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ObjectiveThe prevalence of hypertension, a major cardiovascular risk factor, is increased in patients with rheumatoid arthritis (RA) and may be driven by immune activation. The purpose of this study was to determine if ambulatory 24-hour blood pressure (BP) is elevated in RA vs control participants and whether it is associated with immune activation.MethodsWe conducted a cross-sectional study of 46 patients with RA and 23 control participants. Participants wore an ambulatory BP monitor that obtained diurnal BP every 15-30 minutes and nocturnal BP every 30 minutes. Inflammatory mediators in plasma were measured using an inflammation proteomics panel. Differences in BP measurements were assessed by Mann-Whitney Utest, and association with inflammatory mediators was assessed by Spearman correlation.ResultsPatients with RA and control participants had similar office BP, but median ambulatory systolic BP (SBP) measurements (24-hour [RA 121 mmHg vs control 116 mmHg; P= 0.01], diurnal [RA 128 mmHg vs control 120 mmHg; P= 0.003], and nocturnal [RA 112 mmHg vs control 103 mmHg; P= 0.002]) were higher in patients with RA. Patients with RA also had higher nocturnal diastolic BP (DBP; RA 63 mmHg vs control 57 mmHg; P= 0.02), but other DBP measurements were similar. Nocturnal BP dipping was less in patients with RA (12%) compared to control participants (16%; P= 0.02). In patients with RA, higher 24-hour and nocturnal SBPs and less nocturnal dipping were strongly correlated with a wide range of inflammatory mediators.ConclusionDespite similar office measurements, 24-hour and nocturnal SBP measurements were higher in patients with RA than in control participants and were strongly associated with inflammation.

Background: Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear. Objective: To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastro-duodenal bleeding and serious cardiovascular disease. Design: Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease. Setting: Tennessee Medicaid program. Patients: 20 596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris. Measurements: Baseline and follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death). Results: Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization. Limitations: Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital. Conclusion: In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk. Primary Funding Source: Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.

Pregnant women who have two copies of a gene variation affecting the beta(sub 2)-adrenergic receptor appear to be protected from premature birth to a certain extent. In a study of 279 pregnant women, only four percent of those who gave birth prematurely had two copies of this gene variation, compared to 31% of those who gave birth at term.

IMPORTANCE: Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count. OBJECTIVE: To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count. DESIGN, SETTING, AND PARTICIPANTS: This retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at Vanderbilt University Medical Center, Mount Sinai Health System, or Children’s Hospital of Philadelphia from January 1, 1998, to December 31, 2020. EXPOSURE: The rs2814778-CC genotype. MAIN OUTCOMES AND MEASURES: The proportion of individuals with the CC genotype who underwent BMB for an isolated low WBC count and had a normal biopsy result compared with the proportion of individuals with the CC genotype who underwent BMB for other indications and had a normal biopsy result. RESULTS: Among 399 individuals who underwent a BMB (mean [SD] age, 41.8 [22.5] years, 234 [59%] female), 277 (69%) had the CC genotype. A total of 35 patients (9%) had clinical histories of isolated low WBC counts, and 364 (91%) had other histories. Of those with a clinical history of isolated low WBC count, 34 of 35 (97%) had the CC genotype vs 243 of 364 (67%) of those without a low WBC count history. Among those with the CC genotype, 33 of 34 (97%) had normal results for biopsies performed for isolated low WBC counts compared with 134 of 243 individuals (55%) with biopsies performed for other histories (P < .001). CONCLUSIONS AND RELEVANCE: In this genetic association study, among patients of African American race who had a BMB with a clinical history of isolated low WBC counts, the rs2814778-CC genotype was highly prevalent, and 97% of these BMBs identified no hematologic abnormality. Accounting for the rs2814778-CC genotype in clinical decision-making could avoid unnecessary BMB procedures.

Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank linked to de-identified electronic health records, we studied 157 patients with a baseline pain score higher than 4 (0–10 scale) who received codeine. Based on CYP2D6genotyping, 69 were classified as poor/intermediate and 88 as normal/ultrarapid CYP2D6 metabolizers. Pain response was defined as a score of 4 or lower while receiving codeine. In a propensity-score adjusted model, poor/intermediate metabolizers had lower odds (OR = 0.35, p= 0.02) of achieving a pain response than normal/ultrarapid metabolizers. To discriminate between codeine responders and nonresponders, a score including CYP2D6 phenotype and clinical variables was built. The response rate was 38.5% among patients in the high, 17.3% in the intermediate, and 9.4% in the low-score groups, respectively (p= 0.001).

Low doses of the corticosteroid drug prednisone may benefit many patients with rheumatoid arthritis. Most doctors do not prescribe corticosteroids for these patients because of the severe side effects. However, doses of five milligrams or less per day can slow the progression of the disease.

Hypoglycemia is a common complication among type 2 diabetes mellitus (T2DM) patients receiving sulfonylurea therapy. The aim of this study was to determine if genetic contributions to sulfonylurea pharmacokinetics or pharmacodynamics substantially affect the risk of hypoglycemia in these patients. In a retrospective case–control study in European American patients with T2DM, we examined the potential association between CYP2C9reduced-function variants and sulfonylurea-related hypoglycemia. We also explored the relationship between sulfonylurea-related hypoglycemia and several candidate genetic variants previously reported to alter the response to sulfonylureas. We detected no evidence of association between CYP2C9reduced-function alleles or any of the candidate genetic variants and sulfonylurea-related hypoglycemia. In conclusion, we identified no clinically significant predictors of hypoglycemia among genes associated with sulfonylurea pharmacokinetics or pharmacodynamics.

Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95% CI: 0.54–0.64), 0.75 (0.71–0.80), 0.66 (0.61–0.71), and 0.78 (0.74–0.82) for models 1, 2, 3, and 4, respectively. During the replication phase, models 2 and 4 (AUC = 0.64, 95% CI: 0.59–0.70 and AUC = 0.63, 95% CI: 0.58–0.69, respectively) were significant in an independent group. Compared with TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.

It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, nmax= 40,914) and DIAGRAM (nmax= 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic= 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: −0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.

The relationship between commonly occurring genetic variants (G1 and G2) in the APOL1gene in African Americans and different disease traits, such as kidney disease, cardiovascular disease, and pre-eclampsia, remains the subject of controversy. Here we took a genotype-first approach, a phenome-wide association study, to define the spectrum of phenotypes associated with APOL1high-risk variants in 1,837 African American participants of Penn Medicine Biobank and 4,742 African American participants of Vanderbilt BioVU. In the Penn Medicine Biobank, outpatient creatinine measurement-based estimated glomerular filtration rate and multivariable regression models were used to evaluate the association between high-risk APOL1status and renal outcomes. In meta-analysis of both cohorts, the strongest phenome-wide association study associations were for the high-risk APOL1variants and diagnoses codes were highly significant for “kidney dialysis” (odds ratio 3.75) and “end stage kidney disease” (odds ratio 3.42). A number of phenotypes were associated with APOL1high-risk genotypes in an analysis adjusted only for demographic variables. However, no associations were detected with non-renal phenotypes after controlling for chronic/end stage kidney disease status. Using calculated estimated glomerular filtration rate -based phenotype analysis in the Penn Medicine Biobank, APOL1high-risk status was associated with prevalent chronic/end stage kidney disease /kidney transplant (odds ratio 2.27, 95% confidence interval 1.67-3.08). In high-risk participants, the estimated glomerular filtration rate was 15.4 mL/min/1.73m2; significantly lower than in low-risk participants. Thus, although APOL1high-risk variants are associated with a range of phenotypes, the risks for other associated phenotypes appear much lower and in our dataset are driven by a primary effect on renal disease.

To compare the risk of resistant hypertension (RHTN) in patients with systemic lupus erythematosus (SLE) and in controls without SLE, and to define factors associated with RHTNin patients with SLE. We studied 1,044 patients with SLEand 5,241 control subjects using de‐identified electronic health records from a tertiary care center. SLEwas defined as ≥4 International Classification of Diseases, Ninth Revision codes for SLEand antinuclear antibody titer ≥1:160. RHTNwas defined as uncontrolled blood pressure on 3 antihypertensive medications or requiring 4 or more antihypertensives to attain control. First, we compared the risk of RHTNbetween groups. Second, we examined the association between RHTNand all‐cause mortality in patients with SLE. RHTNwas nearly twice as prevalent in patients with SLEcompared to control subjects (10.2% and 5.3%, respectively), with an incidence rate of 10.2 versus 6.1 cases per 1,000 person‐years of observation (hazard ratio [HR] 1.72 [95% confidence interval 1.28–2.30]; P< 0.001, adjusted for age, sex, race, baseline end‐stage renal disease [ESRD], creatinine, and calendar year). In patients with SLE, we found associations between RHTNand black race, lower renal function, hypercholesterolemia, and increased inflammatory markers. RHTNwas associated with a significantly higher mortality risk (HR2.91, P= 0.0005) after adjustment for age, sex, race, calendar year, creatinine, baseline ESRD, and number of visits. Patients with SLEhave a higher risk of RHTNcompared to frequency‐matched controls, independent of multiple covariates. RHTNis an important comorbidity for clinicians to recognize in SLE, because it is associated with a higher risk of mortality.

Objective.MicroRNA (miRNA) are short noncoding RNA that regulate genes and are both biomarkers and mediators of disease. We used small RNA (sRNA) sequencing and machine learning methodology to develop an miRNA panel to reliably differentiate between rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and control subjects.Methods.Plasma samples from 167 RA and 91 control subjects who frequency-matched for age, race, and sex were used for sRNA sequencing. TIGER was used to analyze miRNA. DESeq2 and random forest analyses were used to identify a prioritized list of miRNA differentially expressed in patients with RA. Prioritized miRNA were validated by quantitative PCR, and lasso and logistic regression were used to select the final panel of 6 miRNA that best differentiated RA from controls. The panel was validated in a separate cohort of 12 SLE, 32 RA, and 32 control subjects. Panel efficacy was assessed by area under the receiver operative characteristic curve (AUC) analyses.Results.The final panel included miR-22-3p, miR-24-3p, miR-96-5p, miR-134-5p, miR-140-3p, and miR-627-5p. The panel differentiated RA from control subjects in discovery (AUC = 0.81) and validation cohorts (AUC = 0.71), seronegative RA (AUC = 0.84), RA remission (AUC = 0.85), and patients with SLE (AUC = 0.80) versus controls. Pathway analysis showed upstream regulators and targets of panel miRNA are associated with pathways implicated in RA pathogenesis.Conclusion.An miRNA panel identified by a bioinformatic approach differentiated between RA or SLE patients and control subjects. The panel may represent an autoimmunity signature, perhaps related to inflammatory arthritis, which is not dependent on active disease or seropositivity.

Background: Cardiovascular (CV) risk estimation calculators for the general population underperform in patients with rheumatoid arthritis (RA). The purpose of this study was to identify relevant protein biomarkers that could be added to traditional CV risk calculators to improve the capacity of coronary artery calcification (CAC) prediction in individuals with RA. In a second step, we quantify the improvement of this prediction of CAC when these circulating biomarkers are added to standard risk scores. Methods: A panel of 141 serum and plasma proteins, which represent a broad base of both CV and RA biology, were evaluated and prioritized as candidate biomarkers. Of these, 39 proteins were selected and measured by commercial ELISA or quantitative mass spectroscopy in 561 individuals with RA in whom a measure of CAC and frozen sera were available. The patients were randomly split 50:50 into a training/validation cohort. Discrimination (using area under the receiver operator characteristic curves) and re-classification (through net reclassification improvement and integrated discrimination improvement calculation) analyses were performed first in the training cohort and replicated in the validation cohort, to estimate the increase in prediction accuracy for CAC using the ACA/AHA (American College of Cardiology and the American Heart Association) score with, compared to without, addition of these circulating biomarkers. Results: The model containing ACC/AHA score pluscytokines (osteopontin, cartilage glycoprotein-39, cystatin C, and chemokine (C–C motif) ligand 18) and plusquantitative mass spectroscopy biomarkers (serpin D1, paraoxonase, and clusterin) had a statistically significant positive net reclassifications index and integrated discrimination improvement for the prediction of CAC, using ACC/AHA score without any biomarkers as the reference category. These results were confirmed in the validation cohort. Conclusion: In this exploratory analysis, the addition of several circulating CV and RA biomarkers to a standard CV risk calculator yielded significant improvements in discrimination and reclassification for the presence of CAC in individuals with RA.

Supplemental Digital Content is available in the text.

Objective.The prevalence of heart failure is increased 2-fold in patients with rheumatoid arthritis (RA); this is not explained by ischemic heart disease or other risk factors for heart failure. We hypothesized that in patients with RA without known heart disease, cardiac magnetic resonance imaging (cMRI) would detect altered cardiac structure, function, and fibrosis.Methods.We performed 1.5-T cMRI in 59 patients with RA and 56 controls frequency-matched for age, race, and sex, and compared cMRI indices of structure, function, and fibrosis [late gadolinium enhancement (LGE), native T1 mapping, and extracellular volume (ECV)] using Mann-Whitney U tests and linear regression, adjusting for age, race, and sex.Results.Most patients with RA had low to moderate disease activity [28-joint count Disease Activity Score–C-reactive protein median 3.16, interquartile range (IQR) 2.03–4.05], and 49% were receiving anti-tumor necrosis factor agents. Left ventricular (LV) mass, LV end-diastolic and -systolic volumes indexed to body surface area, and LV ejection fraction and left atrial size were not altered in RA compared to controls (all p > 0.05). Measures of fibrosis were not increased in RA: LGE was present in 2 patients with RA and 1 control subject; native T1 mapping was similar comparing RA and control subjects, and ECV (median, IQR) was lower (26.6%, 24.7–28.5%) in patients with RA compared to control subjects (27.5%, 25.4–30.4%, p = 0.03).Conclusion.cMRI measures of cardiac structure and function were not significantly altered, and measures of fibrosis were similar or lower in RA patients with low to moderate disease activity compared to a matched control group.

Circulating lipid concentrations are among the strongest modifiable risk factors for coronary artery disease (CAD). Most genetic studies have focused on Caucasian populations with little information available for populations of African ancestry. Using a cohort of ~2800 African–Americans (AAs) from a biobank at Vanderbilt University (BioVU), we sought to trans-ethnically replicate genetic variants reported by the Global Lipids Genetics Consortium to be associated with lipid traits in Caucasians, followed by fine-mapping those loci using all available variants on the MetaboChip. In AAs, we replicated one of 56 SNPs for total cholesterol (TC) (rs6511720 in LDLR, P=2.15 × 10−8), one of 63 SNPs for high-density lipoprotein cholesterol (HDL-C) (rs3764261 in CETP, P=1.13 × 10−5), two of 46 SNPs for low-density lipoprotein cholesterol (LDL-C) (rs629301 in CELSR2/SORT1, P=1.11 × 10−5and rs6511720 in LDLR, P=2.47 × 10−5) and one of 34 SNPs for TG (rs645040 in MSL2L1, P=4.29 × 10−4). Using all available variants on MetaboChip for fine mapping, we identified additional variants associated with TC (APOE), HDL-C (LPLand CETP) and LDL-C (APOE). Furthermore, we identified two loci significantly associated with non-HDL-C: APOE/APOC1/TOMM40and PCSK9. In conclusion, the genetic architecture of lipid traits in AAs differs substantially from that in Caucasians and it remains poorly characterized.

Supplemental Digital Content is available in the text.

Objective.Telomeres protect against chromosomal end damage and shorten with each cell division; their length may be a marker of cardiovascular and overall biological aging. We examined the hypothesis that reduced telomere length is associated with increased coronary atherosclerosis in rheumatoid arthritis (RA).Methods.We performed a cross-sectional study in 145 patients with RA and 87 control subjects frequency-matched for age, race, and sex. Coronary artery calcium score was determined by noncontrast cardiac computed tomography. Telomere length was measured from whole blood DNA, using real-time quantitative polymerase chain reaction and expressed as telomeric product to a single-copy gene product ratio (T/S ratio). Associations between telomere length, coronary artery calcium score, and 28-joint Disease Activity Score (DAS28) were assessed with Spearman correlation, proportional odds logistic regression, and linear regression, adjusting for age, race, and sex.Results.Telomere length was significantly inversely correlated with age in patients with RA (ρ = −0.37, p < 0.001) and control subjects (ρ = −0.39, p = 0.001). Among patients with RA, for every interquartile range (IQR) decrease in telomere length (T/S ratio), the odds of higher coronary artery calcium score increased by 38% (95% CI: 4–60) after adjusting for age, race, and sex (p adjusted = 0.03). Telomere length was not associated with DAS28 (p adjusted = 0.17). Telomere length was not significantly different in patients with RA [median (IQR): 1.02 units (0.9–1.11)] compared to control subjects [1.05 units (0.95–1.17); p = 0.10].Conclusion.Telomere length is inversely associated with coronary artery calcium score, independent of age, race, and sex in patients with RA.

IMPORTANCE: Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone hydrochloride may increase the risk for lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias. OBJECTIVE: To compare the risk of out-of-hospital death in patients receiving methadone for noncancer pain with that in comparable patients receiving sustained-release (SR) morphine sulfate. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted using Tennessee Medicaid records from 1997 through 2009. The cohort included patients receiving morphine SR or methadone who were aged 30 to 74 years, did not have cancer or another life-threatening illness, and were not in a hospital or nursing home. At cohort entry, 32 742 and 6014 patients had filled a prescription for morphine SR or methadone, respectively. The patients’ median age was 48 years, 57.9% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of the patients received the opioid for back pain or other musculoskeletal pain. The median doses prescribed for morphine SR and methadone were 90 mg/d and 40 mg/d, respectively. MAIN OUTCOMES AND MEASURES: The primary study end point was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital. RESULTS: There were 477 deaths during 28 699 person-years of follow-up (ie, 166 deaths per 10 000 person-years). After control for study covariates, patients receiving methadone had a 46% increased risk of death during the follow-up period, with an adjusted hazard ratio (HR) of 1.46 (95% CI, 1.17-1.83; P &lt; .001), resulting in 72 (95% CI, 27-130) excess deaths per 10 000 person-years of follow-up. Methadone doses of 20 mg/d or less, the lowest dose quartile, were associated with an increased risk of death (HR, 1.59; 95% CI, 1.01-2.51, P = .046) relative to a comparable dose of morphine SR (&lt;60 mg/d). CONCLUSIONS AND RELEVANCE: The increased risk of death observed for patients receiving methadone in this retrospective cohort study, even for low doses, supports recommendations that it should not be a drug of first choice for noncancer pain.

Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model.

Objective.Rheumatoid arthritis (RA) is associated with increased risk of cardiovascular disease (CVD). High urinary albumin excretion is a risk factor for CVD in the general population, but its role in atherosclerosis in patients with RA is not well defined.Methods.We determined the urine albumin to creatinine ratio (UACR) in 136 patients with RA and 79 controls. Individuals with diabetes or a clinical history of CVD were excluded. We measured coronary artery calcium (CAC) with electron beam computer tomography and augmentation index (AIx) using pulse wave analysis. In patients with RA, erythrocyte sedimentation rate and concentrations of vascular cell adhesion protein-1 (VCAM-1), interleukin 10 (IL-10), C-reactive protein, IL-6, tumor necrosis factor-α, and cystatin-C were measured and results correlated with UACR.Results.Patients with RA had higher UACR [median (interquartile range): 7.6 (4.0–15.5) mg/g] than control subjects: 5.6 (3.3–9.0) mg/g; p = 0.02. The presence of CAC was not associated with UACR in RA or control subjects. In patients with RA, UACR was significantly correlated with AIx (rho = 0.24, p = 0.01), higher levels of VCAM-1 (rho = 0.2, p = 0.01), and lower levels of IL-10 (rho = −0.2, p = 0.02). The association between AIx and higher UACR remained significant in multivariate analysis [β coefficient of 1.5 (95% CI 0.1–2.8), p = 0.03 that adjusted for age, sex, and race].Conclusion.Urinary albumin excretion was higher in patients with RA than controls and correlated with increased arterial stiffness, higher VCAM-1, and lower IL-10 concentrations.

Objective.MicroRNA (miRNA) are small noncoding RNA that posttranscriptionally regulate gene expression and serve as potential mediators and markers of disease. Recently, plasma miR-24-3p and miR-125a-5p concentrations were shown to be elevated in rheumatoid arthritis (RA) and useful for RA diagnosis. We assessed the utility of 7 candidate plasma miRNA, selected for biological relevance, for RA diagnosis and use as markers of disease activity and subclinical atherosclerosis in RA.Methods.The cross-sectional study included 168 patients with RA and 91 control subjects of similar age, race, and sex. Plasma concentrations of miR-15a-5p, miR-24-3p, miR-26a-5p, miR-125a-5p, miR-146a-5p, miR-155-5p, and miR-223-3p were measured by quantitative PCR. Utility of plasma miRNA concentrations for RA diagnosis was assessed by area under the receiver-operating characteristic curve (AUROC). Associations between plasma miRNA concentrations and RA disease activity and coronary artery calcium score were assessed by Spearman correlations.Results.Plasma concentrations of miR-15a-5p, miR-24-3p, miR-26a-5p, miR-125a-5p, miR-146a-5p, miR-155-5p, and miR-223-3p were significantly increased in patients with RA. The highest AUROC for diagnosis of RA (AUROC = 0.725) was found in miR-24-3p, including among rheumatoid factor–negative patients (AUROC = 0.772). Among all patients with RA, the combination of miR-24-3p, miR-26a-5p, and miR-125a-5p improved the model modestly (AUROC = 0.747). One miRNA, miR-155-5p, was weakly inversely associated with swollen joint count (p = 0.024), but no other miRNA were associated with disease activity or coronary artery calcium score.Conclusion.The combination of miR-24-3p, miR-26a-5p, and miR-125a-5p had the strongest diagnostic accuracy for RA. Candidate miRNA had little or no association with RA disease activity or subclinical atherosclerosis.

Sympathetic activation inhibits insulin secretion through activation of pancreatic 2Aadrenoreceptors (2AARs). A common genetic 2AAR variant (rs553668) is associated with impaired insulin secretion. 2AR agonists would be expected to decrease insulin secretion, but their effects on glucose homeostasis in humans are poorly characterized. We examined the hypotheses that the selective 2AR agonist, dexmedetomidine, decreases plasma insulin levels and increases plasma glucose levels in humans and that these effects are modified by genetic 2AAR variants.

Objective.Hypertension (HTN), a common modifiable cardiovascular risk factor, is more common in patients with rheumatoid arthritis (RA), but the underlying mechanisms are unclear. We examined the hypothesis that mediators of inflammation and markers of cardiovascular risk are associated with HTN in RA.Methods.We compared measures of inflammation [serum C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), homocysteine, and leptin concentrations] and insulin resistance [homeostasis model assessment index (HOMA)] in RA patients with (n = 90) and without HTN (n = 79). HTN was defined as blood pressure ≥ 140/90 mm Hg or treatment with antihypertensive therapy. The independent association of markers of interest with HTN was examined using multivariable logistic regression.Results.Patients with HTN were significantly older and had longer disease duration than those without HTN (both p < 0.001). Concentrations of homocysteine [11.1 (8.5–13.5) μmol/l vs 9.3 (7.8–11.0) μmol/l] were significantly higher in patients with HTN (p < 0.001). After adjustment for age, sex, race, smoking, body mass index, and corticosteroid and nonsteroidal antiinflammatory drugs (NSAID) use, increased concentrations of homocysteine (OR 2.9, 95% CI: 1.5–5.5, p = 0.001), and leptin (OR 2.0, 95% CI: 1.0–3.8, p = 0.046) were significantly associated with HTN, but the 28-joint Disease Activity Score, IL-6, CRP, TNF-α, and HOMA index were not (all p > 0.05).Conclusion.HTN in patients with RA is not associated with generalized systemic inflammation or insulin resistance, but is associated with increasing concentrations of homocysteine and leptin. The pathogenesis of HTN in RA may involve pathways more regularly associated with fat and vascular homeostasis.

Tumor necrosis factor (TNF) inhibitors are effective for achieving disease control in several inflammatory diseases. Although anti-TNF agents can inhibit bone loss in vitro, their role in the prevention of clinically relevant outcomes such as osteoporosis and fractures has not been clearly established.

To examine the hypothesis that genetic variation in enzymes and transporters associated with synthesis, storage, release, and metabolism of catecholamines contributes to the interindividual variability in plasma catecholamine concentrations at rest and after exercise.

OBJECTIVE: We examined the hypothesis that cystatin C, a novel marker of renal function, is elevated in rheumatoid arthritis (RA) and is associated with inflammation and coronary atherosclerosis. METHODS: We measured serum cystatin C, creatinine, tumor necrosis factor-α and interleukin 6 concentrations, coronary artery calcium score (CACS), and Modified Diet in Renal Disease estimated glomerular filtration rate in 167 patients with RA and 91 controls. RESULTS: Cystatin C was higher in RA patients [median (IQR) 1.16 (0.99–1.35) mg/l] than controls [1.01 (0.90–1.19) mg/l; p < 0.001] and correlated positively with erythrocyte sedimentation rate (p < 0.001), C-reactive protein (p = 0.01), 28-joint Disease Activity Score (p = 0.006), and Framingham risk score (FRS; p = 0.02). Cystatin C was correlated with CACS (p < 0.001) in RA, but this was not significant after adjustment for age, race, sex, and FRS (p = 0.44). CONCLUSION: Cystatin C concentrations are higher in RA than controls and may reflect inflammation and undetected subclinical renal dysfunction. Cystatin C provides information regarding the risk of atherosclerosis in RA, but this is not independent of the information provided by conventional cardiovascular risk factors.

Single-nucleotide polymorphisms in genes that affect warfarin metabolism (cytochrome P450 2C9 gene, CYP2C9) and response (vitamin K epoxide reductase complex 1 gene, VKORC1) have an important influence on warfarin therapy, particularly during initiation; however, there is a lack of consensus regarding the optimal pharmacogenetics-based initiation strategy. We conducted a prospective cohort study in which patients requiring warfarin therapy for atrial fibrillation or venous thromboembolism were initiated with a novel pharmacogenetics-initiation protocol (WRAPID, Warfarin Regimen using A Pharmacogenetics-guided Initiation Dosing) that incorporated loading and maintenance doses based on genetics, clinical variables, and response (n = 167, followed up for 90 days), to assess the influence of genetic variations on anticoagulation responses. Application of the WRAPID algorithm resulted in a negligible influence of genetic variation in VKORC1or CYP2C9on time to achievement of first therapeutic response (P= .52, P= .28) and risk of overanticoagulation (P= .64, P= .96). After adjustment for covariates, time to stable anticoagulation was not influenced by VKORC1or CYP2C9genotype. Importantly, time spent within or above the therapeutic range did not differ among VKORC1and CYP2C9genotype groups. Moreover, the overall time course of the anticoagulation response among the genotype groups was similar and predictable. We demonstrate the clinical utility of genetics-guided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism.

The presynaptic norepinephrine transporter (NET) mediates synaptic clearance and recycling of norepinephrine. NET-deficient transgenic mice have elevated blood pressure (BP), heart rate, and catecholamine concentrations. However, the in-vivo effects of common NETvariants on cardiovascular regulation at rest and during exercise are unknown.

2A-Adrenoceptors (2A-ARs) have important roles in sympathetic cardiovascular regulation. Variants of ADRA2Aaffect gene transcription and expression and are associated with insulin release and risk for type 2 diabetes. We examined whether ADRA2Avariants are also associated with cardiovascular responses to the selective 2-AR-agonist dexmedetomidine.

Vascular α1and α2adrenergic receptors mediate vasoconstriction and are major determinants of peripheral vascular tone. There is a wide variability in vasoconstrictor sensitivity to α1and α2adrenergic receptor agonists among individuals. In previous studies, this variability was not explained by identified α1and α2adrenergic receptor genetic variants. Thus, we hypothesized that adrenergic vasoconstrictor sensitivity is determined by shared constrictor mechanisms downstream of the individual receptors and that α1and α2adrenergic receptor-mediated vasoconstrictor sensitivity would therefore be correlated.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of atherosclerosis, but routine lipid measurements differ little from those of people without RA. We examined the hypothesis that lipid subclasses determined by nuclear magnetic resonance spectroscopy (NMR) differed in patients with RA compared to controls and are associated with disease activity and the presence of coronary-artery atherosclerosis. METHODS: We measured lipoprotein subclasses by NMR in 139 patients with RA and 75 control subjects. Lipoproteins were classified as large low-density lipoprotein (LDL; diameter range 21.2–27.0 nm), small LDL (18.0–21.2 nm), large high-density lipoprotein (HDL; 8.2–13.0 nm), small HDL (7.3–8.2 nm), and total very low-density lipoprotein (VLDL; ≥ 27 nm). All subjects underwent an interview and examination; disease activity was quantified by the 28-joint Disease Activity Score (DAS28) and coronary artery calcification (CAC) was measured with electron-beam computed tomography. RESULTS: Concentrations of small HDL particles were lower in patients with RA (18.2 ± 5.4 nmol/l) than controls (20.0 ± 4.4 nmol/l; p = 0.003). In patients with RA, small HDL concentrations were inversely associated with DAS28 (rho = –0.18, p = 0.04) and C-reactive protein (rho = –0.25, p = 0.004). Concentrations of small HDL were lower in patients with coronary calcification (17.4 ± 4.8 nmol/l) than in those without (19.0 ± 5.8 nmol/l; p = 0.03). This relationship remained significant after adjustment for the Framingham risk score and DAS28 (p = 0.025). Concentrations of small LDL particles were lower in patients with RA (1390 ± 722 nmol/l) than in controls (1518 ± 654 nmol/l; p = 0.05), but did not correlate with DAS28 or CAC. CONCLUSION: Low concentrations of small HDL particles may contribute to increased coronary atherosclerosis in patients with RA.

Vascular α2B-adrenergic receptors (α2B-ARs) mediate vasoconstriction and contribute to peripheral regulation of vascular tone. In vitro, a common 301–303 deletion in the α2B-AR gene, ADRA2B, results in loss of α2B-AR desensitization. We examined the hypothesis that ADRA2Bdel301–303 or other common ADRA2Bvariants alter vascular desensitization in vivo.

ObjectiveRheumatoid arthritis RA is an inflammatory disease associated with premature atherosclerosis. We hypothesized that mediators of inflammation associated with atherosclerosis in other populations interleukin6 IL6, tumor necrosis factor α TNFα, serum amyloid A SAA, vascular endothelial growth factor, neutrophil count, IL1α, Eselectin, intercellular adhesion molecule 1 ICAM1, myeloperoxidase MPO, matrix metalloproteinase 9, and vascular cell adhesion molecule 1 would be increased and associated with the severity of coronary atherosclerosis in patients with RA.MethodsClinical variables, concentrations of inflammatory mediators, and coronary artery calcification were measured in 169 patients with RA and 92 control subjects. Differences in concentrations of inflammatory mediators were compared using median quantile regression. The relationship of inflammatory mediators with the severity of coronary calcification in RA and control subjects was examined using proportional odds logistic regression, allowing for interaction with disease status. Models were adjusted for traditional cardiovascular risk factors.ResultsMedian serum concentrations of IL6, SAA, ICAM1, Eselectin, TNFα, and MPO and peripheral blood neutrophil count were higher in patients with RA than controls all P< 0.05, independent of Framingham risk score and diabetes mellitus DM. IL6 main effect odds ratio OR 1.72; 95 confidence interval 95 CI 1.12, 2.66 and TNFα main effect OR 1.49; 95 CI 1.16, 1.90 concentrations were significantly associated with higher amounts of coronary calcium, independent of Framingham risk score and DM, and such main effects significantly differed from controls P 0.001 and 0.03 for interaction, respectively.ConclusionTNFα and IL6 are significantly associated with the severity of subclinical atherosclerosis, independent of Framingham risk score, in RA.

Genetic variants in CYP2C9 and VKORC1 strongly affect steady-state warfarin dose. However, these variants also affect early international normalized ratio (INR) values during warfarin initiation. We examined whether CYP2C9/VKORC1 genotypes provide information about warfarin sensitivity additional to that provided by early INR responses. In 214 patients starting warfarin with INR-guided dose adjustments, we determined whether CYP2C9 and VKORC1 genotypes were associated with early measures of warfarin sensitivity (time to INR ≥ lower limit of therapeutic range; time to INR > 4; and first stable warfarin dose) after adjusting for early (days 4-6) and week 1 (days 7-9) INR values. Early INRs were associated with all outcomes (all P < .001) and were more informative than genotypes. For time to INR more than or equal to the lower limit of therapeutic range, adding either early INRs or genotypes to a baseline model (clinical variables only) increased the goodness-of-fit (R2) from 0.05 to 0.42 and 0.19, respectively (full model, R2 = 0.46). For first stable warfarin dose, adding either early INRs or genotypes to the baseline model increased the R2 from 0.08 to 0.32 and 0.27, respectively (full model, R2 = 0.40). After inclusion of week 1 INRs, CYP2C9 (P = .08) and VKORC1 (P = .30) were not associated with stable warfarin dose. Thus, much of the information provided by CYP2C9 and VKORC1 genotypes during warfarin initiation is captured by the early INR response.

Genetic variants in CYP2C9and VKORC1strongly affect steady-state warfarin dose. However, these variants also affect early international normalized ratio (INR) values during warfarin initiation. We examined whether CYP2C9/VKORC1genotypes provide information about warfarin sensitivity additional to that provided by early INR responses. In 214 patients starting warfarin with INR-guided dose adjustments, we determined whether CYP2C9and VKORC1genotypes were associated with early measures of warfarin sensitivity (time to INR ≥ lower limit of therapeutic range; time to INR > 4; and first stable warfarin dose) after adjusting for early (days 4-6) and week 1 (days 7-9) INR values. Early INRs were associated with all outcomes (all P< .001) and were more informative than genotypes. For time to INR more than or equal to the lower limit of therapeutic range, adding either early INRs or genotypes to a baseline model (clinical variables only) increased the goodness-of-fit (R2) from 0.05 to 0.42 and 0.19, respectively (full model, R2= 0.46). For first stable warfarin dose, adding either early INRs or genotypes to the baseline model increased the R2from 0.08 to 0.32 and 0.27, respectively (full model, R2= 0.40). After inclusion of week 1 INRs, CYP2C9(P= .08) and VKORC1(P= .30) were not associated with stable warfarin dose. Thus, much of the information provided by CYP2C9and VKORC1genotypes during warfarin initiation is captured by the early INR response.