Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
; ; et al
in Nature (2012), 491(7422), 119-24
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome ... [more ▼]
Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD. [less ▲]Detailed reference viewed: 43 (20 ULg)
Quinze ans d'anti-TNF dans la maladie de Crohn: comment tirer le meilleur de cette revolution therapeutique?
Louis, Edouard ; REENAERS, Catherine ; Meuwis, Marie-Alice et al
in Revue Médicale de Liège (2012), 67 Spec No
After fifteen years of use, the anti-TNF antibodies have become the corner stone of the treatment of moderate and severe Crohn's disease. The skill acquired over the years through experimental trials and ... [more ▼]
After fifteen years of use, the anti-TNF antibodies have become the corner stone of the treatment of moderate and severe Crohn's disease. The skill acquired over the years through experimental trials and clinical experience leads to increased therapeutic efficacy and minimized risks. These antibodies are introduced increasingly earlier in Crohn's disease as well as in a broader range of patients, aiming at changing the natural history of the diseases by avoiding the development of intestinal tissue damage and complications. [less ▲]Detailed reference viewed: 55 (4 ULg)
Barrett's metaplasia, dysplasia and esophageal ademnocarcinoma: an inadequate antitumour immunity?
Somja, Joan ; Demoulin, Stéphanie ; et al
Conference (2012, February 09)Detailed reference viewed: 20 (4 ULg)
Safety and cost of infliximab for the treatment of Belgian pediatric patients with Crohn's disease.
; ; et al
in Acta Gastro-Enterologica Belgica (2012), 75(4), 425-31
Biologicals have become an important component in the treatment of Crohn's disease in children. Their increased and long term use raises safety concerns. We describe safety and cost of infliximab in ... [more ▼]
Biologicals have become an important component in the treatment of Crohn's disease in children. Their increased and long term use raises safety concerns. We describe safety and cost of infliximab in Belgian pediatric Crohn's disease patients. All patients on infliximab as part of the present or past treatment for Crohn's Disease until January 1st 2011 were selected from an existing database. Information on disease phenotype, medication and adverse events were extracted. Adverse events occurred in 25.9% of patients exposed to infliximab of which 29.6% were severe. In total 31.7% of patients stopped infliximab therapy. The main reasons for discontinuation were adverse events in 45.4% and loss of response in 30.3%. No malignancies or lethal complications occurred over this 241 patient year observation period. Immunomodulators were concomitant medication in 75% of patients and were discontinued subsequently in 38.4% of them. The cost of infliximab infusions per treated patient per year in the Belgian health care setting is approximately 9 474 euro, including only medication and hospital related costs. Even though infliximab is relatively safe in pediatric CD on the short term, close follow-up and an increased awareness of the possible adverse reactions is highly recommended. Adverse reactions appeared in 25.9% of all patients and were the main reason for discontinuation. Treatment cost has to be balanced against efficacy and modifications in disease course. In the Belgian health care system, the medication is available to all patients with moderate to severe CD. [less ▲]Detailed reference viewed: 23 (8 ULg)
Management of inflammatory bowel disease in pregnancy.
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012), 6(8), 811-23
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning ... [more ▼]
BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic disease affecting mainly young people in their reproductive years. IBD therefore has a major impact on patients' family planning decisions. Management of IBD in pregnancy requires a challenging balance between optimal disease control and drug safety considerations. This article aims to provide a framework for clinical decision making in IBD based on review of the literature on pregnancy-related topics. METHODS: Medline searches with search terms 'IBD', 'Crohn's disease' or 'ulcerative colitis' in combination with keywords for the topics fertility, pregnancy, congenital abnormalities and drugs names of drugs used for treatment of IBD. RESULTS: IBD patients have normal fertility, except for women after ileal pouch-anal anastomosis (IPAA) and men under sulfasalazine treatment. Achieving and maintaining disease remission is a key factor for successful pregnancy outcomes in this population, as active disease at conception carries an increased risk of preterm delivery and low birth weight. Clinicians should discuss the need for drug therapy to maintain remission with their patients in order to ensure therapy compliance. Most IBD drugs are compatible with pregnancy, except for methotrexate and thalidomide. If possible, anti-TNF therapy should be stopped by the end of the second trimester and the choice of delivery route should be discussed with the patient. CONCLUSIONS: Disease control prior to conception and throughout pregnancy is the cornerstone of successful pregnancy management in IBD patients. [less ▲]Detailed reference viewed: 33 (4 ULg)
Fast and sharp decrease in calprotectin predicts remission by infliximab in anti-TNF naive patients with ulcerative colitis.
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012), 6(5), 557-62
AIM: To evaluate the effect of infliximab induction therapy on calprotectin levels in patients with ulcerative colitis (UC). PATIENTS AND METHODS: In this prospective study 53 patients with active UC from ... [more ▼]
AIM: To evaluate the effect of infliximab induction therapy on calprotectin levels in patients with ulcerative colitis (UC). PATIENTS AND METHODS: In this prospective study 53 patients with active UC from 17 centers were treated with infliximab therapy (5 mg/kg) at baseline, week 2, and week 6. Faecal calprotectin was measured every week. Sigmoidoscopies were performed at baseline, week 6 and week 10. RESULTS: Median calprotectin levels decreased from 1260 (IQR 278.5- 3418) at baseline to 72.5 (IQR 18.5 - 463) at week 10 (p<0.001). After 10 weeks, infliximab therapy induced endoscopic remission and a decrease in calprotectin to<50 mg/kg or at least a 80% decrease from baseline level in 58% of patients. A significant and steep decrease of calprotectin levels was seen at week 2 for patients with an endoscopic remission at week 10 as compared to patients who did not show a remission. (p<0.001). At week 10 an excellent correlation was found between endoscopic remission and clinical Mayo score reflected by an AUC of ROC analyses of 0.94 (0.87-1) and with calprotectin measurements (AUC 0.91 (0.81-1)) : all patients with calprotectin levels <50 mg/kg, and a normal clinical Mayo score (=0) were in endoscopic remission. CONCLUSIONS: Infliximab induces a fast and significant decrease of faecal calprotectin levels in anti-TNF naive patients with ulcerative colitis predictive for remission of disease. [less ▲]Detailed reference viewed: 7 (2 ULg)
Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn's patients.
; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012)
BACKGROUND AND AIMS: Adalimumab is efficacious in inducing and maintaining remission in Crohn's disease but dose escalation is needed in 30-40% after 1year. Attempts for dose de-escalation have not been ... [more ▼]
BACKGROUND AND AIMS: Adalimumab is efficacious in inducing and maintaining remission in Crohn's disease but dose escalation is needed in 30-40% after 1year. Attempts for dose de-escalation have not been studied. This study aimed to assess the need for, predictors, and outcome of dose escalation and de-escalation in a large cohort of adalimumab treated Crohn's patients. METHODS: All consecutive patients treated with open label adalimumab for active Crohn's disease from the participating centres were included in this cohort study. A detailed retrospective chart review was performed to look for possible factors predicting outcome. RESULTS: Eighty four percent of 720 patients had a primary response and were followed up for a median of 14months. Thirty four percent needed escalation after a median of 7months (0-55months). Multivariate predictors for dose escalation were the following: prior anti-TNF use (p<0.0001), no concomitant azathioprine or <3m (p<0.02) and abnormal CRP at start (p<0.05). Dose escalation re-induced response for at least 6months in 67%. Only abnormal CRP at start correlated with failure of dose escalation (p=0.02). Dose de-escalation was attempted in 54% and was successful in 63%. After a median follow-up of 14m adalimumab was discontinued in 29% of patients. CONCLUSION: In this study real life nationwide cohort of Crohn's patients treated with adalimumab dose escalation was needed in 34% and was successful in 67%. Dose de-escalation was attempted in 54% and was successful in 63%. Overall 71% of patients maintained long term response on adalimumab. [less ▲]Detailed reference viewed: 17 (3 ULg)
The c-jun N-terminal Kinase (JNK)-binding Protein (JNKBP1) Acts as a Negative Regulator of NOD2 Protein Signaling by Inhibiting Its Oligomerization Process
Lecat, Aurore ; Di Valentin, Emmanuel ; Somja, Joan et al
in Journal of Biological Chemistry (2012), 287(35), 29213-26
NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently ... [more ▼]
NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently induce various signalling pathways leading to NF- kappaB activation and autophagy, both events contributing to an efficient innate and adaptative immune response. Interestingly, loss-of-function nod2 variants were associated with a higher susceptibility for Crohn ' s disease (CD), which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-jun N-terminal kinase binding protein 1 (JNKBP1), a scaffold protein characterized by a N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following MDP activation. This interaction attenuates NOD2-mediated NF-kappaB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signalling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. [less ▲]Detailed reference viewed: 56 (37 ULg)
National differences in ulcerative colitis experience and management among patients from five European countries and Canada: An online survey.
; ; LOUIS, Edouard et al
in Journal of Crohn’s and Colitis [=JCC] (2012)
BACKGROUND AND AIMS: Patients' and physicians' perceptions of ulcerative colitis and its management are important for developing and guiding appropriate therapies. This study explored national differences ... [more ▼]
BACKGROUND AND AIMS: Patients' and physicians' perceptions of ulcerative colitis and its management are important for developing and guiding appropriate therapies. This study explored national differences in patients' and physicians' experiences, expectations, and beliefs about ulcerative colitis. METHODS: Structured, cross-sectional, online surveys evaluating various indices were completed by 775 adult patients with ulcerative colitis and 475 physicians actively managing ulcerative colitis patients from France, Germany, Ireland, Spain, the United Kingdom, and Canada. RESULTS: Patients' classification of their symptom severity differed across countries (mild, 16%-45%; moderate, 46%-58%; severe, 4%-36%). Expectations of disease control also varied, with 26% (Ireland) to 65% (Spain) describing that remission realistically involves "living without symptoms." Within each country, more patients (45%-69%) than physicians (28%-45%) considered ulcerative colitis symptoms to affect patients' quality of life. Mean number of patient-reported flares during the past year ranged from 2.5 in Ireland to 8.0 in France. Self-reported adherence with oral 5-aminosalicylic acid (during remission) was highest in Spain (91% vs 50%-73% across other countries). Spanish patients were more likely to self-adjust their medications (54% vs 2%-5%), but reported the most dissatisfaction with therapy (42% vs 9%-27%). Irish patients were least likely to arrange physician/specialist nurse visits (14% vs 36%-49%) and least open to discussion of their condition. CONCLUSIONS: Important national differences in ulcerative colitis patients' attitudes and perceptions were observed, which may help physicians improve patient care based on country-specific needs and influence self-assessments in clinical trials. The results suggest a need for structured patient education to improve adherence and outcomes. [less ▲]Detailed reference viewed: 9 (0 ULg)
Impact of medical therapies on inflammatory bowel disease complication rate.
REENAERS, Catherine ; Belaiche, Jacques ; Louis, Edouard
in World Journal of Gastroenterology (2012), 18(29), 3823-7
Crohn's disease and ulcerative colitis are progressive diseases associated with a high risk of complications over time including strictures, fistulae, perianal complications, surgery, and colorectal ... [more ▼]
Crohn's disease and ulcerative colitis are progressive diseases associated with a high risk of complications over time including strictures, fistulae, perianal complications, surgery, and colorectal cancer. Changing the natural history and avoiding evolution to a disabling disease should be the main goal of treatment. In recent studies, mucosal healing has been associated with longer-term remission and fewer complications. Conventional therapies with immunosuppressive drugs are able to induce mucosal healing in a minority of cases but their impact on disease progression appears modest. Higher rates of mucosal healing can be achieved with anti-tumor necrosis factor therapies that reduce the risk of relapse, surgery and hospitalization, and are associated with perianal fistulae closure. These drugs might be able to change the natural history of the disease mainly when introduced early in the course of the disease. Treatment strategy in inflammatory bowel diseases should thus be tailored according to the risk that each patient could develop disabling disease. [less ▲]Detailed reference viewed: 10 (0 ULg)
Commentary: endoscopic dilatation for stricturing Crohn's disease.
Louis, Edouard ; GAST, Pierrette ; VAN KEMSEKE, Catherine et al
in Alimentary Pharmacology & Therapeutics (2012), 36(5), 494-6Detailed reference viewed: 3 (1 ULg)
What changes in inflammatory bowel disease management can be implemented today?
LOUIS, Edouard ; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012), 6 Suppl 2
Innovative ideas are required to improve the management of inflammatory bowel disease and to share best practice that can be implemented into clinical practice today. The use of biomarkers such as ... [more ▼]
Innovative ideas are required to improve the management of inflammatory bowel disease and to share best practice that can be implemented into clinical practice today. The use of biomarkers such as calprotectin to monitor disease progression and treatment response could help to improve management of inflammatory bowel disease, but several strategies need to be implemented to make this a reality in clinical practice. The use of calprotectin as a biomarker and the manipulation of the thiopurine pathway to extend the use of current therapies are examples of how basic research can translate into patient benefit. Translational research into the use of microbiota and predictive factors for response and toxicity to drugs, may provide future clinical applications. Global improvement in care in inflammatory bowel disease could also be advanced by improving service provision. For example, the establishment of 'Centres of Excellence', a global interactive inflammatory disease map, and the alignment of processes and standards of care within treatment centres may help to achieve better outcomes for patients with inflammatory bowel disease. Realization of this goal, as well as a better understanding of the aetiology of the disease, may be furthered by collaborative efforts between organizations involved in inflammatory bowel disease as well as wider collaboration across countries and globally. [less ▲]Detailed reference viewed: 12 (0 ULg)
Adalimumab improves patient-reported outcomes and reduces indirect costs in patients with moderate to severe Crohn's disease: Results from the CARE trial.
LOUIS, Edouard ; ; et al
in Journal of Crohn’s and Colitis [=JCC] (2012)
BACKGROUND AND AIMS: Crohn's disease negatively affects patients' quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality of life ... [more ▼]
BACKGROUND AND AIMS: Crohn's disease negatively affects patients' quality of life and ability to work. We investigated the impact of adalimumab on work productivity, daily activities, and quality of life in an open-label trial (N=945). The population comprised both infliximab-naive and -exposed patients, including infliximab primary non-responders. METHODS: Patients received adalimumab induction therapy (160mg/80mg at Weeks 0/2), followed by adalimumab 40mg every other week for up to 20weeks (patients with flares/non-response could receive 40mg weekly at/after Week 12). The Work Productivity and Activity Impairment Questionnaire and Short Inflammatory Bowel Disease Questionnaire were assessed. Indirect cost savings were estimated based on the average work productivity improvements at Week 20. RESULTS: Mean baseline scores indicated severe productivity impairment and poor quality of life. At Week 20, 60% of infliximab-naive and 47% of infliximab primary non-responders achieved clinically important improvements (>/=9 points) on the Short Inflammatory Bowel Disease Questionnaire, and 51% and 43%, respectively, achieved the minimum clinically important difference (improvement >/=7 percentage points) for total work productivity impairment (non-responder imputation). At Week 20, 64% of infliximab-naive and 55% of infliximab primary non-responders achieved clinically important improvements in total activity impairment. Estimated 20-week total indirect productivity-related cost savings were euro3070 per infliximab-naive patient and euro2059 per infliximab-exposed patient. CONCLUSIONS: Adalimumab therapy significantly improved work productivity and disease-specific quality of life for patients with moderate to severe Crohn's disease. Patients who failed prior infliximab therapy and patients naive to infliximab benefited from adalimumab, with potentially greater benefits for infliximab-naive patients (NCT00409617). [less ▲]Detailed reference viewed: 7 (0 ULg)
L'asthme: une maladie complexe mettant en jeu facteurs environnementaux et terrain genetique.
LOUIS, Renaud ; SCHLEICH, FLorence ; Corhay, Jean-Louis et al
in Revue Médicale de Liège (2012), 67(5-6), 286-91
Asthma is a complex disease highly dependent of environmental exposure and genetic background. Through linkage analysis, positional cloning and genome wide association studies, novel asthma genes have ... [more ▼]
Asthma is a complex disease highly dependent of environmental exposure and genetic background. Through linkage analysis, positional cloning and genome wide association studies, novel asthma genes have come out such as ADAM-33 or ORMLD3. Important environmental factors include allergenic exposure, pollutants and especially particulate matters, tobacco, aerosol exposure, viral infections and level of exposure to endotoxin. The effects of environmental factors are modulated by the genetic sequence and numerous single nucleotide polymorphisms (SNPs). Recently, it has also become clear that environmental factors may alter gene expression by DNA methylation or histone methylation/acetylation without changing the gene sequence and thereby changing asthmatic phenotype. [less ▲]Detailed reference viewed: 47 (6 ULg)
Epidemiology of the transition from early to late Crohn's disease.
in Digestive Diseases (2012), 30(4), 376-9
Phenotypically, the transition from early to late Crohn's disease is characterized by the occurrence of complications including strictures, intra-abdominal fistulas and perianal fistulas, all of them ... [more ▼]
Phenotypically, the transition from early to late Crohn's disease is characterized by the occurrence of complications including strictures, intra-abdominal fistulas and perianal fistulas, all of them leading to various types of surgeries and currently non-reversible tissue damage. It must, however, be kept in mind that this transition is not at all a uniform and linear process. According to these simple phenotypic criteria, Crohn's disease can already be a late disease at diagnosis while in other patients, it can still be an early disease after 20 years of evolution. This simply highlights the relativity of time in this field, actually reflecting the nature, location and severity of the inflammatory process. The risk over time of the development of these complications has been described, first in cohort studies and then in population-based studies. Globally, at diagnosis, between 19 and 38% only of Crohn's disease patients have complicated Crohn's disease. After 10 years, between 56 and 65% of patients have developed either stricturing or penetrating complications. After 20 years, these numbers are between 61 and 88%. In parallel to these structural changes, changes in the immunobiology of the disease also seem to occur; the latter seem to happen quicker with major modification already within 2 years of the diagnosis. Beside these general figures, important questions remain pending. First, the real timing of these changes is still unclear. Second, the precise role of genetics and environment in the development of these changes remains to be clarified. Third, the correlation between changes in immunobiology and intestinal structural damages has not been specifically studied. [less ▲]Detailed reference viewed: 11 (5 ULg)
Le syndrome de Lynch et l'instabilité des microsatellites : revue de littérature.
; VERSET, Gontran ; POLUS, Marc et al
in Revue Médicale de Liège (2012), 67(12), 638-642Detailed reference viewed: 41 (3 ULg)
Perception gaps between patients with ulcerative colitis and healthcare professionals: an online survey.
; ; LOUIS, Edouard et al
in BMC Gastroenterology (2012), 12(1), 108
ABSTRACT: BACKGROUND: The purpose of this study was to examine the differing perspectives and perceptual gaps relating to ulcerative colitis (UC) symptoms and their management between patients and ... [more ▼]
ABSTRACT: BACKGROUND: The purpose of this study was to examine the differing perspectives and perceptual gaps relating to ulcerative colitis (UC) symptoms and their management between patients and healthcare professionals (HCPs). METHODS: Structured, cross-sectional, Web-based questionnaires designed to assess a variety of disease indices were completed by adult patients with UC and HCPs involved in the care of patients with UC from Canada, France, Germany, Ireland, Spain, and the United Kingdom. RESULTS: Surveys were completed by 775 patients, 475 physicians, and 50 nurses. Patient self-reported classification of disease severity revealed generally greater severity (mild, 32 %; moderate, 53 %) compared with physician and nurse estimates of UC severity among their caseloads (mild, 52 % and 49 %; moderate, 34 % and 37 %, respectively). Patients reported that an average of 5.5 (standard deviation, 11.0) flares (self-defined) occurred over the past year, compared with 3.4 and 3.8 flares per year estimated by physicians and nurses. Perceived flare triggers differed between patients (stress ranked first) and HCPs (natural disease course ranked first). Fifty-five percent of patients stated that UC symptoms over the past year had affected their quality of life, while physicians and nurses estimated that 35 % to 37 % of patients would have a reduced quality of life over the same period. Patients ranked urgency and pain as the most bothersome symptoms, while physicians and nurses ranked urgency and stool frequency highest. About half of patients (47 %) defined remission as experiencing no symptoms; by comparison, 62 % to 63 % of HCPs defined remission as requiring the complete absence of symptoms. HCPs (doctors/nurses in general practice and/or hospital) were regarded by patients as their main source of UC information by 72 %; however, 59 % reported not arranging regular visits to see their HCPs. CONCLUSIONS: This large survey identified important differences between patients' and HCPs' perceptions of the impact of UC symptoms on patients' lives. Notably, HCPs may underestimate the effect of specific UC symptoms on patients and may fail to recognize issues that are important to patients. [less ▲]Detailed reference viewed: 7 (0 ULg)
Adalimumab in ulcerative colitis: can pharmacodynamics be improved based on pharmacokinetics?
LOUIS, Edouard ;
in Gastroenterology (2012), 142(1), 176-8Detailed reference viewed: 9 (1 ULg)
Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.
; ; et al
in Nature Genetics (2012), 43(11), 1066-73
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants ... [more ▼]
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 x 10(-16), odds ratio approximately 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models. [less ▲]Detailed reference viewed: 16 (1 ULg)