Helle Laustrup

Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance. In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 × 10−10; OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Δ2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point–site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell–receptor signaling and B-cell hyperactivity characteristic of this disease.

A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients

The association between polymorphisms in the programmed death (PD-1) gene and susceptibility to systemic lupus erythematosus (SLE) was determined using genomic DNA, isolated from a population-based cohort of 95 SLE patients and 155 healthy controls. Polymorphisms in the complete PD-1 gene except the large intron 1 were detected by sequencing. Furthermore, the patients were stratified according to the presence or absence of lupus nephropathy. The influence of the detected single nuclear polymorphisms (SNPs) on this specific clinical disease parameter was determined. In total, we identified 12 single nucleotide polymorphisms, of which six were novel and eight were considered to be rare (the frequency of the minor allele of these was less than 1% in our study populations). We found a significant association of an intronic 6867C/G SNP in the PD-1 gene with the presence of lupus nephropathy. As the 6867C/G SNP is located in a putative binding site for the transcriptional repressor ZEB, the associated allele of this SNP potentially alters the transcriptional regulation of PD-1. This report, for the first time, indicates that a 6867C/G SNP of the PD-1 gene is associated with lupus nephropathy in Caucasian SLE patients.

Occurrence of systemic lupus erythematosus in a Danish community: an 8‐year prospective study

Objectives: To determine the prevalence and annual incidence of definite systemic lupus erythematosus (D‐SLE) and incomplete SLE (I‐SLE) in a community‐based lupus cohort of predominantly Nordic ancestry in an 8‐year prospective study from 1995 to 2003, and also to calculate the annual transition rate of I‐SLE to D‐SLE. Methods: In 1995 all SLE patients in the county of Funen were retrieved from four separate and independent sources. Incident cases were subsequently identified by surveillance of these sources. Results: During the 8‐year study period the median annual incidence of D‐SLE (1.04 per 100 000) and I‐SLE (0.36 per 100 000) remained almost constant. The point prevalence (PP) of D‐SLE increased from 21.9 to 28.3 per 100 000, and from 6.19 to 7.53 per 100 000 for I‐SLE. During follow‐up, seven I‐SLE patients transformed into D‐SLE at a progression rate of 3.64 per 100 person‐years at risk [95% confidence interval (CI) 1.44–7.55]. Conclusions: Denmark is a low‐incidence lupus area but lupus prevalence is increasing slowly. I‐SLE is a disease variant that may eventually convert into D‐SLE.

SLE disease patterns in a Danish population-based lupus cohort: an 8-year prospective study.

In 1995 all systemic lupus erythematosus (SLE) patients in the county of Funen were retrieved from four separate and independent sources as part of an 8-year prospective study to determine the pattern of disease activity and damage accumulation in a community based lupus cohort of predominantly Scandinavian ancestry. Incident cases were subsequently identified by surveillance of these sources. Established and new cases underwent annual, structured interviews, clinical examination and blood sampling. The Systemic Lupus Erythematosus Diseases Activity Index SLEDAI and Systemic Lupus International Collaborating Clinics SLICC scores were calculated. Flares were defined as modified — SLEDAI ≥ 4. The annual flare rate in definite SLE (D-SLE) was 0.21 (95%CI 0.18—0.24) versus 0.03 (95%CI 0.01—0.07) in incomplete SLE (I-SLE). Forty-three per cent of the entire study population had no disease exacerbations. Infections requiring hospital admission and thrombocytopenia were significantly more frequent among patients with relapsing disease (p < 0.04—0.01). Patients with flares had slightly shorter disease duration and were younger at disease onset than patients with a quiescent course. The most recently diagnosed patients had the lowest annual rate of damage accrual. According to flare rate, two major subsets of almost equal size were identified — one having a long quiescent course, the other exhibiting relapses alternating with remissions. An increased risk of flares was associated with short disease duration and younger age at disease onset, infections requiring hospital admission and thrombocytopenia. Temporal damage increment was the lowest in the most recently diagnosed patients. Lupus (2010) 19, 239—246.

Survival in systemic lupus erythematosus, 1995–2010. A prospective study in a Danish community:

Objective The objective of this paper is to investigate survival and causes of death in a Danish lupus population. Methods Two hundred and fifteen SLE patients (94% Caucasians) were followed prospectively for up to 16 years. Thirty-eight patients died. Survival rate and causes of death were analysed. Results Overall standardized mortality ratio (SMR) was 2.2. Peak values were recorded for patients aged 20–29 (SMR 21.1). Cumulated survival rates at one, five, 10 and 15 years were 98.6%, 93.6%, 86.5% and 73.0%, respectively. The most common causes of death were cardiovascular events (32%), respiratory system disease (16%) and malignancies (13%). Deaths due to infections and active SLE were rare and predominated within the first seven years after diagnosis and before age 40, while cardiovascular deaths prevailed after 20 years’ follow-up. Conclusion This study shows that despite progress in lupus management, including direct access to specialized hospital care and increased use of hydroxychloroquine, mortality in lupus patients is still increased. Main causes of death were active disease and infections among the young and newly diagnosed, while cardiovascular deaths prevailed in longstanding disease.

Corrigendum: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus

Corrigendum: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus

Single test isolated lupus anticoagulant positivity is associated with increased plasma levels of inflammatory markers and dyslipidemia

Objective To investigate whether a single positive test for lupus anticoagulant (LA) is associated with levels of inflammatory markers and traditional cardiovascular risk factors, independent of autoimmune disease, thrombophilia and occurrence of other antiphospholipid antibodies. Methods In a retrospective observational study we included persons referred for thrombophilia testing during 2011−2014. Persons with autoimmune disease, thrombophilia or presence of specific anti-phospholipid antibodies were excluded. Multivariate logistic regression analyses adjusted for age and sex was performed and odds ratios (ORs) with 95% confidence intervals (95% CI) calculated. Results Of 381 individuals tested, 271 fulfilled the criteria, of whom 22 (8%) were LA positive and 249 (92%) LA negative. LA positivity was associated with higher body mass index (BMI) (OR 1.12, 95% CI: 1.03–1.23, p = 0.01); C-reactive protein (OR 1.08 95% CI:1.04–1.11, p < 0.001); fibrinogen (OR 1.51 95% CI: 1.27–1.78, p < 0.001); coagulation factor VIII (FVIII) (OR 1.73 95% CI: 1.01–2.96, p = 0.046), low high density lipoprotein (HDL) (OR 0.03 95% CI: 0.00–0.19, p < 0.001) and high triglyceride (OR 1.81 95% CI: 1.12–2.92, p = 0.02) compared with LA negative individuals. Conclusion This study shows that single test isolated LA positivity is associated with increased levels of inflammatory markers, low HDL cholesterol, elevated triglyceride and high BMI.

Aquaporin-4-autoimmunity in patients with systemic lupus erythematosus: A predominantly population-based study

Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease (NMOSD). Co-existence of NMOSD with systemic lupus erythematosus (SLE) putatively suggests susceptibility to antibody-mediated autoimmune disease. Objective: To estimate the prevalence of NMOSD in SLE and investigate the immunogenetic background for an association of NMOSD and SLE. Methods: The study included a predominantly population-based cohort with clinical and serological investigations of 208 patients with SLE, followed prospectively since 1995. All patients received immunosuppressive treatment. NMOSD was evaluated retrospectively based on the 2015 International Panel for NMOSD Diagnosis (IPND) criteria. Polymorphisms in programmed cell death protein 1 (PDCD-1) PD-1.3 G/A were genotyped. AGP4-IgG and other autoantibodies, including myelin oligodendrocyte glycoprotein (MOG), was determined blinded to clinical diagnosis. Results: Of 208 patients with SLE, 45(22%) had neuropsychiatric (NP) SLE, and CNS involvement predominated in 30 of 45 (67%) patients. Serum AQP4-IgG was detected in 2 of 30 (6.7%) neuropsychiatric SLE (NPSLE) patients both of whom had myelitis and antiphospholipid syndrome; one patient also had myasthenia gravis. None had MOG-IgG. PD-1.3A allele was not associated with SLE nor with NPSLE. Conclusion: AQP4-IgG autoimmune syndrome may rarely co-exist with SLE, and such patients have other NMOSD-typical syndromes such as myelitis.

Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus (Nature Genetics (2008) 40, (211-216))

Corrigendum: Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus

Autoantibodies persist in relatives to systemic lupus erythematosus patients during 12 years follow-up.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease with presence of autoantibodies and characteristic multi-organ involvement. Relatives of SLE patients have an increased risk of autoantibody production and autoimmune diseases. Methods In 2001, 226 first degree relatives (FDRs) of a population-based cohort of SLE patients were examined for the prevalence of autoantibodies and self-reported health complaints. In 2013, 143 FDRs were re-investigated and deceased’s medical records were examined. Results Participants and non-participants were comparable regarding baseline characteristics, while deceased FDRs were older than participants, but with comparable ANA status. ANA status at baseline correlated to ANA status at follow-up. At follow-up, two FDRs reported SLE and 15 FDRs other autoimmune diseases. No observation at baseline alone could predict self-reported health. During follow-up 33 died at median age 76 years. Three deceased FDRs were diagnosed with an autoimmune disease. Conclusion The study showed that FDRs of SLE patients have an increased prevalence of ANA compared to healthy controls. The prevalence increased during follow-up, and ANA positive FDRs at baseline were prone to be ANA positive at follow-up. ANA positive FDRs had more self-reported autoimmune diseases, including SLE and rheumatoid arthritis, than reported from other population-based investigations.