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Systemic lupus erythematosus (SLE) is propelled by pathogenic autoantibody (AutoAb) and immune pathway dysregulation. Identifying populations at risk of reaching classified SLE is essential to curtail inflammatory damage. Lupus blood relatives (Rel) have an increased risk of developing SLE. We tested factors to identify Rel at risk of developing incomplete lupus (ILE) or classified SLE vs. clinically unaffected Rel and healthy controls (HC), drawing from two unique, well characterized lupus cohorts, the lupus autoimmunity in relatives (LAUREL) follow-up cohort, consisting of Rel meeting <4 ACR criteria at baseline, and the Lupus Family Registry and Repository (LFRR), made up of SLE patients, lupus Rel, and HC. Medical record review determined ACR SLE classification criteria; study participants completed the SLE portion of the connective tissue disease questionnaire (SLE-CSQ), type 2 symptom questions, and provided samples for assessment of serum SLE-associated AutoAb specificities and 52 plasma immune mediators. Elevated SLE-CSQ scores were associated with type 2 symptoms, ACR scores, and serology in both cohorts. Fatigue at BL was associated with transition to classified SLE in the LAUREL cohort ( p≤0.01 ). Increased levels of BLyS and decreased levels of IL-10 were associated with type 2 symptoms (p <0.05 ). SLE-CSQ scores, ACR scores, and accumulated AutoAb specificities correlated with levels of multiple inflammatory immune mediators ( p<0.05 ), including BLyS, IL-2Rα, stem cell factor (SCF), soluble TNF receptors, and Th-1 type mediators and chemokines. Transition to SLE was associated with increased levels of SCF ( p<0.05 ). ILE Rel also had increased levels of TNF-α and IFN-γ, offset by increased levels of regulatory IL-10 and TGF-β ( p<0.05 ). Clinically unaffected Rel (vs. HC) had higher SLE-CSQ scores ( p<0.001 ), increased serology ( p<0.05 ), and increased inflammatory mediator levels, offset by increased IL-10 and TGF-β ( p<0.01 ). These findings suggest that Rel at highest risk of transitioning to classified SLE have increased inflammation coupled with decreased regulatory mediators. In contrast, clinically unaffected Rel and Rel with ILE demonstrate increased inflammation offset with increased immune regulation, intimating a window of opportunity for early intervention and enrollment in prevention trials.

Higher 25-hydroxyvitamin D (25(OH)D) levels have been associated with reduced risk for autoimmune diseases and are influenced by vitamin D metabolism genes. We estimated genetically-determined vitamin D levels by calculating a genetic risk score (GRS) and investigated whether the vitamin D GRS was associated with the presence of autoantibodies related to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in those at increased risk for developing RA and SLE, respectively. In this cross-sectional study, we selected autoantibody positive (aAb+) and autoantibody negative (aAb-) individuals from the Studies of the Etiologies of Rheumatoid Arthritis (SERA), a cohort study of first-degree relatives (FDRs) of individuals with RA (189 RA aAb+, 181 RA aAb-), and the Lupus Family Registry and Repository (LFRR), a cohort study of FDRs of individuals with SLE (157 SLE aAb+, 185 SLE aAb-). Five SNPs known to be associated with serum 25(OH)D levels were analyzed individually as well as in a GRS: rs4588 ( ), rs12785878 ( ), rs10741657 ( ), rs6538691 ( ), and rs8018720 ( ). Both cohorts had similar demographic characteristics, with significantly older and a higher proportion of males in the aAb+ FDRs. The vitamin D GRS was inversely associated with RA aAb+ (OR = 0.85, 95% CI = 0.74-0.99), suggesting a possible protective factor for RA aAb positivity in FDRs of RA probands. The vitamin D GRS was not associated with SLE aAb+ in the LFRR (OR = 1.09, 95% CI = 0.94-1.27). The SNP was associated with RA aAb+ in SERA (OR = 0.65, 95% CI = 0.43-0.99); this SNP was not associated with SLE aAb+ in LFRR (OR = 1.41, 95% CI = 0.90 - 2.19). Genes associated with vitamin D levels may play a protective role in the development of RA aAbs in FDRs of RA probands, perhaps through affecting lifelong vitamin D status. The GRS and the SNP may be of interest for future investigation in pre-clinical RA. In contrast, these results do not support a similar association in SLE FDRs, suggesting other mechanisms involved in the relationship between vitamin D and SLE aAbs not assessed in this study.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study. We conducted latent class analysis (LCA) among the 27 categories of chronic disease medications, excluding COPD treatments and cancer medications at P1 and P2 separately. The best number of LCA classes was determined through both statistical fit and interpretation of the patterns. Results: We found four classes of medication patterns at both phases. LCA showed that both phases shared similar characteristics in their medication patterns: LC0: low medication; LC1: hypertension (HTN) or cardiovascular disease (CVD)+high cholesterol (Hychol) medication predominant; LC2: HTN/CVD+type 2 diabetes (T2D) +Hychol medication predominant; LC3: Hychol medication predominant. Conclusions: We found similar multimorbidity medication patterns among smokers at P1 and P2 in the COPDGene cohort, which provides an understanding of how multimorbidity medication clustered and how different chronic diseases combine in smokers.

Epstein-Barr virus (EBV) infection of B cells is associated with lymphoma and other human cancers. EBV infection is initiated by the binding of the viral envelope glycoprotein (gp350) to the cell surface receptor CR2. We determined the X-ray structure of the highly glycosylated gp350 and defined the CR2 binding site on gp350. Polyglycans shield all but one surface of the gp350 polypeptide, and we demonstrate that this glycan-free surface is the receptor-binding site. Deglycosylated gp350 bound CR2 similarly to the glycosylated form, suggesting that glycosylation is not important for receptor binding. Structure-guided mutagenesis of the glycan-free surface disrupted receptor binding as well as binding by a gp350 monoclonal antibody, a known inhibitor of virus-receptor interactions. These results provide structural information for developing drugs and vaccines to prevent infection by EBV and related viruses.

Yisha Li,1 Ran Dai,2 Yeongjin Gwon,2 Stephen I Rennard,3 Barry J Make,4 Dinah Foer,5 Matthew J Strand,4 Erin Austin,6 Kendra A Young,1 John E Hokanson,1 Katherine A Pratte,7 Rebecca Conway,1 Gregory L Kinney1 On behalf of COPDGene investigators1Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Department of Biostatistics, School of Public Health, University of Nebraska Medical Center, Omaha, NE, USA; 3Division of Pulmonary, Critical Care and Sleep Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 4Department of Medicine, National Jewish Health, Denver, CO, USA; 5Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 6Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, USA; 7Department of Biostatistics, National Jewish Health, Denver, CO, USACorrespondence: Gregory L Kinney, Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, Tel +1 303-724-4437, Email GREG.KINNEY@CUANSCHUTZ.EDU

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging ( n  = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B ( TOR1B ), fat mass and obesity associated ( FTO ), cordon-bleu WH2 repeat protein like 1 ( COBLL1 )/growth factor receptor-bound protein 14 ( GRB14 ), insulin receptor ( INSR ), sterol regulatory element-binding transcription factor 1 ( SREBF1 ) and patatin-like phospholipase domain-containing protein 2 ( PNPLA2 ), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ), transmembrane 6 superfamily 2 ( TM6SF2 ), apolipoprotein E ( APOE ), glucokinase regulator ( GCKR ), tribbles homolog 1 ( TRIB1 ), glycerol-3-phosphate acyltransferase ( GPAM ), mitochondrial amidoxime-reducing component 1 ( MARC1 ), microsomal triglyceride transfer protein large subunit ( MTTP ) , alcohol dehydrogenase 1B ( ADH1B ), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 ( MBOAT7 ) and receptor-type tyrosine-protein phosphatase δ ( PTPRD ). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics. Genome-wide association meta-analysis across individuals of diverse ancestries identifies risk loci for nonalcoholic fatty liver disease. The associated variants implicate plausible biological pathways and improve estimates of disease risk.

Identifying individuals at high risk of developing type 2 diabetes (T2DM) could help with implementing targeted intervention to delay or prevent T2DM.1 In addition to known risk factors such as increased age, male gender, obesity, higher fasting glucose levels, smoking, hypertension and family history of diabetes, measures of beta-cell (β-cell) function have been used to predict progression to diabetes.2–5 However, evaluating β-cell function requires complex measures that may not be feasible in the standard of care setting.3–5 Clinically useful tools that could improve risk assessment beyond these risk factors are desirable. A model whose predictions are 100% wrong has an AUC of 0.0; one whose predictions are 100% correct has an AUC of 1.0. [...]a tool with higher ROC curve AUC will provide better sensitivity and specificity. A large study from China reported associations between elevated TG and TC levels and T2DM incidence independent of age, BMI, family history of diabetes, education, marital status, geographic location, income, current smoking status, alcoholic drinks, hypertension, HDLC, and uric acid levels.9 However, based on ROC curve AUC for prediction of incident T2DM, the optimal cutoff values of TG were >1.15 and >1.23 mmol/L (>102 and >109 mg/dL) in men and women, respectively.

The TG/HDL-C ratio is used as a marker of insulin resistance (IR) in Caucasians; however, there is limited data in other ethnic groups. We hypothesized that the TG/HDL-C ratio is associated with IR in Hispanics and African Americans (AA). Data from the Insulin Resistance Atherosclerosis Family Study was examined for associations between TG/HDL-C ratio and IR, β-cell function and incident diabetes in non-diabetic Hispanics (n = 872, 63% female) and AA (n = 371, 61% female). Insulin sensitivity index (SI) and disposition index (DI) from frequently-sampled intravenous glucose tolerance tests were used as markers of IR and β-cell function respectively. Incident type 2 diabetes was determined by fasting glucose ≥ 126 mg/dl or initiation of anti-hyperglycemia agents over 5 year follow-up. Higher TG/HDL-C ratio was associated with IR in Hispanic and AA men and women (P < 0.0002), as well as β-cell function in Hispanic women and AA men and women (P < 0.02). TG/HDL-C predicted incident type 2 diabetes in women (area under the curves 0.703 and 0.795 for Hispanics and AA respectively). Similar to Caucasians, the TG/HDL-C ratio can be used to identify IR in Hispanics and AA, and may predict type 2 diabetes in women.

ObjectiveSystemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition.MethodsSLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE.ResultsMean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE.ConclusionHeightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.

To improve glycemic control of hospitalized patients with diabetes and hyperglycemia, many medical centers have established dedicated glucose management teams (GMTs). However, the impact of these specialized teams on clinical outcomes has not been evaluated. We conducted a retrospective study of 440 patients with type 2 diabetes admitted to the medical service for cardiac or infection-related diagnosis. The primary endpoint was a composite outcome of several well-recognized markers of morbidity, consisting of: death during hospitalization, transfer to intensive care unit, initiation of enteral or parenteral nutrition, line infection, new in-hospital infection or infection lasting more than 20 days of hospitalization, deep venous thrombosis or pulmonary embolism, rise in plasma creatinine, and hospital re-admissions. Medical housestaff managed the glycemia in 79% of patients (usual care group), while the GMT managed the glycemia in 21% of patients (GMT group). The primary outcome was similar between cohorts (0.95 events per patient versus 0.99 events per patient in the GMT and usual care cohorts, respectively). For subanalysis, the subjects in both groups were stratified into those with average glycemia of <180 mg/dL versus those with glycemia >180 mg/dL. We found a significant beneficial impact of glycemic management by the GMT on the composite outcome in patients with average glycemia >180 mg/dL during their hospital stay. The number of patients who met primary outcome was significantly higher in the usual care group (40 of 83 patients, 48%) than in the GMT-treated cohort (8 of 33 patients, 25.7%) (P<.02). Our data suggest that GMTs may have an important role in managing difficult-to-control hyperglycemia in the inpatient setting. BG = blood glucose GMT = glucose management team HbA1c = hemoglobin A1c ICU = intensive care unit POC = point of care T2D = type 2 diabetes.