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Background: Tularemia is a zoonotic infection caused by Francisella tularensis , an aerobic, facultative intracellular coccobacillus, encountered especially in the Northern hemisphere. F. tularensis is a pathogen of humans and hundreds of animal species. Patients and methods: A Belgian traveler returning from an adventurous vacation in Central Europe presents fever, flu-like symptoms, a skin ulcer with a necrotic center resembling an eschar on the left thigh and painful left inguinal lymphadenopathy. An enzyme linked immunosorbent assay developed by the National Reference Laboratory for Tularemia, Sciensano, Belgium, detected elevated Ig G antibodies against F. tularensis , while the rest of the serologies were negative. Results: A highly likely case of ulceroglandular tularemia is described and the differential diagnosis is discussed. Conclusion: The incidence of tularemia has been increasing throughout Europe in recent years. Physicians should be aware of this disease, its diversity of reservoirs, transmission routes and clinical presentations. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is an arthropod-borne virus that is transmitted by Aedes mosquitoes, and its main features are high fever and (debilitating) arthritis. Infection with CHIKV, as well as other viruses, has been associated with hypercoagulable states and may be linked with the development of venous thrombosis. In fact, the development of deep venous thrombosis has been described in CHIKV infection. We present a case of superficial thrombophlebitis of the thoracic wall, known as Mondor's disease, associated with CHIKV infection. To our knowledge, this probable association has never been described before. [ABSTRACT FROM AUTHOR]

Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. I In nil sapiendo vita iucundissima est. i In knowing nothing, life is most delightful.- Publilius Syrus Daffodils as usual heralded spring when We became knights in casual armour Wearing gloves to cover skin-deep solitude Carrying face shields to hide our deepest dismay Forgetting ourselves and facing our fears and Forging the unthinkable to the barely possible Resilience scattered across the battlefield A little anxious to collect all the pieces I believe I escaped largely Unscathed but shaken Longing for yesteryears ignorance and bliss Declarations Conflict of Interest No conflict of interest. [Extracted from the article]

Objective Previous studies have shown that the majority of patients with PMR have increased 18F-fluorodeoxyglucose (FDG) uptake around the shoulders, hips and processes of the cervical and lumbar spine on PET. The specificity of these findings for PMR is, however, not known. Methods We prospectively included 99 consecutive patients with a possible clinical diagnosis of PMR. All patients underwent 18F-FDG-PET scanning before treatment with glucocorticoids was started. The clinical suspicion of PMR was quantified by the treating physician on a scale from 1 to 5. FDG uptake was scored visually in 12 articular regions (scores 0–2) and a total skeletal score was calculated reflecting the FDG uptake in these 12 articular regions. Receiver operating characteristics analysis was performed to determine the optimal clinical and total skeletal score for diagnosing PMR. The gold standard for a diagnosis of PMR was the judgement of an experienced clinician after at least 6 months of follow-up. Results Sixty-seven patients were diagnosed with PMR while 32 patients got another diagnosis. A clinical score of 4 or more had a sensitivity of 67.2%, specificity of 87.5%, positive predictive value (PPV) of 91.8% and a negative predictive value (NPV) of 56.0% for the diagnosis of PMR. A total skeletal score of 16 or more had a sensitivity, specificity, PPV and NPV of, respectively, 85.1, 87.5, 93.4 and 73.7%. Conclusion 18F-FDG-PET before starting glucocorticoid therapy improves the diagnostic accuracy compared with a clinical scoring system in patients with clinical suspicion of PMR. [ABSTRACT FROM AUTHOR]

Granulomatosis with polyangiitis (GPA) is a systemic inflammatory disease, characterized by the presence of necrotizing vasculitis of small and medium-sized vessels, granulomatous inflammation and anti-neutrophil cytoplasmic antibodies (ANCAs). The diagnosis can be challenging due to the variable clinical presentation and possible involvement of virtually all organ systems. A correct diagnosis is indispensable for a timely start of medical treatment and to avoid unnecessary surgery. Therefore, cooperation with and the input of the pathologist is crucial. We report a case of a woman presenting with suspected metastatic cancer. The diagnosis of GPA was made mainly based on breast biopsy, and the patient was treated accordingly, with full recovery. This report provides a case description and a brief review of the literature. [ABSTRACT FROM AUTHOR]

In patients presenting with nasal septum perforation, the differential diagnosis between ANCA-associated vasculitis and cocaine-induced midline destruction (CIMD) can be challenging. We describe the case of a 28-year old man who presented with a nasal septum perforation. He admitted the use of cocaine and showed no other symptoms of systemic inflammation. Perinuclear anti-neutrophilic cytoplasmatic antibodies (p-ANCAs) came back positive, as did anti-proteinase 3-antibodies. Further testing revealed antibodies to human neutrophil elastase (HNE), typically found in CIMD but rarely in ANCA-associated vasculitis. The combination of an atypical ANCA-pattern and the detection of HNE-antibodies led to the diagnosis of CIMD. In conclusion, HNE antibodies can be used to distinguish between CIMD and ANCA-associated vasculitis. [ABSTRACT FROM AUTHOR]

Background: The outcome of primary sclerosing cholangitis (PSC) has improved by liver transplantation (LT), but patients often develop malignancies. We analysed morbidity and mortality patterns to define strategies to prevent complications. Methods: Two hundred consecutive patients diagnosed before October 2005 were studied. Results: Malignancies developed in 40 (20%) and led to death in 28 patients (45.9% of the 61 mortalities). Cholangiocarcinoma (CCa) developed in 13 patients, and was detected shortly after the diagnosis of PSC in 31%. Colorectal carcinomas were documented in 10 and dysplastic adenomas in four patients; eight had ulcerative colitis, two Crohn's colitis, one unclassified inflammatory bowel disease (IBDu), three had no IBD. Five died of colorectal cancer. Three carcinomas and two adenomas were localized in the caecum or ascending colon, but most ( n=10) in the recto-sigmoidal region. Hepatocellular carcinoma developed in three patients with advanced fibrosis/cirrhosis, and pancreatic cancer in five. LT has been carried out in 42 patients, 6.1 years (median, 0.5-25) after the diagnosis of PSC. Mortality was due to hepatic complications in 13 patients. Within 5 years of the diagnosis, deaths were because of malignancy in 12 patients and to hepatobiliary decompensation in only three, whereas 18 had been transplanted. Conclusions: Since the use of transplantation, malignancies are the major cause of death. CCa has to be searched for in any new symptomatic patient. Colorectal malignancy occurs frequently. Colonoscopy at the diagnosis of PSC is obligatory and should be repeated at 1-2 years interval in the patients with IBD and every 5 years in those without IBD. [ABSTRACT FROM AUTHOR]

The article examines the influence of single nucleotide polymorphisms in selected genes involved in innate immunity on the development of bacteremia or risk of death in patients admitted to a medical intensive care unit. According to the authors, functional polymorphisms predispose to severe infections and death, and may become part of a risk model, allowing identification of patients at risk, who could benefit from early introduction of specific preventive or therapeutic interventions.

Background/Aims: Primary sclerosing cholangitis (PSC) is a progressive cholestatic disease commonly associated with inflammatory bowel disease (IBD) and characterized by fibrosing inflammatory destruction of bile ducts. The histological features in the liver of PSC patients are similar to those observed in cystic fibrosis (CF). Our aim was to study whether variants in the CFTR gene are associated with the occurrence and/or evolution of PSC. Methods: PSC patients (n =140) were genotyped for F508del, the TGmTn variants, and four additional polymorphic loci (1001+11 C>T, M470V, T854T and Q1463Q), and compared to 136 matched healthy controls. Results: The 1540G-allele, encoding V470, was less frequent in PSC (52%) than in controls (64%, p =0.003), and was associated with protection against PSC in individuals without IBD (OR 0.25, 95% CI 0.12–0.52, p =0.0002). Also TG11-T7 was less frequent in PSC (53%) than in controls (61%, p =0.04), this haplotype was associated with reduced risk for PSC (OR 0.34, 95% CI 0.17–0.70, p =0.003) in individuals without IBD. Conclusions: In this cohort of PSC patients, several CFTR-variants affecting the functional properties of the CFTR protein seem to offer protection against the development of PSC, confirming our hypothesis that CFTR might be implicated in the pathogenesis of PSC. [Copyright &y& Elsevier]

Discs large homolog 5 (DLG5), a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, has been associated with Crohn’s disease (CD), but its role in the pathogenesis of this inflammatory bowel disease is disputed. Here, we used sequence comparisons and phylogenies to analyse the DLG5 gene and its protein product. We identified a 5′ exon, which codes for an N-terminal caspase recruitment domain (CARD) and experimentally confirmed its expression in colonic tissue. DLG5 shares this new domain with nucleotide-binding oligomerisation domain containing 2 (NOD2); the first CD susceptibility factor identified in genetic studies. An extensive phylogenetic analysis redefines the family organisation of the MAGUK proteins: DLG5 is closely related to CARD10, CARD11 and CARD14, CARD-containing proteins which initiate pro-inflammatory NFκB signalling, but not to DLG1–4, previously considered the closest related proteins. Therefore, we suggest renaming DLG5 to correctly annotate the gene in its phylogenetic and functional context. Our study provides evidence that the scaffolding protein DLG5 belongs to the CARD protein family. Thus, DLG5 likely acts in the regulation of NFkB activation or caspase activation as part of host defence mechanisms. As there is substantial crosstalk between CARD-mediated pathways, both CD susceptibility genes, NOD2 and DLG5, may interact functionally to contribute to CD risk. [ABSTRACT FROM AUTHOR]

Background and aims: A number of antibodies against microbial epitopes or self-antigens have been associated with Crohn's disease. The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies Crohn's disease, resulting in an exaggerated adaptive immune response to these bacteria. It was hypothesised that the development of antimicrobial antibodies is influenced by the presence of genetic variants in pattern recognition receptor genes. The aim of this study was therefore to investigate the influence of mutations in these innate immune receptor genes (nucleotide oligomerisation domain (NOD) 2/caspase recruitment domain (CARD) 15, NOD1 /CARD4, TUCAN/CARDINAL/CARD8, Toll-like receptor (TLR) 4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in inflammatory bowel disease (IBD). Materials and methods: A cohort of 1163 unrelated patients with IBD (874 Crohn's disease, 259 ulcerative colitis, 30 indeterminate colitis) and 312 controls were analysed for anti-Saccharomyces cerevisiae antibodies (gASCA) IgG, anti-laminaribioside antibodies (ALCA) IgG, anti-chitobioside antibodies (ACCA) IgA, anti-mannobioside antibodies (AMCA) IgG and outer membrane porin (Omp) IgA and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6. Results: When compared with Crohn's disease patients without CARD 15 mutations, the presence of at least one CARD15 variant in Crohn's disease patients more frequently led to gASCA positivity (66.1% versus 51.5%, p < 0.0001) and ALCA positivity (43.3% versus 34.9%, p = 0.018) and higher gASCA titers (85.7 versus 51.8 ELISA units, p < 0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying none, one and two CARD15 variants, respectively, was seen for both markers. Similarly, Crohn's disease patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild-type patients (63.8% versus 55.2%, p = 0.014), also with a gene dosage effect. An opposite effect was observed for the TLR4 D299G and TLR2 P631H variants, with a lower prevalence of ACCA antibodies (23.4% versus 35%, p = 0.013) and Omp antibodies (20.5% versus 34.6%, p = 0.009), respectively. Conclusion: Variants in innate immune receptor genes were found to influence antibody formation against microbial epitopes. In this respect, it is intriguing that an opposite effect of CARD15 and TLR4 variants was observed. These findings may contribute to an understanding of the aetiology of the seroreactivity observed in IBD. [ABSTRACT FROM AUTHOR]

Background and aims: Several antibodies have been associated with Crohn's disease and are associated with distinct clinical phenotypes. The aim of this study was to determine whether a panel of new antibodies against bacterial peptides and glycans could help in differentiating inflammatory bowel disease (IBD), and whether they were associated with particular clinical manifestations. Methods: Antibodies against a mannan epitope of Saccharomyces cerevisiae (gASCA), laminaribioside (ALCA), chitobioside (ACCA), mannobioside (AMCA), outer membrane porins (Omp) and the atypical perinuclear antineutrophilic cytoplasmic antibody (pANCA) were tested in serum samples of 1225 IBD patients, 200 healthy controls and 113 patients with non-IBD gastrointestinal inflammation. Antibody responses were correlated with the type of disease and clinical characteristics. Results: 76% of Crohn's disease patients had at least one of the tested antibodies. For differentiation between Crohn's disease and ulcerative colitis, the combination of gASCA and pANCA was most accurate. For differentiation between IBD, healthy controls and non-IBD gastrointestinal inflammation, the combination of gASCA, pANCA and ALCA had the best accuracy. Increasing amounts and levels of antibody responses against gASCA, ALCA, ACCA, AMCA and Omp were associated with more complicated disease behaviour (44.7% versus 53.6% versus 71.1% versus 82.0%, p < 0.001), and a higher frequency of Crohn's disease-related abdominal surgery (38.5% versus 48.8% versus 60.7% versus 75.4%, p < 0.001). Conclusions: Using this new panel of serological markers, the number and magnitude of immune responses to different microbial antigens were shown to be associated with the severity of the disease. With regard to the predictive role of serological markers, further prospective longitudinal studies are necessary. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning a study on the role of regulated on activation normal T expressed and secreted (RANTES) gene polymorphism in primary sclerosing cholangitis susceptibility.

The article presents the poem "Patience," by Liesbet Henckaerts. First Line: Invisible it is surrounding them; Last Line: me?

Background: Crohn's Disease (CD) has a heterogeneous presentation, and is typically classified according to extent and location of disease. The genetic susceptibility to CD is well known and genome-wide association scans (GWAS) and metaanalysis thereof have identified over 30 susceptibility loci. Except for the association between ileal CD and NOD2 mutations, efforts in trying to link CD genetics to clinical subphenotypes have not been very successful. We hypothesized that the large number of confirmed genetic variants enables (better) classification of CD patients. Methodology/Principal Findings: To look for genetic-based subgroups, genotyping results of 46 SNPs identified from CD GWAS were analyzed by Latent Class Analysis (LCA) in CD patients and in healthy controls. Six genetic-based subgroups were identified in CD patients, which were significantly different from the five subgroups found in healthy controls. The identified CD-specific clusters are therefore likely to contribute to disease behavior. We then looked at whether we could relate the genetic-based subgroups to the currently used clinical parameters. Although modest differences in prevalence of disease location and behavior could be observed among the CD clusters, Random Forest analysis showed that patients could not be allocated to one of the 6 genetic-based subgroups based on the typically used clinical parameters alone. This points to a poor relationship between the genetic-based subgroups and the used clinical subphenotypes. Conclusions/Significance: This approach serves as a first step to reclassify Crohn's disease. The used technique can be applied to other common complex diseases as well, and will help to complete patient characterization, in order to evolve towards personalized medicine. [ABSTRACT FROM AUTHOR]

Studies in adult inflammatory bowel disease (IBD) patients have highlighted associations with genetic and serologic markers and suggest an association with disease location, behaviour and natural history. Data on patients with Crohn's disease (CD, n=80), ulcerative colitis (UC, n=15) and indeterminate colitis (n=4) were collected. All individuals were analysed for CARD15 R702W, G908R and L1007fs for toll-like receptor 4 (TLR4) Asp299Gly and for anti-Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmatic antibodies (pANCA). After a mean of 10.7 years of follow up, the disease behaviour changed in 45% of CD patients, in contrast to disease location, where only 12.5% had a change (p<0.001). The younger the age at diagnosis, the more patients presented with colonic disease (p=0.021). Also, more TLR4 Asp299 Gly variants were found when the age at onset was younger (p=0.018). A large number of concomitant diseases were observed. There was no difference in the prevalence of TLR4 variants nor ASCA or pANCA between the patients with or without concomitant diseases. Patients who progressed more often needed surgery as compared to patients who remained free of stenosing or fistulising disease (27/32 or 84% versus 3/35 or 8.6%, respectively, p<0.0001) and more often had concomitant immune-mediated diseases and a trend for more seroreactivity towards ASCA. [ABSTRACT FROM AUTHOR]

Acute peripheral facial nerve palsy is most frequently idiopathic (Bell's palsy) or virally induced, but can also be due to several other conditions. A rare cause is underlying systemic or autoimmune disease. A 79-year-old man presented with peripheral facial nerve palsy, malaise, and fever. Physical examination revealed tenderness of the left temporal artery and reduced pulsatility. 18F-FDG-PET/CT and biopsy of the temporal artery confirmed the diagnosis of giant cell arteritis (GCA). Prompt institution of corticosteroid therapy produced rapid decrease in inflammatory markers and gradual improvement of the facial nerve palsy. We searched the MEDLINE, Embase, and Scopus databases to identify previous reports of peripheral nerve palsy in GCA, other vasculitides, and autoimmune diseases. Facial nerve palsy as the presenting symptom of GCA has very rarely been reported. Although temporal artery biopsy is the gold standard for diagnosis, it may be negative in up to one-third of cases. In doubtful cases, imaging can help establish the diagnosis. Ultrasound, 3 T MRI, and 18F-FDG-PET/CT have all been previously reported to be useful. Peripheral facial nerve palsy may very rarely be the presenting symptom of GCA. Early correct diagnosis is essential for starting appropriate therapy. In patients with atypical features, 18F-FDG-PET/CT may be useful for establishing the diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: Granulomas are a characteristic microscopic finding in Crohn''s disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn''s disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation. Methods: Surgical specimens from 464 clinically well-documented Crohn''s patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes. Results: Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163). Conclusion: These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation. [Copyright &y& Elsevier]

Background: TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants. Methodology/Principal Findings: Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11- 1.27, p = 8.5×10-7), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes. Conclusions/Significance: Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases [ABSTRACT FROM AUTHOR]

OBJECTIVES:Inflammatory bowel diseases (IBD)—Crohn's disease (CD) and ulcerative colitis (UC)—are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genome-wide association scan by the Wellcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci.METHODS:We performed a large replication study in 2,731 Dutch and Belgian IBD patients (1,656 CD and 1,075 UC) and 1,086 controls. In total, 40 single nucleotide polymorphisms (SNPs) that showed moderate or strong association in the WTCCC study, along with SNPs in the previously identified genes IL23R, ATG16L1, and NELL1, were studied.RESULTS:We confirmed the associations with IL23R (rs11209026, P=2.69E-12), ATG16L1 (rs2241880, P=4.82E-07), IRGM (rs4958847, P=2.26E-05), NKX2-3 (rs10883365, P=5.91E-06), 1q24 (rs12035082, P=1.51E-05), 5p13 (rs17234657, P=2.62E-05), and 10q21 (rs10761659, P=8.95E-04). We also identified associations with cyclin Y (CCNY; rs3936503, P=2.09 E-04) and Hect domain and RCC1-like domain 2 (HERC2; rs916977, P=1.12E-04). Pooling our data with the original WTCCC data substantiated these associations. Several SNPs were also moderately associated with UC. Two genetic risk profiles based on the number of risk alleles and based on a weighted score were created. On the basis of these results, we calculated sensitivities, specificities, positive and negative predictive values, and likelihood ratios for CD.CONCLUSIONS:We replicated genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. Pooling our data with the results of the WTCCC strengthened the results, suggesting genuine genetic associations. We show that a genetic risk profile can be constructed that is clinically useful and that can aid in making treatment decisions.Am J Gastroenterol 2009; 104: 630–638; doi:10.1038/ajg.2008.112; published online 27 January 2009 [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: Infliximab (IFX) and iron sucrose (FeS) are of high value in inflammatory bowel disease (IBD). We aimed to assess the relative role of both therapies in IBD related anaemia and their safety when used in combination. Methods: IBD patients with anaemia receiving a first series of FeS infusions in addition to IFX were prospectively followed. We investigated serum kinetics of erythropoietin (EPO), soluble transferrin receptors (sTFRs) and vascular endothelial growth factor (VEGF). Results: Data analysis included 87 patients of whom 49.4% achieved the target Hb level of 12.0 g/dL. IFX resulted in a significant increase of EPO and sTFR compared to baseline pre-IFX levels (p =0.029 and p =0.005 respectively) and after a 12-week combined FeS and IFX treatment, EPO and sTFR levels dropped significantly compared to pre-FeS levels (p <0.001 for both). Infusion related adverse events were recorded in 2 IFX treated patients (2.3%, 0.7% of the infusions) and were mild. Disease activity and quality of life were not affected. Conclusions: In anaemic IBD patients treated with IFX, combined administration of FeS is safe. Infliximab significantly increases serum EPO and sTFR levels resulting in an increased functional iron deficiency, which is restored after combined treatment with I.V. iron sucrose. [Copyright &y& Elsevier]

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). [ABSTRACT FROM AUTHOR]