History of diabetes and risk of head and neck cancer: a pooled analysis from the international head and neck cancer epidemiology consortium.

BACKGROUND: A history of diabetes is associated with an increased risk of several types of cancers. Whether diabetes is a risk factor for head and neck cancer (HNC) has received little attention. METHODS: We pooled data from 12 case-control studies including 6,448 cases and 13,747 controls, and estimated odds ratios (OR) and 95% confidence intervals (CI) for the associations between diabetes and HNC, adjusted for age, education level, sex, race/ethnicity, study center, cigarette smoking, alcohol use and body mass index (BMI). RESULTS: We observed a weak association between diabetes and the incidence of HNC overall (OR, 1.09; 95% CI, 0.95-1.24). However, we observed a modest association among never smokers (OR, 1.59; 95% CI, 1.22-2.07), and no association among ever smokers (OR, 0.96; 95% CI, 0.83-1.11); likelihood ratio test for interaction p=0.001. CONCLUSIONS: A history of diabetes was weakly associated with HNC overall, but we observed evidence of effect modification by smoking status, with a positive association among those who never smoked cigarettes. Impact: This study suggests that glucose metabolism abnormalities may be a HNC risk factor in subgroups of the population. Prospective studies incorporating biomarkers are needed to improve our understanding of the relationship between diabetes and HNC risk, possibly providing new strategies in the prevention of HNC.

Characterization of a major V3 duplication in the NS5A region of genotype 1b HCV by quasispecies analysis in a French multicenter study

Background and Aims: The NS5A protein of the HCV is known tobe involved in viral replication and assembly and probably in theresistance to Interferon based-therapy. Previous studies identifiedinsertions or deletions from 1 to 12 nucleotides in several genomicregions. In a multicenter study (17 French and 1 Swiss laboratoriesof virology), we identified for the first time a 31 amino acidsinsertion leading to a duplication of the V3 domain in the NS5Aregion with a high prevalence. Quasispecies of each strain withduplication were characterized and the inserted V3 domain wasidentified.Methods: Between 2006 and 2008, 1067 patients chronicallyinfected with a 1b HCV were consecutively included in the study.We first amplified the V3 region by RT-PCR to detect duplication(919 samples successfully amplified). The entire NS5A region wasthen amplified, cloned and sequenced in strains bearing theduplication. V3 sequences (called R1 and R2) from each clonewere analyzed with BioEdit and compared to a V3 consensussequence (C) built from the Database Los Alamos Hepatitis C.Entropy was determined at each position.Results: V3 duplications were identified in 25 patients representinga prevalence of 2.72%. We sequenced 2043 clones from which776 had a complete coding NS5A sequence (corresponding toa mean of 30 clones per patient). At the intra-individual level,6 to 17 variants were identified per V3 region, with a maximum of3 different amino acids. At the inter-individual level, a differenceof 7 and 2 amino acids was observed between C and R1 and R2sequences, respectively. Moreover few positions presented entropyhigher than 1 (4 for the R1, 2 for the R2 and 2 for the C). Among allthe sequenced clones, more than 60% were defective virus (partialfragment of NS5A or stop codon).Conclusions: We identified a duplication of the V3 domain ingenotype 1b HCV with a high prevalence. The R2 domain, which wasthe most similar to the C region, might probably be the "original"domain, whereas R1 should be the inserted domain. Phylogeneticanalyses are under process to confirm this hypothesis.

Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.

BACKGROUND: Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. METHODS: The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. FINDINGS: The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006). Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). INTERPRETATION: Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery. FUNDING: Medical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union.

The Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia: A Meta-analysis of Existing Findings and New Data in a First-Episode Sample.

Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP - CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of "neurocognitively less impaired" patients, who only developed psychosis after a relatively early initiation into cannabis use.

Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.

BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

No consistent association between processes-of-care and health-related quality of life among patients with diabetes : a missing link?

PURPOSE: Health-related quality of life (HRQoL) is considered a representative outcome in the evaluation of chronic disease management initiatives emphasizing patient-centered care. We evaluated the association between receipt of processes-of-care (PoC) for diabetes and HRQoL. METHODS: This cross-sectional study used self-reported data from non-institutionalized adults with diabetes in a Swiss canton. Outcomes were the physical/mental composites of the short form health survey 12 (SF-12) physical composite score, mental composite score (PCS, MCS) and the Audit of Diabetes-Dependent Quality of Life (ADDQoL). Main exposure variables were receipt of six PoC for diabetes in the past 12 months, and the Patient Assessment of Chronic Illness Care (PACIC) score. We performed linear regressions to examine the association between PoC, PACIC and the three composites of HRQoL. RESULTS: Mean age of the 519 patients was 64.5 years (SD 11.3); 60% were male, 87% reported type 2 or undetermined diabetes and 48% had diabetes for over 10 years. Mean HRQoL scores were SF-12 PCS: 43.4 (SD 10.5), SF-12 MCS: 47.0 (SD 11.2) and ADDQoL: -1.6 (SD 1.6). In adjusted models including all six PoC simultaneously, receipt of influenza vaccine was associated with lower ADDQoL (β=-0.4, p≤0.01) and foot examination was negatively associated with SF-12 PCS (β=-1.8, p≤0.05). There was no association or trend towards a negative association when these PoC were reported as combined measures. PACIC score was associated only with the SF-12 MCS (β=1.6, p≤0.05). CONCLUSIONS: PoC for diabetes did not show a consistent association with HRQoL in a cross-sectional analysis. This may represent an effect lag time between time of process received and health-related quality of life. Further research is needed to study this complex phenomenon.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Neuropathological analysis of lacunes and microvascular lesions in late-onset depression.

M. Santos, G. Gold, E. Kövari, F. R. Herrmann, P. R. Hof, C. Bouras and P. Giannakopoulos (2010) Neuropathology and Applied Neurobiology36, 661-672
Neuropathological analysis of lacunes and microvascular lesions in late-onset depression Aims: Previous neuropathological studies documented that small vascular and microvascular pathology is associated with cognitive decline. More recently, we showed that thalamic and basal ganglia lacunes are associated with post-stroke depression and may affect emotional regulation. The present study examines whether this is also the case for late-onset depression. Methods: We performed a detailed analysis of small macrovascular and microvascular pathology in the post mortem brains of 38 patients with late-onset major depression (LOD) and 29 healthy elderly controls. A clinical diagnosis of LOD was established while the subjects were alive using the DSM-IV criteria. Additionally, we retrospectively reviewed all charts for the presence of clinical criteria of vascular depression. Neuropathological evaluation included bilateral semi-quantitative assessment of lacunes, deep white matter and periventricular demyelination, cortical microinfarcts and both focal and diffuse gliosis. The association between vascular burden and LOD was investigated using Fisher's exact test and univariate and multivariate logistic regression models. Results: Neither the existence of lacunes nor the presence of microvascular ischaemic lesions was related to occurrence of LOD. Similarly, there was no relationship between vascular lesion scores and LOD. This was also the case within the subgroup of LOD patients fulfilling the clinical criteria for vascular depression. Conclusions: Our results challenge the vascular depression hypothesis by showing that neither deep white matter nor periventricular demyelination is associated with LOD. In conjunction with our previous observations in stroke patients, they also imply that the impact of lacunes on mood may be significant solely in the presence of acute brain compromise.

Diagnostic Performances of 18F-FDG Positron Emission Tomography in Large Vessels Vasculitis: Meta-analysis

Toperform a meta-analysis of FDG-PET performances in the diagnosis of largevessels vasculitis (Giant Cell Arteritis (GCA) associated or not withPolymyalgia Rheumatica(PMR), Takayasu). Materials and methods : The MEDLINE,Cochrane Library, Embase were searched for relevant original articlesdescribing FDG-PET for vasculitis assessment, using MesH terms ("GiantCell Arteritis or Vasculitis" AND "PET"). Criteria for inclusionwere:(1)FDG-PET for diagnosis of vasculitis(2)American College of Rheumatologycriteria as reference standard(3)control group. After data extraction, analyseswere performed using a random-effects model. Results : Of 184 citations(database search and references screening),70 articles were reviewed of which12 eligible studies were extracted (sensitivity range from 32% to 97%). 7studies fulfilled all inclusion criteria. Owing to overlapping population, 1study was excluded. Statistical heterogeneity justified the random-effectsmodel. Pooled 6 studies analysis(116 vasculitis,224 controls) showed a 81%sensitivity (95%CI:70-89%);a 89% specificity (95%CI:77-95%);a 85%PPV(95%CI:63-95%); a 90% NPV(95%CI:79-95%);a 7.1 positive LR(95%CI:3.4-14.9); a0.2 negative LR(95%CI:0.14-0.35) and 90.1 DOR(95%CI: 18.6-437). Conclusion :FDG-PET has good diagnostic performances in the detection of large vesselsvasculitis. Its promising role could be extended to follow up patients undertreatment, but further studies are needed to confirm this possibility.

Integrated Analysis of High-Resolution Gene Expression and Copy Number Profiling Identified Biallelic Deletion of CDKN2A/2B Tumor Suppressor Locus As the Most Frequent and Unique Genomic Abnormality in Diffuse Large B-Cell Lymphoma (DLBCL) with Strong Prognostic Value in Both GCB and ABC Subtypes and Not Overcome by a Dose-Intensive Immunochemotherapy Regimen Plus Rituximab. Results of a Prospective GELA Clinical Trial Program

Background and aim of the study: Genomic gains and losses play a crucial role in the development and progression of DLBCL and are closely related to gene expression profiles (GEP), including the germinal center B-cell like (GCB) and activated B-cell like (ABC) cell of origin (COO) molecular signatures. To identify new oncogenes or tumor suppressor genes (TSG) involved in DLBCL pathogenesis and to determine their prognostic values, an integrated analysis of high-resolution gene expression and copy number profiling was performed. Patients and methods: Two hundred and eight adult patients with de novo CD20+ DLBCL enrolled in the prospective multicentric randomized LNH-03 GELA trials (LNH03-1B, -2B, -3B, 39B, -5B, -6B, -7B) with available frozen tumour samples, centralized reviewing and adequate DNA/RNA quality were selected. 116 patients were treated by Rituximab(R)-CHOP/R-miniCHOP and 92 patients were treated by the high dose (R)-ACVBP regimen dedicated to patients younger than 60 years (y) in frontline. Tumour samples were simultaneously analysed by high resolution comparative genomic hybridization (CGH, Agilent, 144K) and gene expression arrays (Affymetrix, U133+2). Minimal common regions (MCR), as defined by segments that affect the same chromosomal region in different cases, were delineated. Gene expression and MCR data sets were merged using Gene expression and dosage integrator algorithm (GEDI, Lenz et al. PNAS 2008) to identify new potential driver genes. Results: A total of 1363 recurrent (defined by a penetrance > 5%) MCRs within the DLBCL data set, ranging in size from 386 bp, affecting a single gene, to more than 24 Mb were identified by CGH. Of these MCRs, 756 (55%) showed a significant association with gene expression: 396 (59%) gains, 354 (52%) single-copy deletions, and 6 (67%) homozygous deletions. By this integrated approach, in addition to previously reported genes (CDKN2A/2B, PTEN, DLEU2, TNFAIP3, B2M, CD58, TNFRSF14, FOXP1, REL...), several genes targeted by gene copy abnormalities with a dosage effect and potential physiopathological impact were identified, including genes with TSG activity involved in cell cycle (HACE1, CDKN2C) immune response (CD68, CD177, CD70, TNFSF9, IRAK2), DNA integrity (XRCC2, BRCA1, NCOR1, NF1, FHIT) or oncogenic functions (CD79b, PTPRT, MALT1, AUTS2, MCL1, PTTG1...) with distinct distribution according to COO signature. The CDKN2A/2B tumor suppressor locus (9p21) was deleted homozygously in 27% of cases and hemizygously in 9% of cases. Biallelic loss was observed in 49% of ABC DLBCL and in 10% of GCB DLBCL. This deletion was strongly correlated to age and associated to a limited number of additional genetic abnormalities including trisomy 3, 18 and short gains/losses of Chr. 1, 2, 19 regions (FDR < 0.01), allowing to identify genes that may have synergistic effects with CDKN2A/2B inactivation. With a median follow-up of 42.9 months, only CDKN2A/2B biallelic deletion strongly correlates (FDR p.value < 0.01) to a poor outcome in the entire cohort (4y PFS = 44% [32-61] respectively vs. 74% [66-82] for patients in germline configuration; 4y OS = 53% [39-72] vs 83% [76-90]). In a Cox proportional hazard prediction of the PFS, CDKN2A/2B deletion remains predictive (HR = 1.9 [1.1-3.2], p = 0.02) when combined with IPI (HR = 2.4 [1.4-4.1], p = 0.001) and GCB status (HR = 1.3 [0.8-2.3], p = 0.31). This difference remains predictive in the subgroup of patients treated by R-CHOP (4y PFS = 43% [29-63] vs. 66% [55-78], p=0.02), in patients treated by R-ACVBP (4y PFS = 49% [28-84] vs. 83% [74-92], p=0.003), and in GCB (4y PFS = 50% [27-93] vs. 81% [73-90], p=0.02), or ABC/unclassified (5y PFS = 42% [28-61] vs. 67% [55-82] p = 0.009) molecular subtypes (Figure 1). Conclusion: We report for the first time an integrated genetic analysis of a large cohort of DLBCL patients included in a prospective multicentric clinical trial program allowing identifying new potential driver genes with pathogenic impact. However CDKN2A/2B deletion constitutes the strongest and unique prognostic factor of chemoresistance to R-CHOP, regardless the COO signature, which is not overcome by a more intensified immunochemotherapy. Patients displaying this frequent genomic abnormality warrant new and dedicated therapeutic approaches.

A photometric analysis of the Cepheus OB3 region

Results are presented on Stromgren-Crawford uvby-beta photometry carried out at Calar Alto (Spain) for 45 stars in the Cepheus OB3 region covering an apparent area of 6 deg x 6 deg. The relationship of these stars with the association is examined. Three of these stars (BD +62 deg 2114, BD +62 deg 2152, and BD +62 deg 2156) are identified as members of this association, while two more (BD +64 deg 1714 and BD +64 deg 1717) are classified as possible members. It is noted that intrinsic colors and absolute magnitudes of member stars are consistent with the hypothesis of Blaauw (1964) and Garmany (1973) of the existence of two subgroups with different evolutionary phases.

Active smoking and the risk of type 2 diabetes : a systematic review and meta-analysis

Rapport de synthèse : Introduction : plusieurs études observationnelles suggèrent qu'il existe une association entre le tabagisme actif et l'incidence du diabète de type 2. Toutefois de telles études n'ont jamais été synthétisées de façon systématique. Objectif : conduire une revue systématique avec meta-analyse des études évaluant l'association entre le tabagisme actif et l'incidence du diabète de type 2. Méthode : nous avons effectué une recherche dans les bases de donnée électroniques MEDLINE et EMBASE de 1966 à mai 2007, et l'avons complétée par une recherche manuelle des bibliographies des articles clés retenus ainsi que par la recherche d'abstracts de congrès scientifiques et le contact d'experts. Pour être inclues dans notre revue, les études devaient avoir un design de type cohorte, reporter un risque de glycémies jeun élevée, d'intolérance au glucose ou de diabète de type 2 en relation avec le statut tabagique des participants lors du recrutement et devaient exclure les sujets avec un diabète au début de l'étude. Deux auteurs ont sélectionné de façon indépendante les études et ont extrait les données. Les risques relatifs de diabète étaient ensuite compilés, utilisant un modèle de type « random effect ». Résultats : la recherche a aboutit à 25 études de cohorte prospectives (N=1'165'374 participants) et a reporté en tout 45'844 cas de diabète de type 2 pendant une durée de suivi s'étendant sur 5 à 30 années. Sur les 25 études, 24 reportaient un risque augmenté de diabète chez les fumeurs par comparaison aux non fumeurs. Le risque relatif (RR) commun de toutes les études était de 1.44 (intervalle de confiance (IC) à 95% : 1.31-1.58). Le risque de diabète était plus élevé chez les fumeurs de plus de 20 cigarettes par jour (RR : 1.61, IC 95% : 1.43-1.80) en comparaison aux fumeurs ayant une consommation inférieure (RR : 1.29, IC 95% : 1.13-1.48) et le risque était moindre pour les anciens fumeurs (RR :1.23; IC 95% : 1.14-1.33) comparé aux fumeurs actifs. Ces éléments parlent en faveur d'un effet dose-réponse et donc d'une relation de causalité, sans pour autant la prouver. Conclusion : notre étude révèle que le tabagisme actif est associé avec un risque augmenté de 44% de diabète de type 2. Des recherches futures sont nécessaires pour évaluer si cette association est causale et pour clarifier les mécanismes d'action. Dans l'intervalle, les professionnels de santé devraient mentionner l'éviction du diabète comme une raison supplémentaire d'arrêter de fumer ou de ne pas commencer à fumer.

Genetic Variants of Serum Uric Acid and Gout: An Analysis of > 170,000 Individuals

Background/Purpose: Gout is a common and excruciatingly painful inflammatory arthritis caused by hyperuricemia. In addition to various lifestyle risk factors, a substantial genetic predisposition to gout has long been recognized. The Global Urate Genetics Consortium (GUGC) has aimed to comprehensively investigate the genetics of serum uric acid and gout using data from _ 140,000 individuals of European-ancestry, 8,340 individuals of Indian ancestry, 5,820 African-Americans, and 15,286 Japanese. Methods: We performed discovery GWAS meta-analyses of serum urate levels (n_110,347 individuals) followed by replication analyses (n_32,813 different individuals). Our gout analysis involved 3,151 cases and 68,350 controls, including 1,036 incident gout cases that met the American College of Rheumatology Criteria. We also examined the association of gout with fractional excretion of uric acid (n_6,799). A weighted genetic urate score was constructed based on the number of risk alleles across urate-associated loci, and their association with the risk of gout was evaluated. Furthermore, we examined implicated transcript expression in cis (expression quantitative trait loci databases) for potential insights into the gene underlying the association signal. Finally, in order to further identify urate-associated genomic regions, we performed functional network analyses that incorporated prior knowledge on molecular interactions in which the gene products of implicated genes operate. Results: We identified and replicated 28 genome-wide significant loci in association with serum urate (P 5_10_8), including all previously-reported loci as well as 18 novel genetic loci. Unlike the majority of previouslyidentified loci, none of the novel loci appeared to be obvious candidates for urate transport. Rather, they were mapped to genes that encode for purine production, transcription, or growth factors with broad downstream responses. Besides SLC2A9 and ABCG2, no additional regions contained SNPs that differed significantly (P _ 5_10_8) between sexes. Urateincreasing alleles were associated with an increased risk of gout for all loci. The urate genetic risk score (ranging from 10 to 45) was significantly associated with an increased odds of prevalent gout (OR per unit increase, 1.11; 95% CI, 1.09-1.14) and incident gout (OR, 1.10; 95% CI, 1.08-1.13). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. Detailed characterization of the loci revealed associations with transcript expression and the fractional excretion of urate. Network analyses implicated the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. Conclusion: The novel genetic candidates identified in this urate/gout consortium study, the largest to date, highlight the importance of metabolic control of urate production and urate excretion. The modulation by signaling processes that influence metabolic pathways such as glycolysis and the pentose phosphate pathway appear to be central mechanisms underpinned by the novel GWAS candidates. These findings may have implications for further research into urate-lowering drugs to treat and prevent gout.

Alcohol-attributable injuries in admissions to a swiss emergency room--an analysis of the link between volume of drinking, drinking patterns, and preattendance drinking.

BACKGROUND: An association between alcohol consumption and injury is clearly established from volume of drinking, heavy episodic drinking (HED), and consumption before injury. Little is known, however, about how their interaction raises risk of injury and what combination of factors carries the highest risk. This study explores which of 11 specified groups of drinkers (a) are at high risk and (b) contribute most to alcohol-attributable injuries. METHODS: In all, 8,736 patients, of whom 5,077 were injured, admitted to the surgical ward of the emergency department of Lausanne University Hospital between January 1, 2003, and June 30, 2004, were screened for alcohol use. Eleven groups were constructed on the basis of usual patterns of intake and preattendance drinking. Odds ratios (ORs) comparing injured and noninjured were derived, and alcohol-attributable fractions of injuries were calculated from ORs and prevalence of exposure groups. RESULTS: Risk of injury increased with volume of drinking, HED, and preattendance drinking. For both sexes, the highest risk was associated with low intake, HED, and 4 (women), 5 (men), or more drinks before injury. At the same level of preattendance drinking, high-volume drinkers were at lower risk than low-volume drinkers. In women, the group of low-risk non-HED drinkers taking fewer than 4 drinks suffered 47.5% of the alcohol-attributable injuries in contrast to only 20.4% for men. Low-volume male drinkers with HED had more alcohol-attributable injuries than that of low-volume female drinkers with HED (46.9% vs 23.2%). CONCLUSIONS: Although all groups of drinkers are at increased risk of alcohol-related injury, those who usually drink little but on occasion heavily are at particular risk. The lower risk of chronic heavy drinkers may be due to higher tolerance of alcohol. Prevention should thus target heavy-drinking occasions. Low-volume drinking women without HED and with only little preattendance drinking experienced a high proportion of injuries; such women would be well advised to drink very little or to take other special precautions in risky circumstances.