Tissue sodium content in patients with systemic lupus erythematosus: association with disease activity and markers of inflammation.

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 < 0.001). Skin Na+ 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.

Increased blood pressure visit-to-visit variability in patients with systemic lupus erythematosus: association with inflammation and comorbidity burden.

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 < 0.001 by coefficient of variation. Additional measures of systolic blood pressure visit-to-visit variability (i.e. standard deviation, average real variation, successive variation and maximum measure-to-measure change) were also significantly higher in patients with SLE than in control subjects. In patients with SLE, blood pressure visit-to-visit variability correlated significantly with age, creatinine, CRP, triglyceride concentrations and the Charlson comorbidity score (all P < 0.05). Hydroxychloroquine use was associated with reduced blood pressure visit-to-visit variability (P < 0.001), whereas the use of antihypertensives, cyclophosphamide, mycophenolate mofetil and corticosteroids was associated with increased blood pressure visit-to-visit variability (P < 0.05). 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.

Novel polymorphisms in TICAM2 and NOD1 associated with tuberculosis progression phenotypes in Ethiopian populations.

BACKGROUND: Infection by Mycobacterium tuberculosis (Mtb) is a necessary but not sufficient cause for tuberculosis (TB). Although numerous studies suggest human genetic variation may influence TB pathogenesis, there is a conspicuous lack of replication, likely due to imprecise phenotype definition. We aimed to replicate novel findings from a Ugandan cohort in Ethiopian populations. METHOD: We ascertained TB cases and household controls (n = 292) from three different ethnic groups. Latent Mtb infection was determined using Quantiferon to develop reliable TB progression phenotypes. We sequenced exonic regions of TICAM2 and NOD1. RESULT: Significant novel associations were observed between two variants in NOD1 and TB: rs751770147 [unadjusted p = 7.28 × 10-5] and chr7:30477156(T), a novel variant, [unadjusted p = 1.04 × 10-4]. Two SNPs in TICAM2 were nominally associated with TB, including rs2288384 [unadjusted p = 0.003]. Haplotype-based association tests supported the SNP-based results. CONCLUSION: We replicated the association of TICAM2 and NOD1 with TB and identified novel genetic associations with TB in Ethiopian populations.

A genetic risk score that includes common type 2 diabetes risk variants is associated with gestational diabetes.

OBJECTIVE: Gestational diabetes (GDM) is characterized by maternal glucose intolerance that manifests during pregnancy. Because GDM resembles type 2 diabetes (T2DM), shared genetic predisposition is likely but has not been established. We tested the hypothesis that a genetic risk score (GRS) that included variants known to be associated with T2DM is associated with GDM. STUDY DESIGN: We conducted a case-control study using the Vanderbilt Medical Center biobank (BioVU) and calculated a simple-count GRS using 34 variants previously associated with T2DM or fasting glucose in the general population, or with GDM or glucose intolerance in pregnancy. We assessed the association of the GRS with GDM adjusting for maternal age, parity, and body mass index (BMI) and calculated the area under the curve for the receiver-operating characteristic curve (c-statistic). STUDY POPULATION: Among Caucasian women, we identified 458 cases of GDM and 1538 pregnant controls with normal glucose tolerance. RESULTS: Cases of GDM had a higher number of risk alleles compared to controls (38.9±4.0 vs 37.4±4.0 risk alleles, P=1.6×10-11 ). The GRS was significantly associated with GDM; the adjusted odds ratio associated with each additional risk allele was 1.10 (95% CI: 1.07-1.13, P=6×10-11 ). Clinical variables predicted the risk of GDM (c-statistic 0.67, 95% CI: 0.64-0.70), and adding the GRS modestly improved prediction (0.70, 95% CI: 0.67-0.73). CONCLUSIONS: Among Caucasian women, a GRS that included common T2DM genetic risk variants was associated with increased risk of GDM but showed limited utility in the identification of GDM cases.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update.

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.

Genetic variation in the alpha1B-adrenergic receptor and vascular response.

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.

The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy.

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.

Association of estimated sodium and potassium intake with blood pressure in patients with systemic lupus erythematosus.

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 (ß coefficient = 4.01, p = 0.023) and DBP (ß 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.

GlycA, a novel marker of inflammation, is elevated in systemic lupus erythematosus.

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 < 0.001. In patients with SLE, concentrations of GlycA were significantly associated with sedimentation rate (rho = 0.43), C-reactive protein (rho = 0.59), e-selectin (rho = 0.28), intracellular adhesion molecule-1 (rho = 0.30), triglycerides (rho = 0.45), all p < 0.0023 to account for multiple comparisons, but not with creatinine, SLEDAI, SLICC, or coronary calcium scores. 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.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing.

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).

The DYX2 locus and neurochemical signaling genes contribute to speech sound disorder and related neurocognitive domains.

A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social and behavioral development. Speech sound disorder is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples - Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families) - and then combined results by meta-analysis. DYX2 markers, specifically those in the 3' untranslated region of DCDC2 (P = 1.43 × 10(-4) ), showed the strongest associations with phonological awareness. We also observed suggestive associations of dopaminergic-related genes ANKK1 (P = 1.02 × 10(-2) ) and DRD2 (P = 9.22 × 10(-3) ) and nicotinic-related genes CHRNA3 (P = 2.51 × 10(-3) ) and BDNF (P = 8.14 × 10(-3) ) with case-control status and articulation. Our results further implicate variation in putative regulatory regions in the DYX2 locus, particularly in DCDC2, influencing language and cognitive traits. The results also support previous studies implicating variation in dopaminergic and nicotinic neural signaling influencing human communication and cognitive development. Our findings expand the literature showing genetic factors (e.g., DYX2) contributing to multiple related, yet distinct neurocognitive domains (e.g., dyslexia, language impairment, and SSD). How these factors interactively yield different neurocognitive and language-related outcomes remains to be elucidated.

Genetic variation in the α1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

There is large interindividual variability and ethnic differences in phenylephrine-mediated vasoconstriction. We tested the hypothesis that genetic variation in ADRA1A, the α1A adrenergic receptor gene, contributes to the variability and ethnic differences. We measured local dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 42 African-Americans and genotyped for 32 ADRA1A single nucleotide polymorphisms. The ED50 ranged from 11 to 5442 ng min(-1), and the Emax ranged from 13.5-100%. The rs574647 variant was associated with a trend towards lower logED50 in each race and in the combined cohort (P=0.008). In addition, rs1079078 was associated with a trend to higher logED50 in each race and in the combined cohort (P=0.011). Neither variant accounted for the ethnic differences in response. None of the ADRA1A haplotypes was associated with the outcomes. In conclusion, ADRA1A variants do not contribute substantially to the marked interindividual variability or ethnic differences in phenylephrine-mediated venoconstriction.

Clinical predictors and time course of the improvement in ß-cell function with short-term intensive insulin therapy in patients with Type 2 diabetes.

AIMS: In patients with Type 2 diabetes, a short course of intensive insulin therapy can improve ß-cell function and even induce transient remission of diabetes. However, not all patients respond to this therapy. Although the achievement of fasting glucose  < 7.0 mmol/l one day after stopping intensive insulin therapy can identify patients in whom ß-cell function has improved, we sought to determine clinical predictors for the early identification of such responders and the time course of response. METHODS: We pooled data from two studies in which 97 patients with Type 2 diabetes mellitus (median 3 years duration) and HbA1c 51 ± 8.7 mmol/mol (6.8 ± 0.8%) underwent 4-8 weeks of intensive insulin therapy, consisting of basal detemir and pre-meal insulin aspart. They were classified as responders (n = 74) or non-responders (n = 23), defined by the achievement of fasting glucose  < 7.0 mmol/l after stopping intensive insulin therapy. RESULTS: On logistic regression analyses, duration of diabetes (odds ratio [OR] = 0.72, 95% confidence interval [CI] 0.56-0.92, P = 0.009) and baseline fasting glucose (OR = 0.40, 95% CI 0.24-0.68, P = 0.001) emerged as predictors of the likelihood of responding. Ninety per cent of patients with duration ≤ 4 years and fasting glucose ≤ 8.0 mmol/l responded to intensive insulin therapy. Despite having lower glucose levels during intensive insulin therapy, responders had less hypoglycaemia than non-responders (median 0.3 vs. 1.6 episodes/week, P < 0.0001), with rates of hypoglycaemia diverging sharply from the third week onwards. CONCLUSION: At baseline, shorter duration of diabetes and lower fasting glucose can identify patients most likely to benefit from short-term intensive insulin therapy. Most importantly, during therapy, responders had less hypoglycaemia from the third week onwards, despite lower glycaemia, suggesting that 2 weeks of intensive insulin therapy may be needed to improve endogenous islet function.

Association of Toll-like receptor polymorphisms with HIV status in North Americans.

Single-nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes TLR2-4 and TLR7-9, but not in TLR1 and TLR6, have been previously evaluated regarding human immunodeficiency virus (HIV) acquisition and disease progression in various populations, most of which were European. In this study, we examined associations between a total of 41 SNPs in 8 TLR genes (TLR1-4, TLR6-9) and HIV status in North American subjects (total n=276 (Caucasian, n=102; African American, n=150; other, n=24)). Stratification of the data by self-identified race revealed that a total of nine SNPs in TLR1, TLR4, TLR6 and TLR8 in Caucasians, and two other SNPs, one each in TLR4 and TLR8, in African Americans were significantly associated with HIV status at P<0.05. Concordant with the odds ratios of these SNPs, significant differences were observed in the SNP allele frequencies between HIV+ and HIV- subjects. Finally, in Caucasians, certain haplotypes of single (TLR1 and TLR4) and heterodimer (TLR2_TLR6) genes may be inferred as 'susceptible' or 'protective'. Our study provides in-depth insight into the associations between TLR variants, particularly TLR1 and TLR6, and HIV status in North Americans, and suggests that these associations may be race specific.

Genetic variation and coronary atherosclerosis in patients with systemic lupus erythematosus.

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.

Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update.

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).

Free fatty acids are associated with metabolic syndrome and insulin resistance but not inflammation in systemic lupus erythematosus.

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 < 0.001). FFAs were positively correlated with insulin resistance (HOMA) (rho = 0.23, P = 0.004, P adjusted = 0.006) and triglyceride levels (rho = 0.22, P = 0.01, P adjusted = 0.004). FFAs were not associated with inflammatory cytokines (IL-6, TNF-α) (all P > 0.05) but were positively associated with levels of E-selectin (rho = 0.33, P = < 0.001, P adjusted = 0.001) and ICAM-1 (rho = 0.35, P < 0.001, P adjusted = 0.001). FFAs were correlated with coronary artery calcium score (rho = 0.20, P = 0.01) but this was attenuated after adjustment for age, race and sex (P = 0.33). From our study we concluded that FFAs are elevated in patients with SLE, particularly those with metabolic syndrome. FFAs in patients with SLE are not associated with markers of generalized inflammation but are associated with insulin resistance and markers of endothelial activation.

Cystatin C is associated with inflammation but not atherosclerosis in systemic lupus erythematosus.

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 < 0.001 after adjustment for age, race, sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (p = 0.04), erythrocyte sedimentation rate (ESR) (p = 0.02), TNF-α (p = 0.008) and IL-6 (p = 0.01) after adjustment for age, race, and sex. Cystatin C was not significantly correlated with coronary calcium score in SLE (rho=0.096, p = 0.31) and the association remained non-significant after adjustment for age, race, sex, and Framingham risk score (p = 0.99). 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.

Novel cardiovascular risk prediction models in patients with systemic lupus erythematosus.

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 < 0.001 for all). The camFRS (8%, p = 0.016) but not camRRS (5%, p = 0.221) assigned significantly more SLE patients to a category of ≥ 10% risk than conventional FRS (1%) and RRS (2%). The RRS was of limited use but coronary age may improve CHD risk prediction in SLE.