Promoter Variant of PIK3C3 Is Associated with Autoimmunity against Ro and Sm Epitopes in African-American Lupus Patients

The PIK3C3 locus was implicated in case-case genome-wide association study of systemic lupus erythematosus (SLE) which we had performed to detect genes associated with autoantibodies and serum interferon-alpha (IFN-α). Herein, we examine a PIK3C3 promoter variant (rs3813065/-442 C/T) in an independent multiancestral cohort of 478 SLE cases and 522 controls. rs3813065 C was strongly associated with the simultaneous presence of both anti-Ro and anti-Sm antibodies in African-American patients [OR = 2.24 (1.34–3.73), P = 2.0 × 10−3]. This autoantibody profile was associated with higher serum IFN-α (P = 7.6 × 10−6). In the HapMap Yoruba population, rs3813065 was associated with differential expression of ERAP2 (P = 2.0 × 10−5), which encodes an enzyme involved in MHC class I peptide processing. Thus, rs3813065 C is associated with a particular autoantibody profile and altered expression of an MHC peptide processing enzyme, suggesting that this variant modulates serologic autoimmunity in African-American SLE patients

Osteopontin Alleles Are Associated with Clinical Characteristics in Systemic Lupus Erythematosus

Variants of the osteopontin (OPN) gene have been associated with systemic lupus erythematosus (SLE) susceptibility and cytokine profiles in SLE patients. It is not known whether these alleles are associated with specific clinical phenotypes in SLE. We studied 252 well-characterized SLE patients from a multiethnic cohort, genotyping the rs11730582, rs28357094, rs6532040, and rs9138 SNPs in the OPN gene. Ancestry informative markers were used to control for genetic ancestry. The SLE-risk allele rs9138C in the 3′ UTR region was associated with photosensitivity in lupus patients across all ancestral backgrounds (meta-analysis OR = 3.2, 95% CI = 1.6–6.5, P = 1.0 × 10−3). Additionally, the promoter variant rs11730582C demonstrated suggestive evidence for association with two hematologic traits: thrombocytopenia (OR = 2.1, P = 0.023) and hemolytic anemia (OR = 2.6, P = 0.036). These clinical associations with SNPs in the promoter and 3′ UTR regions align with previously reported SLE-susceptibility SNPs in OPN and suggest potential roles for these variants in antibody-mediated cytopenias and skin inflammation in SLE

Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus

INTRODUCTION: Systemic lupus erythematosus (SLE) is a highly heterogeneous disorder, characterized by differences in autoantibody profile, serum cytokines, and clinical manifestations. SLE-associated autoantibodies and high serum interferon alpha (IFN-α) are important heritable phenotypes in SLE which are correlated with each other, and play a role in disease pathogenesis. These two heritable risk factors are shared between ancestral backgrounds. The aim of the study was to detect genetic factors associated with autoantibody profiles and serum IFN-α in SLE. METHODS: We undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serology and serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci were selected for follow-up in a large independent cohort of 538 SLE patients and 522 controls using a multi-step screening approach based on novel metrics and expert database review. The seven loci were: leucine-rich repeat containing 20 (LRRC20); protein phosphatase 1 H (PPM1H); lysophosphatidic acid receptor 1 (LPAR1); ankyrin repeat and sterile alpha motif domain 1A (ANKS1A); protein tyrosine phosphatase, receptor type M (PTPRM); ephrin A5 (EFNA5); and V-set and immunoglobulin domain containing 2 (VSIG2). RESULTS: SNPs in the LRRC20, PPM1H, LPAR1, ANKS1A, and VSIG2 loci each demonstrated strong association with a particular serologic profile (all odds ratios > 2.2 and P < 3.5 × 10(-4)). Each of these serologic profiles was associated with increased serum IFN-α. SNPs in both PTPRM and LRRC20 were associated with increased serum IFN-α independent of serologic profile (P = 2.2 × 10(-6 )and P = 2.6 × 10(-3 )respectively). None of the SNPs were strongly associated with SLE in case-control analysis, suggesting that the major impact of these variants will be upon subphenotypes in SLE. CONCLUSIONS: This study demonstrates the power of using serologic and cytokine subphenotypes to elucidate genetic factors involved in complex autoimmune disease. The distinct associations observed emphasize the heterogeneity of molecular pathogenesis in SLE, and the need for stratification by subphenotypes in genetic studies. We hypothesize that these genetic variants play a role in disease manifestations and severity in SLE

Gene-Expression-Guided Selection of Candidate Loci and Molecular Phenotype Analyses Enhance Genetic Discovery in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disorder characterized by differences in autoantibody profiles, serum cytokines, and clinical manifestations. We have previously conducted a case-case genome-wide association study (GWAS) of SLE patients to detect associations with autoantibody profile and serum interferon alpha (IFN-α). In this study, we used public gene expression data sets to rationally select additional single nucleotide polymorphisms (SNPs) for validation. The top 200 GWAS SNPs were searched in a database which compares genome-wide expression data to genome-wide SNP genotype data in HapMap cell lines. SNPs were chosen for validation if they were associated with differential expression of 15 or more genes at a significance of P<9×10−5. This resulted in 11 SNPs which were genotyped in 453 SLE patients and 418 matched controls. Three SNPs were associated with SLE-associated autoantibodies, and one of these SNPs was also associated with serum IFN-α (P<4.5×10−3 for all). One additional SNP was associated exclusively with serum IFN-α. Case-control analysis was insensitive to these molecular subphenotype associations. This study illustrates the use of gene expression data to rationally select candidate loci in autoimmune disease, and the utility of stratification by molecular phenotypes in the discovery of additional genetic associations in SLE

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ABSTRACT. Objective. While work disability is common in patients with systemic lupus erythematosus (SLE), it is not known which lupus disease characteristics predispose toward work disability. We examined demographic, clinical, serological, and neuropsychological factors in a group of disabled and nondisabled patients with SLE. Methods. Fifty patients meeting American College of Rheumatology criteria for SLE were assessed for work status, disease characteristics, fatigue, anxiety, depressive symptoms, and quality of life. All subjects underwent an abbreviated panel of neuropsychological tests. Subjects who had formal work disability (social security or longterm disability, n = 16) and subjects who self-reported work disability without formal recognition (n = 8) were compared to subjects denying work disability from lupus (n = 26). Results. Education level, African-American race, and SLICC Damage Index score were significantly associated with formal work disability relative to other subjects. Neurocognitive impairment (OR 14.44, 95% CI 3.01, 68.20; p = 0.001), nephritis (OR 3.75, 95% CI 1.01, 13.9; p = 0.048), and discoid lupus (OR 19.93, 95% CI 3.51, 113.3; p = 0.001) were all associated with formal disability. Formally disabled patients had higher fatigue and anxiety scores and more impaired quality of life in many domains relative to nondisabled subjects. Subjects with self-reported work disability also had neurocognitive dysfunction, high fatigue scores, and poor quality of life, but in other respects appeared to have milder disease than formally disabled subjects. Conclusion. Neurocognitive dysfunction and fatigue are 2 manifestations that may contribute materially to work disability in lupus. Other associated factors include low education levels, SLICC Damage Index scores, discoid lupus, nephritis, and possibly African-American race. (J Rheumatol 2006; 33:531-8)

Work disability, lost productivity and associated risk factors in patients diagnosed with systemic lupus erythematosus.

ObjectiveTo assess prevalence and correlates of work presenteeism, absenteeism and work disability (WD) in patients with systemic lupus erythematous (SLE) and matched controls.MethodsPatients with SLE from six medical centres were recruited to complete a questionnaire consisting of several prevalidated survey instruments. The subject's rheumatologist completed medical history. Subjects recruited two non-SLE 'best friend' controls with matching demographics to complete a control survey. Analyses employed Student's t tests, χ(2) tests and logistic regression models.Results344 subjects with SLE and 322 controls submitted completed questionnaires. Mean pain, fatigue, Brief Cognitive Symptoms Index (BCSI) scores and depressive symptoms were worse in patients with SLE with WD (all p&lt;0.01). WD was associated with African-American race, older age (51-65 years) and less than 4-year college education (all p&lt;0.01). High presenteeism was associated with low pain and fatigue levels, higher BCSI scores and negatively correlated with depressive symptoms (all p&lt;0.05). Increased pain and fatigue were associated with elevated absenteeism (p&lt;0.05). Subjects with physically and cognitively demanding work reported worse presenteeism compared with controls with similar jobs (77% vs 85%, p&lt;0.05 and 75% vs 85%, p&lt;0.001), respectively. Patients with most cognitively demanding jobs reported greater weekly absenteeism (mean, 5.9 h) compared with controls (mean, 6.9 overtime hours, p&lt;0.05).ConclusionsThe questionnaire demonstrated increased WD in SLE. Highly physical and highly cognitive jobs are challenging to patients with SLE and had increased absenteeism compared with controls. Depressive symptoms were correlated with better presenteeism without major socio-demographic determinants. Employability may be enhanced by improving treatment of depressive symptoms in patients with SLE

Work disability, lost productivity and associated risk factors in patients diagnosed with systemic lupus erythematosus.

ObjectiveTo assess prevalence and correlates of work presenteeism, absenteeism and work disability (WD) in patients with systemic lupus erythematous (SLE) and matched controls.MethodsPatients with SLE from six medical centres were recruited to complete a questionnaire consisting of several prevalidated survey instruments. The subject's rheumatologist completed medical history. Subjects recruited two non-SLE 'best friend' controls with matching demographics to complete a control survey. Analyses employed Student's t tests, χ(2) tests and logistic regression models.Results344 subjects with SLE and 322 controls submitted completed questionnaires. Mean pain, fatigue, Brief Cognitive Symptoms Index (BCSI) scores and depressive symptoms were worse in patients with SLE with WD (all p&lt;0.01). WD was associated with African-American race, older age (51-65 years) and less than 4-year college education (all p&lt;0.01). High presenteeism was associated with low pain and fatigue levels, higher BCSI scores and negatively correlated with depressive symptoms (all p&lt;0.05). Increased pain and fatigue were associated with elevated absenteeism (p&lt;0.05). Subjects with physically and cognitively demanding work reported worse presenteeism compared with controls with similar jobs (77% vs 85%, p&lt;0.05 and 75% vs 85%, p&lt;0.001), respectively. Patients with most cognitively demanding jobs reported greater weekly absenteeism (mean, 5.9 h) compared with controls (mean, 6.9 overtime hours, p&lt;0.05).ConclusionsThe questionnaire demonstrated increased WD in SLE. Highly physical and highly cognitive jobs are challenging to patients with SLE and had increased absenteeism compared with controls. Depressive symptoms were correlated with better presenteeism without major socio-demographic determinants. Employability may be enhanced by improving treatment of depressive symptoms in patients with SLE

Increased Whole Blood Viscosity Is Associated with the Presence of Digital Ulcers in Systemic Sclerosis: Results from a Cross-Sectional Pilot Study

Objective. To investigate the role of whole blood viscosity in digital ulcer (DU) development in patients with diffuse and limited Systemic sclerosis. Methods. A convenience sample of patients with Systemic sclerosis (SSc) was selected from the adult Rheumatology clinic at the University of Chicago. The study group consisted of patients with SSc (with ulcers present, a history of ulcers, and no ulcers); the control group consisted of matched healthy Rheumatology clinic staff. WBV was measured using a scanning capillary viscometer at different shear rates (1–1000 1/s). Results. Whole blood viscosity as measured by a scanning capillary viscometer was increased in patients with SSc compared to healthy controls (p<0.0001). Additionally, patients with present DU had significantly higher whole blood viscosity when compared to patients with a history of DU and patients with no history of DU (p<0.0001). These findings were most pronounced at lower shear rates between 1 and 10 1/s. Conclusion. Whole blood viscosity might be a contributing factor in DU development in patients with SSc. Further studies with larger patient cohorts are required to fully evaluate how increased WBV contributes to the development of DU and whether the currently available treatment options improve the microcirculation by influencing WBV