Double-blinded randomised placebo controlled trial of enterosgel (polymethylsiloxane polyhydrate) for the treatment of IBS with diarrhoea (IBS-D).

OBJECTIVE: Irritable bowel syndrome with diarrhoea (IBS-D) is a common and challenging condition that significantly reduces quality of life. Enterosgel (polymethylsiloxane polyhydrate) is an intestinal adsorbent which sequesters harmful molecules and is safe and effective in acute infective diarrhoea. This randomised controlled multicentre trial aimed to investigate its safety and efficacy in patients with IBS-D. DESIGN: After a 2-week screening phase, participants were randomised into an 8-week double-blind phase, followed by an 8-week open-label and follow-up phase. Participants recorded stool consistency, pain and global symptoms in e-diaries and questionnaires. The primary outcome was the percentage of responders on a composite abdominal pain (≥30% decrease in the weekly score) and stool consistency (50% reduction in days per week with at least one stool of BSFS type 6 or 7) score during at least 4 weeks of the treatment period. RESULTS: 440 patients with IBS-D were randomised to the double-blind phase with 393 continuing to the open-label phase. The Primary outcome responder rate by intention-to-treat for enterosgel versus placebo was 37.4% vs 24.3% (OR 1.95, NNT 8, p=0.002). Enterosgel also improved stool consistency (48.5% vs 32.5%, p<0.0001) abdominal pain (53.3% vs 40.2%, p=0.003), stool frequency (treatment effect -0.32 (-0.62 to -0.02)) and urgency (treatment effect -0.59 (-0.85 to -0.33)). 60% of patients reported adequate relief of symptoms after open-label treatment. Adverse event frequency was similar in both groups, with no serious events attributable to enterosgel. CONCLUSION: Enterosgel is safe and effective in IBS-D, providing an alternative to the limited current treatment options. TRIAL REGISTRATION NUMBER: ISRCTN17149988.

Predictive value of control of COPD for risk of exacerbations: An international, prospective study.

BACKGROUND AND OBJECTIVE: The concept of clinical control in COPD has been developed to help in treatment decisions, but it requires validation in prospective studies. METHODS: This international, multicentre, prospective study aimed to validate the concept of control in COPD. Patients with COPD were classified as controlled/uncontrolled by clinical criteria or CAT scores at baseline and followed up for 18 months. The main outcome was the difference in rate of a composite endpoint of moderate and severe exacerbations or death over the 18-month follow-up period. RESULTS: A total of 307 patients were analysed (mean age = 68.6 years and mean FEV1 % = 52.5%). Up to 65% and 37.9% of patients were classified as controlled by clinical criteria or CAT, respectively. Controlled patients had significantly less exacerbations during follow-up (by clinical criteria: 1.1 vs 2.6, P < 0.001; by CAT: 1.1 vs 1.9, P = 0.014). Time to first exacerbation was significantly prolonged for patients controlled by clinical criteria only (median: 93 days, IQR: 63; 242 vs 274 days, IQR: 221; 497 days; P < 0.001). Control status by clinical criteria was a better predictor of exacerbations compared to CAT criteria (AUC: 0.67 vs 0.57). CONCLUSION: Control status, defined by easy-to-obtain clinical criteria, is predictive of future exacerbation risk and time to the next exacerbation. The concept of control can be used in clinical practice at each clinical visit as a complement to the current recommendations of initial treatment proposed by guidelines.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Confounding underlies the apparent month of birth effect in multiple sclerosis.

OBJECTIVE: Several groups have reported apparent association between month of birth and multiple sclerosis. We sought to test the extent to which such studies might be confounded by extraneous variables such as year and place of birth. METHODS: Using national birth statistics from 2 continents, we assessed the evidence for seasonal variations in birth rate and tested the extent to which these are subject to regional and temporal variation. We then established the age and regional origin distribution for a typical multiple sclerosis case collection and determined the false-positive rate expected when comparing such a collection with birth rates estimated by averaging population-specific national statistics. RESULTS: We confirm that seasonality in birth rate is ubiquitous and subject to highly significant regional and temporal variations. In the context of this variation we show that birth rates observed in typical case collections are highly likely to deviate significantly from those obtained by the simple unweighted averaging of national statistics. The significant correlations between birth rates and both place (latitude) and time (year of birth) that characterize the general population indicate that the apparent seasonal patterns for month of birth suggested to be specific for multiple sclerosis (increased in the spring and reduced in the winter) are expected by chance alone. INTERPRETATION: In the absence of adequate control for confounding factors, such as year and place of birth, our analyses indicate that the previous claims for association of multiple sclerosis with month of birth are probably false positives.

MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis.

A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was to evaluate the role of these potential risk loci in a large and independent data set of ≈ 20,000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. In addition, we assessed the overall evidence for association by combining these newly generated data with the results from the original genome-wide association study by meta-analysis. All five tested single nucleotide polymorphisms showed consistent and statistically significant evidence for association with multiple sclerosis in our validation data sets (rs228614: odds ratio = 0.91, P = 2.4 × 10(-6); rs630923: odds ratio = 0.89, P = 1.2 × 10(-4); rs2744148: odds ratio = 1.14, P = 1.8 × 10(-6); rs180515: odds ratio = 1.12, P = 5.2 × 10(-7); rs6062314: odds ratio = 0.90, P = 4.3 × 10(-3)). Combining our data with results from the previous genome-wide association study by meta-analysis, the evidence for association was strengthened further, surpassing the threshold for genome-wide significance (P < 5 × 10(-8)) in each case. Our study provides compelling evidence that these five loci are genuine multiple sclerosis susceptibility loci. These results may eventually lead to a better understanding of the underlying disease pathophysiology.

Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene.

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

Genetic and pathological links between Parkinson's disease and the lysosomal disorder Sanfilippo syndrome.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. The characteristic α-synuclein aggregation of PD is also a feature of Sanfilippo syndrome, a storage disorder caused by α-N-acetylglucosaminidase (NAGLU) gene mutations. We explored genetic links between these disorders and studied the pathology of Sanfilippo syndrome to investigate a common pathway toward α-synuclein aggregation. METHODS: We typed the 2 single-nucleotide polymorphisms that tag the common haplotypes of NAGLU in 926 PD patients and 2308 controls and also stained cortical tissue from 2 cases of Sanfilippo A syndrome using the anti-α-synuclein antibody, Per7. RESULTS: Allelic analysis showed an association between rs2071046 and risk for PD (P 1.3 × 10(-3) ). Intracellular α-synuclein accumulation was observed in the cortical tissue of both Sanfilippo A syndrome cases. CONCLUSIONS: This study suggests a possible role of NAGLU in susceptibility to PD while extending evidence for α-synuclein aggregation in the brain in lysosomal storage disorders. Our findings support a mechanism involving lysosomal dysfunction more generally in the pathogenesis of PD.

Maximizing Adherence and Gaining New Information For Your Chronic Obstructive Pulmonary Disease (MAGNIFY COPD): Study Protocol for the Pragmatic, Cluster Randomized Trial Evaluating the Impact of Dual Bronchodilator with Add-On Sensor and Electronic Monitoring on Clinical Outcomes.

BACKGROUND: Poor treatment adherence in COPD patients is associated with poor clinical outcomes and increased healthcare burden. Personalized approaches for adherence management, supported with technology-based interventions, may offer benefits to patients and providers but are currently unproven in terms of clinical outcomes as opposed to adherence outcomes. METHODS: Maximizing Adherence and Gaining New Information For Your COPD (MAGNIFY COPD study), a pragmatic cluster randomized trial, aims to evaluate the impact of an adherence technology package (interventional package), comprising an adherence review, ongoing provision of a dual bronchodilator but with an add-on inhaler sensor device and a connected mobile application. This will compare time to treatment failure and other clinical outcomes in patients identified at high risk of exacerbations with historic poor treatment adherence as measured by prescription collection to mono/dual therapy over one year (1312 patients) versus usual care. Treatment failure is defined as the first occurrence of one of the following: (1) moderate/severe COPD exacerbation, (2) prescription of triple therapy (inhaled corticosteroid/long-acting ß2-agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]), (3) prescription of additional chronic therapy for COPD, or (4) respiratory-related death. Adherence, moderate/severe exacerbations, respiratory-related healthcare resource utilization and costs, and intervention package acceptance rate will also be assessed. Eligible primary care practices (N=176) participating in the Optimum Patient Care Quality Improvement Program will be randomized (1:1) to either adherence support cluster arm (suitable patients already receiving or initiated Ultibro® Breezhaler® [indacaterol/glycopyrronium] will be offered interventional package) or the control cluster arm (suitable patients continue to receive usual clinical care). Patients will be identified and outcomes collected from anonymized electronic medical records within the Optimum Patient Care Research Database. On study completion, electronic medical record data will be re-extracted to analyze outcomes in both study groups. REGISTRATION NUMBER: ISRCTN10567920. CONCLUSION: MAGNIFY will explore patient benefits of technology-based interventions for electronic adherence monitoring.

Characteristics of patients in platform C19, a COVID-19 research database combining primary care electronic health record and patient reported information.

BACKGROUND: Data to better understand and manage the COVID-19 pandemic is urgently needed. However, there are gaps in information stored within even the best routinely-collected electronic health records (EHR) including test results, remote consultations for suspected COVID-19, shielding, physical activity, mental health, and undiagnosed or untested COVID-19 patients. Observational and Pragmatic Research Institute (OPRI) Singapore and Optimum Patient Care (OPC) UK established Platform C19, a research database combining EHR data and bespoke patient questionnaire. We describe the demographics, clinical characteristics, patient behavior, and impact of the COVID-19 pandemic using data within Platform C19. METHODS: EHR data from Platform C19 were extracted from 14 practices across UK participating in the OPC COVID-19 Quality Improvement program on a continuous, monthly basis. Starting 7th August 2020, consenting patients aged 18-85 years were invited in waves to fill an online questionnaire. Descriptive statistics were summarized using all data available up to 22nd January 2021. FINDINGS: From 129,978 invitees, 31,033 responded. Respondents were predominantly female (59.6%), white (93.5%), and current or ex-smokers (52.6%). Testing for COVID-19 was received by 23.8% of respondents, of which 7.9% received positive results. COVID-19 symptoms lasted ≥4 weeks in 19.5% of COVID-19 positive respondents. Up to 39% respondents reported a negative impact on questions regarding their mental health. Most (67%-76%) respondents with asthma, Chronic Obstructive Pulmonary Disease (COPD), diabetes, heart, or kidney disease reported no change in the condition of their diseases. INTERPRETATION: Platform C19 will enable research on key questions relating to COVID-19 pandemic not possible using EHR data alone.

Changes in Control Status of COPD Over Time and Their Consequences: A Prospective International Study.

INTRODUCTION: Control status may be a useful tool to assess response to treatment at each clinical visit in COPD. Control status has demonstrated to have long-term predictive value for exacerbations, but there is no information about the short-term predictive value of the lack of control and changes in control status over time. METHOD: Prospective, international, multicenter study aimed at describing the short-term (6 months) prognostic value of control status in patients with COPD. Patients with COPD were classified as controlled/uncontrolled at baseline and at 3,6-month follow-up visits using previously validated criteria of control. Moderate and severe exacerbation rates were compared between controlled and uncontrolled visits and between patients persistently controlled, uncontrolled and those changing control status over follow-up. RESULTS: A total of 267 patients were analyzed: 80 (29.8%) were persistently controlled, 43 (16%) persistently uncontrolled and 144 (53.7%) changed control status during follow-up. Persistently controlled patients were more frequently men, with lower (not increased) body mass index and higher FEV1(%). During the 6 months following an uncontrolled patient visit the odds ratio (OR) for presenting a moderate exacerbation was 3.41 (95% confidence interval (CI) 2.47-4.69) and OR=4.25 (95%CI 2.48-7.27) for hospitalization compared with a controlled patient visit. CONCLUSIONS: Evaluation of control status at each clinical visit provides relevant prognostic information about the risk of exacerbation in the next 6 months. Lack of control is a warning signal that should prompt investigation and action in order to achieve control status.

Risk Predictors and Symptom Features of Long COVID Within a Broad Primary Care Patient Population Including Both Tested and Untested Patients.

INTRODUCTION: Symptoms may persist after the initial phases of COVID-19 infection, a phenomenon termed long COVID. Current knowledge on long COVID has been mostly derived from test-confirmed and hospitalized COVID-19 patients. Data are required on the burden and predictors of long COVID in a broader patient group, which includes both tested and untested COVID-19 patients in primary care. METHODS: This is an observational study using data from Platform C19, a quality improvement program-derived research database linking primary care electronic health record data (EHR) with patient-reported questionnaire information. Participating general practices invited consenting patients aged 18-85 to complete an online questionnaire since 7th August 2020. COVID-19 self-diagnosis, clinician-diagnosis, testing, and the presence and duration of symptoms were assessed via the questionnaire. Patients were considered present with long COVID if they reported symptoms lasting ≥4 weeks. EHR and questionnaire data up till 22nd January 2021 were extracted for analysis. Multivariable regression analyses were conducted comparing demographics, clinical characteristics, and presence of symptoms between patients with long COVID and patients with shorter symptom duration. RESULTS: Long COVID was present in 310/3151 (9.8%) patients with self-diagnosed, clinician-diagnosed, or test-confirmed COVID-19. Only 106/310 (34.2%) long COVID patients had test-confirmed COVID-19. Risk predictors of long COVID were age ≥40 years (adjusted Odds Ratio [AdjOR]=1.49 [1.05-2.17]), female sex (adjOR=1.37 [1.02-1.85]), frailty (adjOR=2.39 [1.29-4.27]), visit to A&E (adjOR=4.28 [2.31-7.78]), and hospital admission for COVID-19 symptoms (adjOR=3.22 [1.77-5.79]). Aches and pain (adjOR=1.70 [1.21-2.39]), appetite loss (adjOR=3.15 [1.78-5.92]), confusion and disorientation (adjOR=2.17 [1.57-2.99]), diarrhea (adjOR=1.4 [1.03-1.89]), and persistent dry cough (adjOR=2.77 [1.94-3.98]) were symptom features statistically more common in long COVID. CONCLUSION: This study reports the factors and symptom features predicting long COVID in a broad primary care population, including both test-confirmed and the previously missed group of COVID-19 patients.

Randomised, double-blind, placebo controlled multi-centre study to assess the efficacy, tolerability and safety of Enterosgel® in the treatment of irritable bowel syndrome with diarrhoea (IBS-D) in adults.

BACKGROUND: Irritable bowel syndrome (IBS) with diarrhoea (IBS-D) is a common and chronic condition that can significantly impair quality of life. The emergence of new drugs for IBS-D has been slow and there is a need for new treatments, including drug-free treatments, which are easy to use and suitable for different patient groups. Currently available drug-free treatments include Enterosgel®, an intestinal adsorbent approved for use in IBS-D and acute diarrhoea and available over-the-counter in the UK and 30 countries worldwide. The aim of this randomised, double-blind, placebo-controlled, multi-centre study is to test the efficacy and safety of Enterosgel® compared to placebo in symptomatic treatment in IBS-D. METHODS/DESIGN: We will recruit 430 participants with IBS-D from approximately 30 primary and secondary care sites in England. Participants meeting the required abdominal pain and stool consistency criteria over a 2-week screening period will be randomly allocated to receive blinded treatment (Enterosgel® or placebo) for 8 weeks. This will be followed by an 8-week open-label treatment phase with Enterosgel®. Participants will be allowed to adjust their daily dosage during both phases based on their symptoms. Participants will then return to standard care and those who responded to treatment will receive a follow-up call 8 weeks later. Co-medication with loperamide will be permitted and use recorded. The primary outcome measure is the percentage of participants defined as responders for abdominal pain and stool consistency during at least 4 weeks in the 8-week blinded phase. Secondary outcome measures include stool frequency, stool consistency, abdominal pain, bloating, urgency, adequate relief, questionnaire scores and rescue medication use. Exploratory outcomes will be assessed in subsets of participants including qualitative and quantitative data on faecal microorganisms and biomarkers and gut-related measurements from magnetic resonance imaging data. DISCUSSION: This is the first large scale randomised controlled trial investigating Enterosgel® in IBS-D. A study design with blinded phase followed by an open-label phase was chosen to encourage participation and study completion. Demonstrating that Enterosgel® is effective and safe in IBS-D could encourage adoption by patients and healthcare professionals and foster future clinical trials assessing its use in related conditions. TRIAL REGISTRATION: ISRCTN17149988. Prospectively registered on 14 November 2017.

Enterosgel for the treatment of adults with acute diarrhoea in a primary care setting: a randomised controlled trial.

BACKGROUND: Acute intestinal infections are common conditions causing high morbidity and mortality especially in the young and elderly, resulting in a significant burden on health service resources and the economy. Current National Institute for Health and Care Excellence guidance are fluid and nutritional management; however, this does not reduce the duration of diarrhoea and the challenge of treating diarrhoea itself remains. We investigated the efficacy, tolerability and safety of intestinal adsorbent Enterosgel (polymethylsiloxane polyhydrate) compared with standard care in adults with acute diarrhoea. METHODS: This was a randomised controlled trial enrolling 105 subjects to receive the medical device Enterosgel up to six times daily for up to 8 days with standard care (oral rehydration solution), or standard care alone. The primary endpoint was the duration of diarrhoea (hours) from randomisation to first non-loose stool in the Enterosgel versus control group. RESULTS: A total of 51 subjects were randomised into the Enterosgel group and 54 into the control group, after excluding missing data, the data from 43 subjects in each group were analysed. Duration of diarrhoea was significantly shorter in the Enterosgel group at 27 hours versus 39 hours in the control group (HR was 1.74 [95% CI 1.06 to 2.87]) (p=0.03). This yielded a number needed to treat value of 5. Enterosgel was well tolerated and safe with no serious adverse events. One serious diarrhoea-related event resulting in hospitalisation was reported in the control group. CONCLUSIONS: Enterosgel treatment was associated with a significant reduction in the duration of diarrhoea in adults with patient-reported acute diarrhoea, compared with standard care. These findings support the role of Enterosgel in acute diarrhoea especially in vulnerable groups where rapid resolution of symptoms is required. Reduction in symptom duration could translate to less healthcare costs and socioeconomic burden. TRIAL REGISTRATION NUMBER: ISRCTN20758708.

Comparison of clinical baseline characteristics between Asian and Western COPD patients in a prospective, international, multicenter study.

We aimed to compare clinical characteristics between Asian and Western chronic obstructive pulmonary disease (COPD) patients. This was a sub-analysis of an international, multicenter, prospective cohort study. Asian patients were enrolled in Singapore and South Korea. Western patients were enrolled in Spain, Poland, Ireland, the United Kingdom, and Malta. A total of 349 patients were analyzed. Among them, 110 (32%) patients were Asian and 239 (68%) Western. Male sex was more predominant in Asian than in Western (95% versus 63%, respectively; P<0.01). Body mass index was significantly lower in Asian (23.5 versus 27.1; P<0.01). The proportion of patients with a history of exacerbation was lower in Asian (12% versus 64%; P<0.01). Although patients were enrolled by same inclusion criteria, there were several differences between Asian and Western COPD patients. Our study has shown unbiased real-world differences between Asian and Western COPD patients. Since prospective follow-up study is currently ongoing, the result of this study can be fundamental base of future analysis.

Evaluation of criteria for clinical control in a prospective, international, multicenter study of patients with COPD.

BACKGROUND: The concept of clinical control in COPD has been developed to help in treatment decisions, but it requires validation in prospective studies. METHOD: This international, multicenter, prospective study aimed to validate the concept of control in COPD [control = stability (no exacerbations or impairment in CAT scores) + low impact (low level of symptoms)]. Data from the screening visit was used to: investigate the level of control, compare characteristics of patients according to the control status, and perform a sensitivity analysis of the levels of control using either clinical criteria or questionnaires (COPD Assessment Test -CAT- or Clinical COPD Questionnaire -CCQ-). RESULTS: A total of 314 patients were analysed, mean age was 68.5 years and mean FEV1 was 52.6% of predicted. According to the prespecified criteria 21% of patients were classified as controlled, all of them with mild/moderate COPD (Body mass index, Obstruction, Dyspnea and Exacerbations, -BODEx-index <5). A high level of dyspnea, a high CAT score or an exacerbation in the previous 3 months were found, using univariate analysis, to be the main reasons for patients not being classified as controlled. Multivariate analysis showed that female sex, chronic bronchitis and having exacerbations in the previous year were associated with uncontrolled COPD. Changing the severity cut off of BODEx from 5 to 3 did not change significantly the percentage of patients fulfilling the criteria of control. CONCLUSIONS: The proposed criteria of control were only fulfilled by 21% of patients. The suggested cut offs and their predictive value for poor outcomes need to be refined in prospective studies.

A Randomized Pragmatic Trial of Changing to and Stepping Down Fluticasone/Formoterol in Asthma.

BACKGROUND: Guidelines recommend reducing treatment in patients with well-controlled asthma after 3 months of stability. However, there is inadequate real-life data to guide physicians on therapy change in daily practice. OBJECTIVE: To assess asthma control after change to and step-down of fluticasone propionate/formoterol fumarate dihydrate (FP/FOR) in real-life patients. METHODS: In a randomized controlled, pragmatic, open-label trial, 225 well-controlled patients with asthma were randomized (1:2) to maintain high-dose fluticasone propionate/salmeterol xinafoate (FP/SAL, 1000/100 µg) or switch to FP/FOR (1000/40 µg) daily for 12 weeks (phase 1). One hundred sixteen patients stable on FP/FOR at week 12 were subsequently randomized (1:1) to maintain this therapy, or stepped down to FP/FOR (500/20 µg) daily for 12 weeks (phase 2). The primary end point was the 7-question Asthma Control Questionnaire (ACQ7) score. RESULTS: In phase 1, FP/FOR (1000/40 µg) (n = 126) was noninferior to FP/SAL (1000/100 µg) (n = 73) for ACQ7 (difference in means, -0.12; 95% CI, -0.32 to 0.09). In phase 2, FP/FOR (500/20 µg) (n = 52) was noninferior to FP/FOR (1000/40 µg) (n = 52) for ACQ7 (difference in means, 0.01; 95% CI, -0.20 to 0.22). There was no significant difference in exacerbation rate between the groups in either phase. However, 1 to 2 exacerbations in 12 months before phase 1 were associated with the occurrence of an exacerbation after step-down (P = .007). CONCLUSIONS: In patients with well-controlled asthma, a change from FP/SAL to FP/FOR did not compromise asthma control. Step-down of FP/FOR was well tolerated; however, in contrast to current guidelines, our data suggest caution in stepping down patients uncontrolled in the last 12 months. Larger step-down studies are required to confirm these findings.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Genome-wide association studies in multiple sclerosis: lessons and future prospects.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease with complex aetiology. A haplotype within the major histocompatibility region is the major risk factor for MS, but despite clear evidence for a genetic component additional risk variants were not identified until the recent advent of genome-wide association studies (GWAS). At present, 10 GWAS have been conducted in MS, and together with follow-up studies these have confirmed 16 loci with genome-wide significance. Many of these common risk variants are located at or near genes with central immunological functions and the majority are associated with other autoimmune diseases. However, evidence from pathway analyses on more modestly associated variants also supports the involvement of neurological genes. Although the mechanisms by which the associated variants exert their effects are still poorly understood, some have been shown to correlate with expression of nearby genes. Further studies are required to define the functionally relevant variants in the identified regions and to investigate their effects at the molecular and cellular level. Finally, many genetic risk variants for MS remain to be identified. In order to expose some of the loci with more modest effects, a GWAS in nearly 10,000 MS patients has recently been completed.

Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany.

The association between common variants in the FTO gene with weight, adiposity and body mass index (BMI) has now been widely replicated. Although the causal variant has yet to be identified, it most likely maps within a 47 kb region of intron 1 of FTO. We performed a genome-wide association study in the Sorbian population and evaluated the relationships between FTO variants and BMI and fat mass in this isolate of Slavonic origin resident in Germany. In a sample of 948 Sorbs, we could replicate the earlier reported associations of intron 1 SNPs with BMI (eg, P-value=0.003, beta=0.02 for rs8050136). However, using genome-wide association data, we also detected a second independent signal mapping to a region in intron 2/3 about 40-60 kb away from the originally reported SNPs (eg, for rs17818902 association with BMI P-value=0.0006, beta=-0.03 and with fat mass P-value=0.0018, beta=-0.079). Both signals remain independently associated in the conditioned analyses. In conclusion, we extend the evidence that FTO variants are associated with BMI by putatively identifying a second susceptibility allele independent of that described earlier. Although further statistical analysis of these findings is hampered by the finite size of the Sorbian isolate, these findings should encourage other groups to seek alternative susceptibility variants within FTO (and other established susceptibility loci) using the opportunities afforded by analyses in populations with divergent mutational and/or demographic histories.

A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis.

A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency=0.04), genome-wide significant association has been hard to establish. We genotyped 5429 Nordic MS cases and 6167 healthy controls for this TYK2 non-synonymous single-nucleotide polymorphism (ns-SNP), and combined the Nordic genotype data with raw genotypes from previous studies. The combined Nordic analysis showed significant association with MS (P=5 x 10(-4), odds ratio (OR) 0.78), and by mega-analysis of 10 642 MS patients, 10 620 controls and 2110 MS trios, the association at genome-wide significance level (P=5.08 x 10(-9), OR 0.77) was shown.