Genetic risk factors for thrombosis in systemic lupus erythematosus.

OBJECTIVE: Thrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts. METHODS: Our discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications. RESULTS: In the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL) rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFR rs1801131 (OR 1.51, p = 0.01), MTHFR rs1801133 (OR 0.70, p = 0.04), FVL rs6025 (OR 2.69, p = 0.002), and FGG rs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGG rs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics. CONCLUSION: Our results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups.

Cardiovascular disease and cognitive dysfunction in systemic lupus erythematosus.

OBJECTIVE: Cognitive dysfunction and cardiovascular disease are common and debilitating manifestations of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between cardiovascular events, traditional cardiovascular risk factors, and SLE-specific risk factors as predictors of cognitive dysfunction in a large cohort of participants with SLE. METHODS: Subjects included 694 participants from the Lupus Outcomes Study (LOS), a longitudinal study of SLE outcomes based on an annual telephone survey querying demographic and clinical variables. The Hopkins Verbal Learning Test-Revised and the Controlled Oral Word Association Test were administered to assess cognitive function. Multiple logistic regression was used to identify cardiovascular events (myocardial infarction, stroke), traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, obesity, smoking), and SLE-specific risk factors (antiphospholipid antibodies [aPL], disease activity, disease duration) associated with cognitive impairment in year 7 of the LOS. RESULTS: The prevalence of cognitive impairment as measured by verbal memory and verbal fluency metrics was 15%. In adjusted multiple logistic regression analyses, aPL (odds ratio [OR] 2.10, 95% confidence interval [95% CI] 1.3-3.41), hypertension (OR 2.06, 95% CI 1.19-3.56), and a history of stroke (OR 2.27, 95% CI 1.16-4.43) were significantly associated with cognitive dysfunction. In additional analyses evaluating the association between these predictors and severity of cognitive impairment, stroke was significantly more prevalent in participants with severe impairment when compared to those with mild or moderate impairment (P = 0.036). CONCLUSION: These results suggest that the presence of aPL, hypertension, and stroke are key variables associated with cognitive impairment, which may aid in identification of patients at greatest risk.

Genetics research in systemic lupus erythematosus for clinicians: methodology, progress, and controversies.

PURPOSE OF REVIEW: Clinical journals are reporting genetic associations with systemic lupus erythematosus (SLE) with increasing frequency. Interpreting these studies is difficult for clinicians without rigorous training in epidemiology, statistics, and genetics. In this review, we discuss basic issues important to understanding and contextualizing new genetic association studies. We, therefore, highlight literature related to methodology as well as recent genetic discoveries in SLE. RECENT FINDINGS: Functional single nucleotide polymorphisms (SNPs) and/or haplotypes have now been identified for ITGAM, PTPN22, and IRF5, and several additional loci have been highlighted in recent genome-wide association studies in SLE. Recent work also indicates that several regions within the extended major histocompatibility complex contribute independently to SLE risk. Evidence of additive statistical interaction has been found between IRF5 and TYK2, IRF5, and STAT4, and between NAT2 and exposure to tobacco smoke. SUMMARY: Many new genes have been associated with SLE susceptibility, revealing insight into SLE pathophysiology. Current research is focusing on further refining the initial genetic association results and extending this work to non-European populations. Research is also expanding beyond SNP associations to investigate the contribution of copy number variants (CNVs) and DNA methylation to SLE risk.

Incidence of lymphoma in patients with rheumatoid arthritis: a systematic review of the literature.

To our knowledge, this review is the most broad and only systematic survey to date of the rheumatology, oncology, and epidemiology literature to determine the prevalence of lymphoma in patients with rheumatoid arthritis (RA). This survey is analyzed to determine whether the association between RA and increased lymphoma risk is a result of the risks conferred by medications used to treat RA or a result of the disease itself. PubMed was searched for articles from 1964 to May 2007 using the Medical Subject Heading terms "arthritis, rheumatoid, and lymphoma." Twenty-six studies met inclusion and exclusion criteria and are included for review. Most studies confirmed an approximate 2-fold increase in lymphoma incidence in patients with RA. Contrary to a widely held belief about medication toxicity in RA, most studies did not reveal a statistically significant increased risk of lymphoma with methotrexate or azathioprine. An increased lymphoma incidence with tumor necrosis factor-alpha inhibitors was suggested; however, follow-up in the studies considered was too short to definitively determine increased risk. Most studies differed in which medications they evaluated in determining their impact on lymphoma risk, making studies difficult to compare. Confounding by disease severity (patients with the most severe disease are treated with the strongest medications) in most studies makes the association between lymphoma risk and medications and/or disease severity difficult to assess. Recent work suggests that it is the disease itself, not its treatment, that is associated with increased risk of lymphoma in patients with RA.