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Background Vibration-induced white finger (VWF) is often assessed using the Stockholm Workshop Scale (SWS) and cold challenge plethysmography. However, long-term longitudinal studies using both methods are scarce. Aims To study the long-term course and prognostic factors of VWF assessed with the SWS and photoplethysmography (PPG), and to examine the effects of lifestyle on PPG score, regardless of VWF status. Methods Forty male construction workers were examined with a test battery and clinical examination in 1994 and 2016/17. Results At baseline, the sample comprised 27 workers with, and 13 without, symptoms of hand-arm vibration syndrome (HAVS). Thirty-five workers reported vibration exposure during follow-up. The mean age of the workers was 60 years (45-78) at follow-up. The paired t-test showed that PPG scores deteriorated from 1994 to 2017 in the 27 workers with HAVS in 1994 (mean difference 2.7 min, 95% confidence interval (CI) 0.2-5.2). However, there was no statistically significant change in SWS scores in these workers over time. Smoking and age were associated with PPG score deterioration. Vibration exposure during follow-up predicted SWS score deterioration: 1000 h of exposure predicted a deterioration stage of 0.09 (95% CI 0.03-0.16). Analysis of all 40 workers showed that 2017 PPG scores were associated with positive serum cotinine and self-reported smoking during follow-up. Conclusions Whereas age and smoking predicted a PPG deterioration, continued vibration exposure predicted worsening of white finger symptoms. The association of PPG score and smoking should be considered in diagnostic and prognostic factor evaluations.

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154���) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202���) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 �� 10���5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154���) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10���7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants���namely p.Ala104Val, p.Arg138Cys, p.Trp154���, and p.Arg202������reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

Idiopathic scoliosis (IS), the most common spinal deformity, affects otherwise healthy children and adolescents during growth. The aetiology is still unknown, although genetic factors are believed to be important. The present review corroborates the understanding of IS as a complex disease with a polygenic background. Presumably IS can be due to a spectrum of genetic risk variants, ranging from very rare or even private to very common. The most promising candidate genes are highlighted.

Background: CCAAT enhancer-binding protein epsilon (C/EBP epsilon) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBP epsilon is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality. Objective: The aim of this study was to molecularly characterize the effects of C/EBP epsilon transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome. Methods: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed. Results: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages. Conclusion: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBP epsilon. Mutated C/EBPe acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBP epsilon. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.

Coeliac disease is caused by dietary gluten, triggering a chronic inflammation of the small intestine in genetically predisposed individuals. Recently, a risk locus on chromosome 2q11-q12, harbouring interleukin 18 receptor accessory protein (IL18RAP) and three other genes, was suggested for coeliac disease. IL18 has been shown to play an important role in T helper type 1 activity in coeliac disease, making this locus a highly interesting candidate. In this study, two previously indicated risk variants at the IL18RAP locus (rs13015714 and rs917997) were tested for genetic association in 1638 cases with coeliac disease and 1385 control individuals from the Finnish, Hungarian and Italian populations. The protein expression level of IL18RAP was also compared between risk allele carriers and non-carriers by Western blotting. Furthermore, immunohistochemical analysis was performed to study IL18RAP protein expression in small intestinal biopsies of untreated and treated coeliac patients and controls. We confirmed genetic association and dose effects of variants at the 2q12.1 locus with coeliac disease in the Hungarian population. The GA haplotype of the markers rs13015714 and rs917997 showed the strongest association (P = 0.0001, odds ratio = 1.475, 95% confidence interval 1.21-1.80). Two putative isoforms of IL18RAP were detected and the ratios and total levels of these isoforms may contribute to the aetiology of coeliac disease. Our study supports IL18RAP as a novel predisposing gene for coeliac disease and highlights the need for further functional studies on this relatively unknown gene in coeliac disease pathogenesis. © The Author 2008. Published by Oxford University Press. All rights reserved.

Twenty-eight sponge specimens were collected at a shallow water hydrothermal vent site north of Iceland. Extracts were prepared and tested in vitro for cytotoxic activity, and eight of them were shown to be cytotoxic. A mass spectrometry (MS)-based metabolomics approach was used to determine the chemical composition of the extracts. This analysis highlighted clear differences in the metabolomes of three sponge specimens, and all of them were identified as Haliclona (Rhizoniera) rosea (Bowerbank, 1866). Therefore, these specimens were selected for further investigation. Haliclona rosea metabolomes contained a class of potential key compounds, the 3-alkyl pyridine alkaloids (3-APA) responsible for the cytotoxic activity of the fractions. Several 3-APA compounds were tentatively identified including haliclamines, cyclostellettamines, viscosalines and viscosamines. Among these compounds, cyclostellettamine P was tentatively identified for the first time by using ion mobility MS in time-aligned parallel (TAP) fragmentation mode. In this work, we show the potential of applying metabolomics strategies and in particular the utility of coupling ion mobility with MS for the molecular characterization of sponge specimens., The authors would like to thank Erlendur Bogason for his assistance in sample collection as well as being the "protector" of Strytan, the hydrothermal vent site. This project was funded by the Eimskip University Fund, The University of Iceland Research Fund, and the Icelandic Research Fund (grant no.: 110403021).

Background Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases. Methods We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease. Results Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples. Conclusion Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.

IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyte-associated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14–18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P=0.0015) and CVID (P=0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P=0.0005) and found association of CTLA4-ICOS with CD (P=0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P=0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.