ( p > 0.05), but were all significantly higher in SLE patients with CAC compared with those without ( p

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field. 1 Focused Literature review The Supplementary Notes online include a systematic literature review of CYP2C9 and VKORC1 genotype and warfarin dosing, which forms the basis for this guideline. drug: w arF arin Warfarin (Coumadin and others) is the most commonly used oral anticoagulant worldwide, with annual prescriptions typically equaling 0.5–1.5% of the population. It is prescribed for treatment and prevention of thrombotic disorders. 2 Although highly efficacious, warfarin’s narrow therapeutic index and wide interindividual variability make its dosing notoriously challenging. 3–5 Complications from inappropriate warfarin dosing are among the adverse events most frequently reported to the US Food and Drug Administration (FDA) and one of the most common reasons for emergency room visits. 6 Warfarin is often dosed empirically: an initial dose is prescribed, typically followed by at least weekly measurement of the INR and subsequent dose adjustment. The initial dose is often based on population averages (e.g., 3–5 mg/day), but stable doses to achieve an INR of 2–3 can range from 1–20 mg/ day. The iterative process to define the appropriate dose can take weeks to months, and during this period patients are at increased risk of over- or under-anticoagulation and thus at risk of thromboembolism or bleeding.

To examine changes in patterns of medication utilization in patients with RA.Data from Tennessee Medicaid (TennCare) databases (1995-2004) were used to identify adults with both a diagnosis of RA and at least one DMARD prescription each year. Annual age-specific utilization of DMARDs, glucocorticoids, NSAIDs and narcotics was measured on the last day of each year to determine the point prevalence of use of these agents.Records from 23 342 patients with treated RA were analysed. Most patients were females (78%) and white (74%). The median age was 57 yrs (interquartile range: 48-65). The proportion of patients who had a current DMARD prescription on the index date increased from 62% in 1995 to 71% in 2004 (P0.001). MTX was the most commonly used DMARD. By the end of 2004, 22% of patients had a current prescription for a biologic, and etanercept represented 51% of all biologic therapies. During the study period, the overall utilization of glucocorticoids decreased from 46% to 38% (P0.001), whereas NSAID utilization increased from 33% to 38% (P0.001), and use of narcotics increased from 38% to 55% (P0.001). A secondary analysis that identified RA patients based on diagnosis codes alone, showed similar patterns, but lower DMARD utilization which increased from 33% to 52% overall and from 0% to 16% for biologics.The utilization of DMARDs increased in TennCare patients with RA, and by 2004, use of biologics was substantial. Although glucocorticoid utilization decreased, use of both NSAIDs and narcotics increased.

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.

Biologic disease-modifying antirheumatic drugs (DMARDs) are efficacious for treating rheumatoid arthritis (RA). However, measurements of relative effectiveness, including treatment adherence and persistence, are lacking. We evaluated adherence and persistence during new episodes of use of traditional and biologic DMARDs.Using Tennessee Medicaid databases (1995-2004), we assembled a retrospective cohort of patients diagnosed with RA, and identified new episodes of use for 12 DMARD regimens. We evaluated persistence through survival analyses, and adherence within episodes through the medication possession ratio. A risk score was included in the analyses to account for measured confounders.We identified 14,932 patients with RA; 6018 patients had 10,547 episodes of new use of DMARDs. Considering methotrexate as the reference and after adjustment for measured confounders, episodes of new use of sulfasalazine [adjusted hazard ratio (aHR) = 1.59; 95% confidence interval (CI) = 1.47-1.72] and infliximab alone (aHR = 1.37, 95% CI = 1.09-1.73) were more likely to be discontinued; and new episodes of etanercept (aHR = 0.82, 95% CI = 0.73-0.92) and methotrexate + adalimumab (aHR = 0.63, 95% CI = 0.48-0.84) were less likely to be discontinued. Compared with methotrexate, adherence was higher for leflunomide, infliximab, etanercept, and adalimumab and lower for sulfasalazine and all combined therapies.We developed an approach to assess persistence on and adherence to the most common DMARD therapies. In this large cohort, persistence and adherence to leflunomide and most biologic DMARD therapies were at least comparable to methotrexate. Adherence was lower for sulfasalazine and all combined therapies.

Methadone, a µ-opioid agonist long used as evidence-based treatment for opioid dependence,1 has been increasingly prescribed for chronic pain. In 2009, 4.4 million methadone prescriptions in the U.S. were for treatment of pain, accounting for 9% of prescribed opioid analgesics on a dose-adjusted basis.1 Methadone's primary advantages as an analgesic are a long elimination half-life,2 and low cost;1 however, its efficacy is comparable to that of other long-acting opioids.3 There are major concerns regarding methadone's relative safety. The risk for accidental overdose and lethal respiratory depression may be greater than that for other long-acting opioids. Because the duration of methadone's respiratory depressant effects is longer than that for its analgesic effects,4;5 inadvertent intoxication can occur as dose is increased to provide greater pain relief. This risk may be exacerbated by methadone's highly variable pharmacokinetics.4;5 In 2006, the FDA issued an advisory and the label was modified to warn of the potential for unintentional overdose.5–7 This concern was reinforced by autopsy series of opioid overdose deaths with over-representation of methadone-related cases8;9 and a U.S. study demonstrating a disproportionate number of prescription-opioid-related overdose deaths with methadone involvement.1 Methadone also has adverse cardiac effects. It prolongs the QT interval10 and has been implicated in numerous case reports of life-threatening ventricular arrhythmias.10–13 Cases of sudden cardiac death, the majority of which are due to ventricular arrhythmias,14;15 have been reported in methadone patients.16 These data have led to questions regarding the appropriateness of the widespread use of methadone for the treatment of chronic pain, particularly given other equally effective alternatives.1;3;17 However, the one cohort study comparing methadone to sustained-release (SR) morphine unexpectedly found that adjusted overall mortality was 44% lower for the methadone users.18 Given this controversy, we conducted a cohort study of patients receiving either methadone or morphine SR for non-cancer pain. Given the multiple mechanisms by which an opioid could increase mortality, the primary endpoint was total mortality during study followup.

The Framingham risk score is widely used to identify patients at increased cardiovascular risk, and women with systemic lupus erythematosus (SLE) have a marked increased prevalence of cardiovascular events. Thus, we examined the hypothesis that cardiovascular risk scores would identify women with SLE who had asymptomatic coronary atherosclerosis. Ninety-three women with SLE and 65 control subjects were studied. The Framingham score and a score for younger populations developed from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study were compared in both groups. Coronary atherosclerosis was ascertained by electron beam computed tomography. There were no significant differences in the median (interquartile range) Framingham [5 (2-10) compared to 7 (0-10), P = 0.88] and PDAY [15 (14-18) compared to 16 (13-18), P = 0.99] scores in patients with SLE and controls, respectively. Coronary atherosclerosis was associated with higher Framingham [12 (3-15) compared to 4 (1-8), P = 0.008] and PDAY [17 (15-19 compared to 15 (12-18), P = 0.03)] scores in patients with SLE; however, 99% of patients were classified as low-risk with a 10-year predicted risk of 1% (

Background A common polymorphism of the β1-adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance. Methods and results Resting and exercise hemodynamic responses were measured in subjects homozygous for Arg389 (n = 21) or Gly389 (n = 13) alleles before and 3 hours after administration of a β-blocker, atenolol. Demographic characteristics and atenolol concentrations were similar in the two genotypic groups. Genotype had a marked effect on resting hemodynamic responses to atenolol, with Arg389-homozygous subjects having a larger decrease in resting systolic blood pressure (8.7 ± 1.3 mm Hg versus 0.2 ± 1.7 mm Hg, P < .001) and mean arterial blood pressure (7.2 ± 1.0 mm Hg versus 2.0 ± 1.7 mm Hg, P = .009). Attenuation of exercise-induced hemodynamic responses by atenolol was not affected by genotype. Conclusions There is reduced sensitivity of Gly389 homozygotes to a β-adrenergic receptor antagonist, and this polymorphism may be an important determinant of variability in response to β-blockade. Clinical Pharmacology & Therapeutics (2003) 73, 366–371; doi: 10.1016/S0009-9236(02)17734-4

Endothelial nitric oxide synthase catalyses the formation of the vasodilator nitric oxide, a major regulator of vascular tone. The Asp298 polymorphism of the nitric oxide synthase gene is associated with altered function and expression of the enzyme in vitro and myocardial infarction and coronary artery spasm in vivo. We examined the effect of the Glu298Asp polymorphism on: (1) local vascular responses to phenylephrine, acetylcholine, glyceryl trinitrate and prostaglandin E1 in the dorsal hand vein; (2) changes in forearm blood flow during mental stress, a measure of nitric oxide-mediated effect on resistance vessels; (3) excretion of urinary nitrite/nitrate as a measure of total body nitric oxide production; and (4) F2-isoprostane metabolite, a measure of oxidative stress, in healthy Glu298 (n = 12) and Asp298 (n = 13) homozygotes. There were no significant differences in acetylcholine dose responses (P = 0.29) in Glu298 and Asp298 homozygotes. Responses to glyceryl trinitrate, prostaglandin E1 and the alpha-adrenergic agonist phenylephrine did not differ by genotype. Forearm blood flow was similar at rest and increased significantly (from 7.5 ml/min/100 ml to 12.2 ml/min/100 ml; P = 0.003), but similarly (P = 0.2), during mental stress in both genotypes. Asp298 homozygotes excreted significantly less nitrate/nitrite than Glu298 homozygotes (nitrate + nitrite/creatinine ratio 0.05 +/- 0.01 vs. 0.09 +/- 0.01, respectively; P < 0.005). Urinary F2-isoprostane metabolite excretion did not differ (Glu298, 2.04 +/- 0.25 ng/mg creatinine; Asp298, 1.85 +/- 0.37 ng/mg creatinine; P = 0.7). We conclude that in healthy volunteers the Glu298Asp polymorphism affects endogenous nitric oxide production without affecting nitric oxide-mediated vascular responses. This polymorphism may only have clinical significance in the presence of endothelial dysfunction.

Content. The risk for serious gastrointestinal complications due to nonsteroidal anti-inflammatory drugs (NSAIDs) is high in the elderly. Acetaminophen-based regimens are safer and may be as effective as NSAIDs for the treatment of osteoarthritis in many patients. Objective. To determine the effects of an educational program on NSAID use and clinical outcomes in nursing homes. Design and Setting. Randomized controlled study. Ten pairs of Tennessee nursing homes with ≥8% of residents receiving NSAIDs were randomized to intervention or control. Subjects. Nursing home residents (intervention n = 76 and control n = 71) aged 65 years and older taking NSAIDs regularly. Interventions. An educational program for physicians and nursing home staff that included the risks and benefits of NSAIDs in the elderly and an algorithm that substituted acetaminophen, topical agents, and nonpharmacologic measures for the treatment of noninflammatory musculoskeletal pain. Intervention and control subjects were assessed at baseline and 3 months later. Main Outcome Measures. Differences in NSAID and acetaminophen use, and pain, function, and disability scores in intervention and control nursing home subjects. Results. The intervention was effective resulting in markedly decreased NSAID use and increased acetaminophen use. Mean number of days of NSAID use in the 7 day periods before the baseline and 3 month assessments decreased from 7.0 to 1.9 days in intervention home subjects compared with a decrease from 7.0 to 6.2 days in control homes (P = 0.0001). Acetaminophen use in the 7 days immediately before the 3 month assessment increased by 3.1 days in intervention home subjects compared with 0.31 days in control homes (P = 0.0001). A similar proportion of subjects in control (32.5%) and intervention (35.4%) groups had worsening of their arthritis pain score (P = 0.81). Conclusions. An educational intervention effectively reduced NSAID use in nursing homes without worsening of arthritis pain.

Hypertension is more frequent and more severe in some Black populations. Although many studies have focused on hypertension in black people in an attempt to understand the genetic and environmental factors that regulate blood pressure, this approach has not been productive. Study of the relationship between specific phenotypes and genotypes, both within and across ethnic groups, is more likely to advance our understanding of the regulation of blood pressure than studies focused on race and blood pressure.

The alpha1-adrenergic receptor (alpha1-AR) mediates vasoconstriction and plays an important role in the regulation of vascular tone. Increased alpha1-AR-mediated vasoconstrictor sensitivity, increased vascular reactivity to stress, and an increased prevalence of hypertension occur in African-Americans. The human alpha1A-AR is the predominant alpha1-AR subtype in vascular smooth muscle. The potential relevance of alpha1A-AR genetic variation to ethnic differences in vascular response and to the pathogenesis of hypertension prompted us to determine the frequency distribution of a recently identified polymorphism (Arg492 to Cys) in the alpha1A-AR in normotensive and hypertensive black and white American individuals. Polymerase chain reaction-based PstI restriction fragment length polymorphisms in the human alpha1A-AR gene were determined in 231 African-American and 282 Caucasian individuals, both with and without hypertension. There were marked differences in the genotypic and allelic distributions of the Arg492 to Cys alpha1A-AR polymorphism between African-American and Caucasian individuals (Cys492/Cys492 genotype, normotensive: 7.6% versus 30.1%; hypertensive: 7.1% versus 26.2%; Cys492 allele, normotensive: 29.5% versus 53.8%; hypertensive: 28.8% versus 55.2%; blacks versus whites, P 0.05). The data indicate that this polymorphism is not associated with essential hypertension in black or white Americans, but that the frequency of the alpha1A-AR Arg492 allele occurs significantly more commonly in African-Americans than in Caucasians. The potential role of the Arg492 to Cys alpha1A-AR polymorphism in ethnic differences in vascular alpha1-adrenergic response requires further investigation.

Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. The reported population prevalence of the CYP2C19 poor metabolizer phenotype in Caucasians of European descent has been described as ranging from 0.9% to 7.7%. To address the question of whether the difference in the frequency of poor metabolizers represents an ethnic genetic microheterogeneity in the structure and expression of the CYP2C19 gene in Caucasian individuals, we performed a pooled analysis of available studies. Combined data from the 22 homogeneous studies showed that the frequency of poor metabolizers in healthy unrelated Caucasians determined by phenotyping was 2.8% (110 of 3990; 95% confidence interval 2.3-3.3). Data obtained from eight homogeneous studies that determined the frequency of poor metabolizers by genotyping showed that the genotypic frequency of poor metabolizers was 2.1% (28 of 1356; 95% confidence interval 1.3-2.8), consistent with the poor metabolizer frequency determined by phenotyping. In the extensive metabolizers, 26% (471 of 1786; 95% confidence interval 24.4-28.4) were heterozygotes. The observed frequencies of the three Mendelian genotypes were 73% for wt/wt, 26% for wt/m, and 2.1% for m/m. Based on the overall phenotypic poor metabolizer frequency of 2.8%, the expected genotypic frequencies were 69% for wt/wt, 28% for wt/m and 2.8% for m/m, which are in good agreement to the observed values. However, in the 84 Caucasian phenotyped and genotyped poor metabolizers, approximately 10% of the putative poor metabolizer alleles (17 of 168) were unknown. This study provides a systematic overview of the population distribution of the CYP2C19 poor metabolizer phenotype and CYP2C19 alleles and genotypes in healthy Caucasians living in different geographical areas, and shows a similar polymorphic pattern in the structure and expression of the CYP2C19 gene in the worldwide Caucasian populations.

Aims The frequency of CYP2C19 poor metabolizers (PMs) in populations of African descent has been reported to range from 1.0% to 35.4%. In order to determine with greater certainty the frequency of CYP2C19 PMs in such black populations we have performed a meta-analysis of the studies. Methods Relevant data on the frequency of both the PM phenotype of probe drugs (mephenytoin, omeprazole, and proguanil), and the distribution frequencies of CYP2C19 alleles and genotypes in black populations were summarized and reanalysed using a meta-analytical approach. Results Of nine reported studies two were excluded because of significant heterogeneity (χ2=115, P

Background —Although quinidine is known to elevate plasma digoxin concentrations, the mechanism underlying this interaction is not fully understood. Digoxin is not extensively metabolized, but it is known to be transported by the drug efflux pump P-glycoprotein, which is expressed in excretory tissues (kidney, liver, intestine) and at the blood-brain barrier. Accordingly, we tested the hypothesis that inhibition of P-glycoprotein–mediated digoxin transport by quinidine contributes to the digoxin-quinidine interaction. Methods and Results —First, we demonstrated active transcellular transport of both digoxin and quinidine in cultured cell lines that express P-glycoprotein in a polarized fashion. In addition, 5 μmol/L quinidine inhibited P-glycoprotein–mediated digoxin transport by 57%. Second, the effect of quinidine on digoxin disposition was studied in wild-type and in mdr1a (−/−) mice, in which the gene expressing the major digoxin-transporting P-glycoprotein has been disrupted. Because the in vitro data showed that quinidine itself is a P-glycoprotein substrate, quinidine doses were reduced in mdr1a (−/−) mice to produce plasma concentrations similar to those in wild-type control animals. Quinidine increased plasma digoxin concentrations by 73.0% ( P =0.05) in wild-type animals, compared with 19.5% ( P =NS) in mdr1a (−/−) mice. Moreover, quinidine increased digoxin brain concentrations by 73.2% ( P =0.05) in wild-type animals; by contrast, quinidine did not increase digoxin brain concentrations in mdr1a (−/−) mice but rather decreased them (−30.7%, P Conclusions —Quinidine and digoxin are both substrates for P-glycoprotein, and quinidine is a potent inhibitor of digoxin transport in vitro. The in vivo data strongly support the hypothesis that inhibition of P-glycoprotein–mediated digoxin elimination plays an important role in the increase of plasma digoxin concentration occurring with quinidine coadministration in wild-type mice and thus support a similar mechanism in humans.

Abstract It has been postulated that delayed facilitation of norepinephrine release by epinephrine is causally related to the development of hypertension. It has been proposed that a brief increase in epinephrine concentrations results in the uptake of epinephrine into the sympathetic nerve terminal. Subsequent rerelease of epinephrine stimulates presynaptic β-adrenergic receptors, resulting in a prolonged increase in plasma norepinephrine (NE) concentrations, with amplified sympathetic responses and vasoconstriction. To determine whether such epinephrine-induced, delayed facilitation of NE release occurs in a vascular bed draining resistance vessels and, if it occurs, whether that facilitation differs in hypertension, we used a radioisotope dilution method to measure unstimulated and isoproterenol-stimulated forearm NE spillover before, during, and after a 50 ng/min infusion of epinephrine for 30 minutes directly into the brachial artery. No delayed facilitatory effects of epinephrine on forearm NE spillover were observed in either 6 normotensive (NT) or 8 borderline hypertensive (BHT) subjects (NT unstimulated forearm NE spillover preepinephrine 1.79±0.41 ng/min versus postepinephrine 2.36±0.65 ng/min, P =.38; BHT preepinephrine 2.24±0.70 ng/min versus postepinephrine 1.93±0.46 ng/min, P =.51; NT isoproterenol-stimulated forearm NE spillover preepinephrine 4.61±1.01 ng/min versus postepinephrine 4.4±0.98 ng/min, P =.9; BHT preepinephrine 4.04±1.36 ng/min versus postepinephrine 4.69±1.49 ng/min P =.5). We conclude that the short-term local infusion of epinephrine does not have a delayed facilitatory effect on forearm NE spillover in NT or BHT subjects. Therefore, the prolonged increase in NE concentrations after epinephrine infusion previously shown systemically, and not seen locally in the forearm, suggests that the delayed facilitatory response to epinephrine may occur in other organs.

Summary The influence of genetic variation on warfarin dose requirement is limited for paediatric patients. We performed a retrospective, cross-sectional study to examine the effect of variant CYP2C9 and VKORC1 genotypes on warfarin dose in 100 children. Those with VKORC1 genotype AA required 48% of the dose of homozygous wild-type (GG, P

Coronary artery disease is the major cause of mortality in patients with systemic lupus erythematosus (SLE). Increased cardiovascular risk in SLE is not explained by traditional risk factors. We examined the hypothesis that genetic variation contributes to the presence of coronary atherosclerosis in patients with SLE. The genotypes of single-nucleotide polymorphisms (SNP) in 152 candidate genes linked with autoimmune or cardiovascular risk were determined in 125 patients with SLE. Coronary artery calcium (CAC), a measure of coronary atherosclerosis, was detected in 32 patients (26%) by electron-beam computed tomography. Polymorphism in 20 of the candidate genes ( ADAM33, ADIPOQ, CCL5, CCR7, CDKN2B, CSF1, IL4, IL12A, IL23R, INS, IRF5, MIF, MS4A1, PTGS1, PTPN22, RETN, SELE, TNFSF4, TNFRSF11B, and VCAM1) were nominally associated with the presence of CAC ( p-values = 0.001–0.047 after adjustment for age, sex and race). Some of these are known susceptibility genes for SLE and others have been implicated in cardiovascular disease in other populations. No association withstood false discovery rate adjustment. Replication studies in additional cohorts of patients with SLE may be informative.

Objectives α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is considerable interindividual variability in dorsal hand vein (DHV) constriction responses to α2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify the genetic factors contributing toward the interindividual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine. Methods DHV constriction responses to a local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable for constriction was log-transformed dexmedetomidine ED50. A genome-wide association study (GWAS) of 433 378 single-nucleotide polymorphisms (SNPs) was carried out for determining the sensitivity of DHV responses in 64 healthy Finnish individuals. Twenty SNPs were selected on the basis of the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals. Results In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type β was consistently associated with dexmedetomidine ED50 for DHV constriction (unadjusted P=0.00016 for the combined population). Conclusion Genetic variation in protein kinase C type β may contribute toward the interindividual variation in DHV constriction responses to α2-AR activation by the agonist dexmedetomidine.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org). The CPIC of the Pharmacogenomics Research Network (http://www.pgrn.org) and the Pharmacogenomics Knowledge Base (PharmGKB, http://www.pharmgkb.org) provides peer-reviewed, updated, evidence-based, freely accessible guidelines for the translation of genetic laboratory tests into actionable prescribing recommendations for specific drugs.1 CPIC guidelines undergo continuous peer review, and information pertaining to gene-specific alleles and nomenclature is updated periodically on the PharmGKB website. Furthermore, approximately every 2 years, each published guideline and associated Supplementary Data online are reviewed and updated accordingly. The first guideline to be reviewed is the CPIC Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing originally published in March 2011.2 We have done a focused review of the literature between June 2010 and November 2012 on TPMT genotype and thiopurine use (see Supplementary Data, Tables S1–S5, and Figure S1 online). At this time, there is no new evidence that would change our original recommendations in the published guideline; therefore, the original guideline publication remains current. Since the first CPIC guideline was published, the CPIC Steering Committee has recommended that authors address dosing in pediatrics or, at a minimum, comment that there is not enough supporting evidence to allow therapeutic recommendations in pediatrics. As thiopurines are a staple of childhood acute lymphoblastic leukemia and inflammatory bowel disease treatment regimens, much of the evidence (summarized in Supplementary Table S5 online) used to support the original dosing recommendation was generated in children. Furthermore, the dosing recommendations in Table 2 of the main guideline are presented in units of mg/m2 and mg/kg. Therefore, our original guideline dosing recommendations can be used in both the adult and pediatric populations. Although we are not modifying the original main guideline, we have updated the Supplementary Data online to include additional studies that further support our original recommendations (see Supplementary Table S5 online and the Other Considerations subsection of the Supplementary Data online).3,4,5 In addition, we have added information for additional variant alleles not included in the original guideline (see Supplementary Tables S1 and S2 online). Up-to-date information on TPMT gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).

SummaryPharmacogenetic dosing algorithms help predict warfarin maintenance doses, but their predictive performance differs in different populations, possibly due to unsuspected population-specific genetic variants. The objectives of this study were to quantify the effect of the VKORC1 D36Y variant (a marker of warfarin resistance previously described in 4% of Ashkenazi Jews) on warfarin maintenance doses and to examine how this variant affects the performance of the International Warfarin Pharmacogenetic Consortium (IWPC) dose prediction model. In 210 Israeli patients on chronic warfarin therapy recruited at a tertiary care centre, we applied the IWPC model and then added D36Y genotype as covariate to the model (IWPC+D36Y) and compared predicted with actual doses. Median weekly warfarin dose was 35 mg (interquartile range [IQR], 24.5 to 52.5 mg). Among 16 heterozygous D36Y carriers (minor allele frequency = 3.8%), warfarin weekly dose was increased by a median of 43.7 mg (IQR, 40.5 to 47.2 mg) compared to non-carriers after adjustment for all IWPC parameters, a greater than two-fold dose increase. The IWPC model performed suboptimally (coefficient of determination R2=27.0%; mean absolute error (MAE), 14.4 ± 16.2 mg/ week). Accounting for D36Y genotype using the IWPC+D36Y model resulted in a significantly better model performance (R2=47.2%, MAE=12.6±12.4 mg/week). In conclusion, even at low frequencies, variants with a strong impact on warfarin dose may greatly decrease the performance of a commonly used dose prediction model. Unexpected discrepancies of the performance of universal prediction models in subpopulations should prompt searching for unsuspected confounders, including rare genetic variants.

Identification of patients’ drug exposure information is critical to drug-related research that is based on electronic medical records (EMRs). Drug information is often embedded in clinical narratives and drug regimens change frequently because of various reasons like intolerance or insurance issues, making accurate modeling challenging. Here, we developed an informatics framework to determine patient drug exposure histories from EMRs by combining natural language processing (NLP) and machine learning (ML) technologies. Our framework consists of three phases: 1) drug entity recognition - identifying drug mentions; 2) drug event detection - labeling drug mentions with a status (e.g., “on” or “stop”); and 3) drug exposure modeling - predicting if a patient is taking a drug at a given time using the status and temporal information associated with the mentions. We applied the framework to determine patient warfarin exposure at hospital admissions and achieved 87% precision, 79% recall, and an area under the receiver-operator characteristic curve of 0.93.

Oxidative stress may play a role in the pathogenesis of depression. We tested the hypothesis that urinary F2 isoprostane, a robust marker of oxidative stress, was increased in patients with depression and associated with symptoms and response to treatment. Urinary F2 isoprostane was compared in 18 patients with depression and 36 age and sex matched control subjects. In patients, we tested the association between oxidative stress, depression questionnaires and antidepressant treatment. Urinary F2 isoprostane excretion was significantly higher in patients with depression than in control subjects. This association remained significant after adjustment for age, sex and BMI. Depression symptom severity scores were not correlated with F2 isoprostane excretion. Nine patients were treated with sertraline or bupropion for eight weeks. Depression severity rating scale scores decreased significantly and F2 isoprostane excretion increased. The increase in F2 isoprostane excretion was inversely correlated with the improvement in Hamilton Depression Rating 17 items. In conclusion, oxidative stress is increased in patients with depression. However, although treatment with either bupropion or sertraline reduces the symptoms of depression, it may increase F2 isoprostane excretion. These results suggest that alternative mechanisms, beyond oxidative stress, may be involved in the development of depression and subsequent responses to treatment.

Background: Even mild renal impairment is associated with increased atherosclerosis and cardiovascular mortality. Cystatin C, a novel measure of renal function, is more sensitive than conventional creatinine-based measures for the detection of subtle renal impairment. Increased cystatin concentrations are also associated with cardiovascular risk, independently of conventional measures of renal function. This study examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis. Methods: Serum cystatin C, creatinine, tumor necrosis factor (TNF)-α, interleukin (IL)-6, coronary artery calcium score (CACS), Framingham risk score (FRS), Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR), and other clinical parameters were measured in 118 patients with SLE and 83 control subjects. The independent association between concentrations of cystatin C and SLE was evaluated using multivariable linear regression models, and the relationship between renal measures and coronary calcium was assessed with multivariable proportional odds logistic regression models. Results: Cystatin C, but not other measures of renal function, was significantly higher in patients with SLE than in controls (1.09 [interquartile range, IQR: 0.85–1.28] mg/l vs. 0.89 [IQR: 0.76–0.99] mg/l; p Conclusions: Cystatin C was higher in patients with SLE than in control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.