Maria I. Danila

Annotating the human genome with Disease Ontology.

BackgroundThe human genome has been extensively annotated with Gene Ontology for biological functions, but minimally computationally annotated for diseases.ResultsWe used the Unified Medical Language System (UMLS) MetaMap Transfer tool (MMTx) to discover gene-disease relationships from the GeneRIF database. We utilized a comprehensive subset of UMLS, which is disease-focused and structured as a directed acyclic graph (the Disease Ontology), to filter and interpret results from MMTx. The results were validated against the Homayouni gene collection using recall and precision measurements. We compared our results with the widely used Online Mendelian Inheritance in Man (OMIM) annotations.ConclusionThe validation data set suggests a 91% recall rate and 97% precision rate of disease annotation using GeneRIF, in contrast with a 22% recall and 98% precision using OMIM. Our thesaurus-based approach allows for comparisons to be made between disease containing databases and allows for increased accuracy in disease identification through synonym matching. The much higher recall rate of our approach demonstrates that annotating human genome with Disease Ontology and GeneRIF for diseases dramatically increases the coverage of the disease annotation of human genome.

Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort

OBJECTIVE To assess whether hydroxychloroquine can delay renal damage development in lupus nephritis patients. METHODS Lupus nephritis patients (n = 256) from the LUpus in MInorities, NAture versus nurture study (n = 635), a multiethnic cohort of African Americans, Hispanics, and Caucasians, age > or =16 years with disease duration < or =5 years at baseline (T0) were studied. Renal damage was defined using the Systemic Lupus International Collaborating Clinics Damage Index (> or =1 of the following lasting at least 6 months: estimated/measured glomerular filtration rate <50%, 24-hour proteinuria > or =3.5 gm and/or end-stage renal disease, regardless of dialysis or transplantation). Patients with renal damage before T0 were excluded (n = 53). The association between hydroxychloroquine use and renal damage (as defined, or omitting proteinuria) was estimated using Cox proportional regression analyses adjusting for potential confounders. Kaplan-Meier survival curves based on hydroxychloroquine intake or the World Health Organization (WHO) class glomerulonephritis were also derived. RESULTS Sixty-three (31.0%) of the 203 patients included developed renal damage over a mean +/- SD disease duration of 5.2 +/- 3.5 years. The most frequent renal damage domain item was proteinuria. Patients who received hydroxychloroquine (79.3%) exhibited a lower frequency of WHO class IV glomerulonephritis, had lower disease activity, and received lower glucocorticoid doses than those who did not take hydroxychloroquine. After adjusting for confounders, hydroxychloroquine was protective of renal damage occurrence in full (hazard ratio [HR] 0.12, 95% confidence interval [95% CI] 0.02-0.97, P = 0.0464) and reduced (HR 0.29, 95% CI 0.13-0.68, P = 0.0043) models. Omitting proteinuria provided comparable results. The cumulative probability of renal damage occurrence was higher in those who did not take hydroxychloroquine and those classified as WHO class IV glomerulonephritis (P < 0.0001). CONCLUSION After adjusting for possible confounding factors, the protective effect of hydroxychloroquine in retarding renal damage occurrence in systemic lupus erythematosus is still evident.

Renal damage is the most important predictor of mortality within the damage index: data from LUMINA LXIV, a multiethnic US cohort

OBJECTIVE Damage accrual in SLE has been previously shown to be an independent predictor of mortality. We sought to discern which SLICC Damage Index (SDI) domains are the most important predictors of survival in SLE. METHODS SLE patients (ACR criteria), age > or =16 years, disease duration < or =5 years at enrolment, of African-American, Hispanic or Caucasian ethnicity were studied. Disease activity was assessed using the SLAM-Revised (SLAM-R) at diagnosis. Damage was ascertained using the SDI at the last visit. The SDI domains associated with time to death (and interaction terms) were examined by univariable and multivariable Cox proportional hazards regression analyses; those significant in the multivariable analyses were added to the final two models (with and without poverty) that included other variables known to be associated with shorter survival. RESULTS A total of 635 SLE patients were studied of whom 97 (15.3%) have died over a mean (s.d.) total disease duration of 5.7 (3.7) years. Patients were predominantly women [570 (89.8%)]; their mean (s.d.) age was 36.5 (12.6) years; 126 (19.8%) had developed renal damage, 62 (9.3%) cardiovascular, 48 (7.8%) pulmonary and 34 (5.4%) peripheral vascular damage. When excluding poverty from the multivariable model, the renal domain of the SDI was independently associated with a shorter time to death (hazard ratio = 1.65; 95% CI 1.03, 2.66). CONCLUSIONS The renal domain of the damage index is associated with a shorter time to death when poverty, a strong predictor of this outcome, is removed from the model. Preventing renal damage in lupus patients has long-term prognostic implications.

Bisphosphonate-associated osteonecrosis of the jaw, with healing after teriparatide: a review of the literature and a case report.

This paper reports the case history of a patient who had bisphosphonate-associated osteonecrosis of the jaw (ONJ) in which adjunctive treatment with teriparatide was used. The patient was treated for 5 years with alendronate for osteoporosis and developed ONJ after extraction of maxillary teeth. An implant was placed at the site of the extracted teeth. The pathology report confirmed the clinical diagnosis of ONJ; treatment was changed from alendronate to teriparatide and the ONJ resolved. To our knowledge, this is the third case history reported in the literature in which teriparatide was successfully used as adjunct therapy in ONJ because it has an anabolic effect and presumed role in accelerating bone healing. ONJ is a serious but infrequent condition that has been recently associated with nitrogen-containing bisphosphonate therapy. Teriparatide may be a useful adjunctive therapy when ONJ develops.

Markers of Treatment Response to Methotrexate in Rheumatoid Arthritis: Where Do We Stand?

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea), or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG) levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX.

Biologics and heart failure in rheumatoid arthritis: are we any wiser?

Purpose of reviewTo summarize the recent literature concerning the role of TNF-α in heart failure, epidemiology of heart failure in rheumatoid arthritis and risk of heart failure associated with biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Recent findingsTNF-α has been implicated in the pathogenesis of heart failure. It has direct deleterious effects on the myocardium in the setting of acute injury or chronic heart failure. In animal models, TNF-α is important in cardiac remodeling, leading to cardiac dysfunction following acute injury. Both incident and worsening heart failure have been reported in patients with rheumatoid arthritis who are treated with anti-TNF-α therapy. Recent cohort studies, however, have shown no increased risk and, in some, a protective effect on the risk of heart failure. Certain traditional cardiovascular risk factors have a relatively lesser contribution to cardiovascular morbidity and mortality in patients with rheumatoid arthritis, suggesting that disease-related perturbations of the cytokine network may contribute to the excess risk of heart failure in these patients. SummaryOverall mortality in rheumatoid arthritis has remained stagnant despite advances in rheumatoid arthritis and heart failure management and improved cardiovascular mortality in the general population. Heart failure prevalence is increased in patients with rheumatoid arthritis and leads to greater mortality. Despite current expert consensus contraindicating the use of anti-TNF-α agents in patients with moderate to severe heart failure, epidemiological studies in rheumatoid arthritis have not consistently substantiated this association.

Genetic variants of STAT4 associated with rheumatoid arthritis in persons of Asian and European ancestry do not replicate in African Americans

Rheumatoid arthritis (RA) was recently genetically associated with signal transducer and activator of transcription 4 ( STAT4 ) in white individuals.1 This study included over 6000 participants to produce an odds ratio (OR) of 1.32 at rs7574865 (p<0.001). Three other single-nucleotide polymorphisms (SNP) located in intron 3 of STAT4 (rs8179673, rs10181656, rs6752770), three SNP in strong linkage disequilibrium with rs7574865 (r2=1.0; rs7582694, rs7568275, rs11889341) and a haplotype driven by the T allele of rs7574865 are also associated with RA susceptibility.1 Association with rs7574865 replicated in several Asian and European-based populations (see table 1). As racial/ethnic differences have been observed at RA susceptibility loci, including CTLA4, PADI4, PTPN22, RUNX1 and SLC22A4 , we aimed to determine if an association with these STAT4 markers and RA susceptibility is consistent in African Americans. View this table: Table 1 Previously published genetic associations with the T allele of rs7574865 …

Radiographic severity of Rheumatoid Arthritis in African Americans: Results from a multicenter observational study

To describe radiographic changes in African Americans with rheumatoid arthritis (RA) from the Consortium for the Longitudinal Evaluations of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry, a multicenter observational study.

Pharmacogenetics of etanercept in rheumatoid arthritis.

Etanercept is one of several TNF inhibitors approved for rheumatoid arthritis (RA) and a variety of other immune-mediated inflammatory conditions. Given the plethora of drugs approved for RA, and the wide variations in cost and treatment response, markers of efficacy would be very useful. Several candidate genes, including HLA-DRB1 alleles and those encoding TNF, TNF receptors and Fc receptors, have been examined for a role in the response to treatment with etanercept. In this review, we discuss pharmacogenetic studies of etanercept in RA and other diseases, and comment on the future of such analyses to advance the goal of personalized medicine in RA.

HLA–DRB1–Associated Rheumatoid Arthritis Risk at Multiple Levels in African Americans: Hierarchical Classification Systems, Amino Acid Positions, and Residues

To evaluate HLA–DRB1 genetic risk of rheumatoid arthritis (RA) in African Americans by 3 validated allele classification systems and by amino acid position and residue, and to compare genetic risk between African American and European ancestries.