Karolinska Institutet

About: Karolinska Institutet is a education organization based out in Stockholm, Sweden. It is known for research contribution in the topics: Population & Poison control. The organization has 46212 authors who have published 121142 publications receiving 6008130 citations.

TRAF1–C5 as a Risk Locus for Rheumatoid Arthritis — A Genomewide Study

Abstract: A B S T R AC T Background Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheu- matoid arthritis. Methods We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case- control study of 1522 case subjects with rheumatoid arthritis and 1850 matched con - trol subjects. The patients were seropositive for autoantibodies against cyclic citrul- linated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Inves- tigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran- Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1×10 −8 ) were genotyped in an independent set of case subjects with anti- CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). Results We observed associations between disease and variants in the major-histocompat- ibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P = 4×10 − � 4 ). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). Conclusions A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.

Common variants associated with plasma triglycerides and risk for coronary artery disease

Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Genetically Distinct Subsets within ANCA-Associated Vasculitis

Abstract: BACKGROUND Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS A genomewide association study was performed in a discovery cohort of 1233 U. K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding alpha(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2x10(-89), P = 5.6x10(-12), and P = 2.6x10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1x10(-8)). CONCLUSIONS This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)

Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats

Abstract: Postinjury recovery in most tissues requires an effective dialog with macrophages; however, in the mammalian central nervous system, this dialog may be restricted (possibly due to its immune-privileged status), which probably contributes to its regeneration failure We circumvented this by implanting macrophages, pre-exposed ex vivo to peripheral nerve segments, into transected rat spinal cord This stimulated tissue repair and partial recovery of motor function, manifested behaviorally by movement of hind limbs, plantar placement of the paws and weight support, and electrophysiologically by cortically evoked hind-limb muscle response We substantiated these findings immunohistochemically by demonstrating continuity of labeled nerve fibers across the transected site, and by tracing descending fibers distally to it by anterograde labeling In recovered rats, re-transection of the cord above the primary transection site led to loss of recovery, indicating the involvement of long descending spinal tracts Injection of macrophages into the site of injury is relatively non-invasive and, as the cells are autologous, it may be developed into a clinical therapy