Peter Junker

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.

Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation

Objective: To estimate the influence of genetic effects in the aetiology and pathogenesis of ankylosing spondylitis (AS). Methods: The study comprised one Norwegian and two Danish nationwide twin surveys. In 1994 and 2002, respectively, 37 388 and 46 331 Danish twin individuals were asked by questionnaire if they had AS. Similarly, in 1998, 12 718 Norwegian twins were asked if they had AS using a questionnaire phrased according to the Danish survey. Twins reporting AS were categorized according to the modified New York criteria. Results: A total of 113 twin individuals reported AS, of whom 81 (72.3%) participated in validation of the diagnosis. After validation, 39 probands were diagnosed with AS. Subsequent invitation of co‐twins resulted in 27 complete pairs. The point prevalence and the annual incidence of AS was 0.1% and 3/100 000 person‐years (pyr) among the Danish twins. The positive predictive value of self‐reported AS was 49.3%. Probandwise concordance rates on AS were (2/5) 40% in monozygotic (MZ) and (1/23) 4% in dizygotic (DZ) twins [difference 35% (95% CI 2.9–72.8), p = 0.26]. Heredity analysis including previously published and the present HLA‐B27‐positive twin pairs indicated that additive genetic effects account for 94% (95% CI 0.56–0.99) of the variance in the causation of AS. Conclusion: Self‐reported AS needs careful validation. The occurrence of AS in a Danish twin population was 0.1% and accords well with previous studies on singletons in hospital settings. The present study adds to previous evidence of a major genetic effect in the pathogenesis of AS.

On the heritability of psoriatic arthritis. Disease concordance among monozygotic and dizygotic twins

Objective: A nationwide unselected twin population to estimate the relative importance of genetic and environmental effectors in the aetiopathogenesis of psoriatic arthritis (PsA). Methods: The study comprised three Danish nationwide twin cohorts. In 1994 and 2002 a total of 37 388 and 46 418 Danish twin individuals respectively were asked by questionnaire if they had PsA. Twins reporting PsA were invited to participate in a clinical examination. Patients were classified according to the Moll and Wright and the CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria. Heritability was estimated by probandwise concordance rates and variance component analysis. Results: 228 twin individuals reported PsA. Following diagnostic validation in 164 (70%), 50 probands were diagnosed with PsA according to the Moll and Wright criteria. Five of their co-twins were either dead, had emigrated, or did not participate in the twin study and nine did not respond, resulting in 36 complete pairs. A total of one of 10 monozygotic pairs and one of 26 dizygotic pairs were concordant for PsA, yielding a 6.2% difference in proportions (95% CI: −11%, 37%). Five of 10 monozygotic pairs and four of 26 dizygotic pairs were concordant for psoriatic skin disease implying a 35% difference (95% CI: 2%, 60%, p<0.05). Conclusions: This first twin study on PsA confirms that genes are important in the causation of psoriatic skin disease. Despite the limited statistical power, the almost identical concordance rates for PsA in monozygotic and dizygotic twins stresses the importance of the continued search for non-genetic effectors in PsA.

The occurrence of psoriatic arthritis in Denmark

Objective: To apply and compare different classification criteria on a representative nationwide sample of psoriatic arthritis (PsA) twins and to estimate the prevalence and incidence of PsA. Methods: The study comprised three Danish nationwide twin cohorts. In 1994 37 388 Danish twin individuals and in 2002 46 418 twin individuals received a questionnaire, including questions on rheumatic diseases. Twins reporting PsA and their co-twins were classified according to the Moll and Wright and CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria based on interview, clinical examination and scrutiny of medical records. Results: 228 twin individuals reported PsA and 164 (72%) participated in clinical validation. By using the Moll and Wright and CASPAR criteria, 54 and 50 cases were diagnosed with PsA respectively. The positive predictive value of self-reported PsA was 31%. According to the Moll and Wright and CASPAR criteria the prevalence was 0.15% (95% CI: 0.13%, 0.22%) and 0.14% (95% CI: 0.11%, 0.19%) respectively. The annual incidence rate based on new self-reported cases in 2002 was 6/100 000 person-years (95% CI: 3/100 000 person-years, 11/100 000 person-years). Conclusions: The positive predictive value of self-reported PsA was 31%. The prevalence and incidence figures of PsA were equivalent to the previously reported occurrence in population- and hospital-based studies.

Adaptation of the Bath measures on disease activity and function in ankylosing spondylitis into Danish

Objective: Adaptation of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Global Score (BASG), and the Bath Ankylosing Spondylitis Functional Index (BASFI) for defining disease status in ankylosing spondylitis (AS) and related diseases for use in Denmark. Methods: The BASDAI, BASFI, and BASG were translated into Danish and subsequently field‐tested among 17 AS patients for relevance, face, and content validity. Reliability and validity were assessed by administering the new measures and a comparator instrument to 113 AS patients on two occasions. Results: Test–retest reliability was high (>0.90) and the random measurement error was within±2.0 for the BASG and within approximately±1.5 for BASDAI and BASFI, which is acceptable for most clinical settings. The measures have good internal consistency and are able to discriminate between functional impairment and disease activity according to the Nottingham Health Profile (NHP) and the Stanford Health Assessment Questionnaire (HAQ). Conclusion: Danish versions of the BASG, BASDAI, and BASFI are feasible for application in clinical trials and epidemiological studies on AS in Denmark.

Circulating Surfactant Protein D is Decreased in Early Rheumatoid Arthritis: A 1‐year Prospective Study

Innate immune system abnormalities, e.g., mannan‐binding lectin (MBL) genotype variants, have been demonstrated to modify the disease course of rheumatoid arthritis (RA). Surfactant protein D (SP‐D) shares important structural and functional properties with MBL suggesting that SP‐D may be an additional RA disease modifier. The Met11Thr polymorphism in the N‐terminal part of SP‐D is an important determinant for the SP‐D serum level, but this polymorphism is also essential to the function and assembly into oligomers. We aimed to compare the serum levels of SP‐D in a cohort of newly diagnosed untreated RA patients with healthy matched controls, and to investigate if there was an association to core measures of disease activity within the first year after disease onset. Secondly, we aimed to investigate whether the Met11Thr polymorphism was associated with RA. Serum SP‐D was significantly lower in DMARD naive RA patients compared with healthy controls (P = 0.016). Median SP‐D concentration at inclusion was 878 ng/ml (95% CI: 730–1033) and 1164 ng/ml (95% CI: 1093–1366) in RA patients and matched controls, respectively. SP‐D increased during Methotrexate treatment (P < 0.0001), and at 1‐year follow‐up median SP‐D was 1032 ng/ml (95% CI: 777–1255). SP‐D levels did not correlate with traditional disease activity measures. The Thr11/Thr11 genotype and the Thr11 allele tended to be more frequent in RA patients. In conclusion, the low serum level of SP‐D and the lack of correlation with traditional disease activity measures indicate that SP‐D reflects a distinctive aspect in the RA pathogenesis.