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Objectives Genetic variation in the renal urate transporters SLC2A9 (GLUT9) and SLC22A11 (OAT4) has been reported to interact with diuretics to increase the risk of developing gout. The aim of this study was to determine whether variation in SLC2A9 or SLC22A11 influences acute renal handling of uric acid in response to frusemide. Methods Following an overnight fast, healthy participants (n=100) attended a study visit with oral intake of 40 mg frusemide. Blood and urine samples were obtained at baseline and 30, 60, 120 and 180 min after frusemide intake. The primary end point was change in fractional excretion of uric acid (FEUA). Results Following intake of frusemide, FEUA initially increased (mean (SD) change from baseline +1.9% (3.0%) at 60 min, p

Introduction Gout results from an innate immune response to monosodium urate (MSU) crystals deposited in joints. Increased very low-density lipoprotein (VLDL) has been associated with gout. The apolipoprotein B (apo B), which is present on VLDL, regulates neutrophil response to MSU crystals and has been positively associated with gout. Furthermore, the gene (A1CF) encoding the complementation factor for the APOB mRNA-editing enzyme is associated with urate levels. However, the relationship of apo B and VLDL with gout and hyperuricaemia (HU) is still unclear. Therefore, we tested the association of VLDL and apo B with HU and with gout compared to HU. Methods New Zealand European (n = 90) and Māori and Pacific Island (Polynesian) (n = 90) male gout case and control sample sets were divided into normouricaemia (NU), asymptomatic HU and gout groups. Size exclusion chromatography and enzyme-linked immunosorbant assay was used to measure VLDL and apo B. Multivariate logistic regression was used to assess the risk of gout and HU per unit change in VLDL and apo B. Results Increased levels of VLDL triglycerides (Tg) were observed in the gout sample set compared to NU and HU in Europeans (P = 1.8 × 10-6 and 1 × 10-3, respectively), but only compared to NU in Polynesians (P = 0.023). This increase was driven by increased number of VLDL particles in the European participants and by the Tg-enrichment of existing VLDL particles in the Polynesian participants. Each mmol/L increase in VLDL Tg was significantly associated with gout in the presence of HU in Europeans, with a similar trend in Polynesians (OR = 7.61, P = 0.011 and 2.84, P = 0.069, respectively). Each μmol/L increase in total apo B trended towards decreased risk of HU (OR = 0.47; P = 0.062) and, conversely, with increased risk of gout compared to HU (OR = 5.60; P = 0.004). Conclusions Increased VLDL Tg is associated with the risk of gout compared to HU. A genetic approach should be taken to investigate the possibility for causality of VLDL in gout. Apolipoprotein B may have pleiotropic effects in determining HU and gout.

BackgroundDiuretic-induced gout might occur only among those with a genetic predisposition to hyperuricaemia, as suggested by a recent study with 108 self-reported gout cases.MethodsWe examined the role of urate genes on the risk of diuretic-induced incident gout in 6850 women from the Nurses’ Health Study (NHS) and in 4223 men from the Health Professionals Follow-up Study (HPFS). Two published genetic risk scores (GRSs) were calculated using urate-associated single-nucleotide polymorphisms for 8 (GRS8) and 29 genes (GRS29).ResultsOur analyses included 727 and 354 confirmed incident gout cases in HPFS and NHS, respectively. The multivariate relative risk (RR) for diuretic use was 2.20 and 1.69 among those with GRS8 < and ≥ the median (p for interaction=0.27). The corresponding RRs using GRS29 were 2.19 and 1.88 (p for interaction=0.40). The lack of interaction persisted in NHS (all p values >0.20) and in our analyses limited to those with hypertension in both cohorts. SLC22A11 (OAT4) showed a significant interaction only among women but in the opposite direction to the recent study.ConclusionsIn these large prospective studies, individuals with a genetic predisposition for hyperuricaemia are not at a higher risk of developing diuretic-induced gout than those without.

Recent advances in high-throughout sequencing technologies have made it possible to accurately assign copy number (CN) at CN variable loci. However, current analytic methods often perform poorly in regions in which complex CN variation is observed. Here we report the development of a read depth-based approach, CNVrd2, for investigation of CN variation using high-throughput sequencing data. This methodology was developed using data from the 1000 Genomes Project from the CCL3L1 locus, and tested using data from the DEFB103A locus. In both cases, samples were selected for which paralogue ratio test data were also available for comparison. The CNVrd2 method first uses observed read-count ratios to refine segmentation results in one population. Then a linear regression model is applied to adjust the results across multiple populations, in combination with a Bayesian normal mixture model to cluster segmentation scores into groups for individual CN counts. The performance of CNVrd2 was compared to that of two other read depth-based methods (CNVnator, cn.mops) at the CCL3L1 and DEFB103A loci, and the highest concordance with the paralog ratio test method was observed for CNVrd2 (77.8%/90.4% for CNVrd2, 36.7%/4.8% for cn.mops and 7.2%/1% for CNVnator at CCL3L1 and DEF103A). CNVrd2 is available as an R package as part of the Bioconductor project: http://www.bioconductor.org/packages/release/bioc/html/CNVrd2.html.

The detection of “signatures of selection” is now possible on a genome-wide scale in many plant and animal species, and can be performed in a population-specific manner due to the wealth of per-population genome-wide genotype data that is available. With genomic regions that exhibit evidence of having been under selection shown to also be enriched for genes associated with biologically important traits, detection of evidence of selective pressure is emerging as an additional approach for identifying novel gene-trait associations. While high-density genotype data is now relatively easy to obtain, for many researchers it is not immediately obvious how to go about identifying signatures of selection in these data sets. Here we describe a basic workflow, constructed from open source tools, for detecting and examining evidence of selection in genomic data. Code to install and implement the pipeline components, and instructions to run a basic analysis using the workflow described here, can be downloaded from our public GitHub repository: http://www.github.com/smilefreak/selectionTools/

The etiology of Crohn's disease (CD) implicates both genetic and environmental factors. Smoking behavior is one environmental risk factor to play a role in the development of CD. The study aimed to assess the contribution of the interleukin 23 receptor (IL23R) in determining disease susceptibility in two independent cohorts of CD, and to investigate the interactions between IL23R variants, smoking behavior, and CD-associated genes, NOD2 and ATG16L1.Ten IL23R single-nucleotide polymorphisms (SNPs) were genotyped in 675 CD cases, and 1255 controls from Brisbane, Australia (dataset 1). Six of these SNPs were genotyped in 318 CD cases and 533 controls from Canterbury, New Zealand (dataset 2). Case-control analysis of genotype and allele frequencies, and haplotype analysis for all SNPs was conducted.We demonstrate a strong increased CD risk for smokers in both datasets (odds ratio 3.77, 95% confidence interval 2.88-4.94), and an additive interaction between IL23R SNPs and cigarette smoking. Ileal involvement was a consistent marker of strong SNP-CD association (P ≤ 0.001), while the lowest minor allele frequencies for location were found in those with colonic CD (L2). Three haplotype blocks were identified across the 10 IL23R SNPs conferring different risk of CD. Haplotypes conferred no further risk of CD when compared with single SNP analyses.IL23R gene variants determine CD susceptibility in the Australian and New Zealand population, particularly ileal CD. A strong additive interaction exists between IL23R SNPs and smoking behavior resulting in a dramatic increase in disease risk depending upon specific genetic background.

Gout results from deposition of monosodium urate (MSU) crystals. Elevated serum urate concentrations (hyperuricemia) are not sufficient for the development of disease. Genome-wide association studies (GWAS) have identified 28 loci controlling serum urate levels. The largest genetic effects are seen in genes involved in the renal excretion of uric acid, with others being involved in glycolysis. Whereas much is understood about the genetic control of serum urate levels, little is known about the genetic control of inflammatory responses to MSU crystals. Extending knowledge in this area depends on recruitment of large, clinically ascertained gout sample sets suitable for GWAS.

Objectives Gout is one of the most common forms of arthritis. It is well established that urate-lowering therapy that aims for a serum urate less than at least 0.36 mmol/l (6 mg/dl) is required for the successful management of gout. Allopurinol, a xanthine oxidase (XO) inhibitor, is the most commonly used urate-lowering therapy. However, many patients fail to achieve the target serum urate on allopurinol; these patients can be considered to have “inadequate response” to allopurinol. Herein, we examine the potential mechanisms and implications of inadequate response to allopurinol. Methods The literature was reviewed for potential causes for failure to reach target serum urate in patients receiving allopurinol. Results The two most common causes of inadequate response to allopurinol are poor adherence and under-dosing of allopurinol. Adherent patients who fail to achieve target serum urate on standard doses of allopurinol form a group that could be considered to be “partially resistant” to allopurinol. There are four potential mechanisms for partial allopurinol resistance: decreased conversion of allopurinol to oxypurinol; increased renal excretion of oxypurinol; abnormality in XO structure and/or function such that oxypurinol is rendered less effective and/or drug interactions. Conclusions It is important to determine the reasons for failure to achieve treatment targets with allopurinol, particularly as newer agents become available. The knowledge of the mechanisms for inadequate response may help guide the clinician towards making a therapeutic choice that is more likely to result in achieving the serum urate target.

The choice of which population to study in the mapping of common disease genes may be critical. Isolated founder populations, such as that found in Finland, have already proved extremely useful for mapping the genes for specific rare monogenic disorders and are being used in attempts to map the genes underlying common, complex diseases. But simulation results suggest that, under the common disease-common variant hypothesis, most isolated populations will prove no more useful for linkage disequilibrium (LD) mapping of common disease genes than large outbred populations. There is very little empirical data to either support or refute this conclusion at present. Therefore, we evaluated LD between 21 common microsatellite polymorphisms on chromosome 18q21 in 2 genetic isolates (Finland and Sardinia) and compared the results with those observed in two mixed populations (United Kingdom and United States of America). Mean levels of LD were similar across all four populations. Our results provide empirical support for the expectation that genetic isolates like Finland and Sardinia will not prove significantly more valuable than general populations for LD mapping of common variants underlying complex disease.

Allelic association methods based on increased transmission of marker alleles will have to be employed for the mapping of complex disease susceptibility genes. However, because the extent of association of single marker alleles with disease is a function of the relative frequency of the allele on disease-associated chromosomes versus non disease-predisposing chromosomes, the most associated marker allele in a region will not necessarily be closest to the disease locus. To overcome this problem we describe a haplotype-based approach developed for mapping of the putative type 1 diabetes susceptibility gene IDDM6. Ten microsatellite markers spanning a 550 kb segment of chromosome 18q21 in the putative IDDM6 region were genotyped in 1708 type 1 diabetic Caucasian families from seven countries. The most likely ancestral diabetogenic chromosome was reconstructed in a stepwise fashion by analysing linkage disequilibrium between a previously defined haplotype of three adjacent markers and the next marker along the chromosome. A plot of transmission from heterozygous parents to affected offspring of single marker alleles present on the ancestral chromosome versus the physical distance between them, was compared with a plot of transmission of haplotypes of groups of three adjacent markers. Analysing transmission of haplotypes largely negated apparent decreases in transmission of single marker alleles. Peak support for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P = 0.01). The results also demonstrate the utility of polymorphic microsatellite markers to trace and delineate extended and presumably ancient haplotypes in the analysis of common disease and in the search for identical-by-descent chromosome regions that carry an aetiological variant.

The Kidd blood group locus encodes a urea transporter which is expressed on human red cells and in the kidney. This gene is located on chromosome 18q12, and evidence for linkage and association with type 1 diabetes mellitus has been reported. To investigate this further, the genetic basis for the blood group Jk(a)/Jk(b) polymorphism was first determined by sequencing reverse-transcribed reticulocyte RNAs from Jk(a+b-) and Jk(a-b+) donors. The Jk(a)/Jk(b) polymorphism was caused by a transition (G838A), resulting in a Asp280Asn amino acid substitution and an MnlI restriction fragment length polymorphism (RFLP). Using the MnlI RFLP, we found that the Jk(a)/Jk(b) polymorphism was not in linkage disequilibrium with type 1 diabetes in 228 multiplex UK and US families tested.

Monosodium urate (MSU) crystal induced interleukin-1 (IL-1β) secretion is a critical pathogenic factor in the development of gout and serves as therapeutic target in these patients. Nevertheless, without co-stimulation by a pro-IL-1s inducing factor, e.g. lipopolysaccharides (LPS), MSU alone cannot induce IL-1β secretion in vitro. The endogenous Toll-like receptor 4 (TLR-4) agonists myeloid related protein (MRP) 8 and MRP14 play a significant role in human inflammatory diseases, reflect disease activity and have been shown to be an important pathogenic factor in murine arthritis models.

Gout results from an innate immune reaction to monosodium urate crystals deposited in the joints of individuals with elevated serum urate levels (hyperuricaemia). Urate, the primary cause of gout, is a metabolite with beneficial properties. The use of genome-wide association scanning has identified 28 loci that control serum urate levels. Predominant among these are loci containing uric acid transporter genes involved in renal and gut excretion of uric acid. The SLC2A9 (GLUT9) and ABCG2 genes have particularly strong effects on serum urate and risk of gout. In contrast to serum urate, the genetic control of inflammatory gout is very poorly understood, largely because no genome-wide association scan has been conducted using clinically ascertained gout cases. Similarly, the full-scope of the beneficial (or harmful) properties of urate is currently unknown; a genetic technique called Mendelian randomisation is being employed to better understand the relationship between urate and other metabolic conditions. Key Concepts: Urate is evolutionarily beneficial. Urate is under genetic control. Genetic variants in genes involved in the excretion of uric acid have the strongest effect on serum urate. A total of 28 loci have been associated with control of serum urate. Not all genes associated with serum urate have been associated with gout. There are no genes associated with inflammatory gout with robust statistical evidence. Keywords: urate; gout; gene; association; single-nucleotide polymorphism; genome-wide association study; SLC2A9; ABCG2; mendelian randomisation

Pacific Island populations, particularly those of Polynesian descent, have a high prevalence of hyperuricaemia and gout. This is due to an inherently higher urate level among these populations with a demonstrated genetic predisposition. While an excess of urate can cause pathology, urate is also important for human health. It has been implicated as an antioxidant, has a neuroprotective role and is involved in innate immune responses. This paper provides a brief review of urate levels worldwide, with a particular focus on island Southeast Asia and the Pacific. We then present possible evolutionary explanations for the elevated serum urate levels among Pacific populations in the context of the physiological importance of urate and of the settlement history of the region. Finally, we propose that ancestry may play a significant role in hyperuricaemia in these populations and that exposure to malaria prior to population expansion into the wider Pacific may have driven genetic selection for variants contributing to high serum urate.

Gout is a growing health problem worldwide especially in affluent countries, such as Australia. Gout and hyperuricaemia are associated with the metabolic syndrome, diabetes mellitus, obesity and hypertension. More importantly, Australia has a growing prevalence of these important health problems. The aim of this study was to systematically review published information regarding the prevalence of gout and hyperuricaemia in Australia.A systematic search was undertaken of the MEDLINE, EMBASE and Web of Science databases, as well as relevant websites for journal articles and reports relating to the prevalence of hyperuricaemia and gout in Australia.Twenty-five journal articles and five reports were included in the review. Data collected in a standardised way show gout increased in prevalence from 0.5% population prevalence to 1.7% population prevalence from 1968 to 1995/1996. There has been a significant rise in the prevalence of gout in the Australian Aboriginal population from 0% in 1965 to 9.7% in men and 2.9% in women in 2002. Consistent with the rise in gout prevalence, serum uric acid in blood donors has increased from 1959 to 1980 (17% in 30- to 40-year-old men).The rate of gout and hyperuricaemia in Australia is high in relation to comparable countries and is increasing. The prevalence of gout in elderly male Australians is second only to New Zealand, which has the highest reported rate in the world. Further research on Aboriginal and Torres Strait Islander gout and hyperuricaemia is required as a result of the lack of contemporary data.

Solute carrier family 17 member 1 (SLC17A1) is an anion exchanger that secretes uric acid into the urine.1 ,2 Genetic variation in SLC17A1 has been associated with hyperuricaemia and gout.3–5 The minor allele (A) of single nucleotide polymorphism (SNP) rs1183201 is associated with a reduced risk of gout in European and western Polynesian people, with a weaker (non-significant) effect in eastern Polynesian people.4 rs1183201 is a tag SNP in strong linkage disequilibrium for the possible aetiological variant ( rs1165196 ) in SLC17A1 .4 Variation in another renal uric acid transporter SLC2A9 influences serum urate (SU) and fractional excretion of uric acid (FEUA) responses to a fructose load in European, but not Polynesian participants.6 It is unknown whether other genetic factors also contribute to fructose-induced SU responses. The aim of this study was to determine the influence of SLC17A1 variation on SU and FEUA responses during a fructose load. Healthy volunteers provided serum and urine samples immediately before and 30, 60, 120 and 180 min after ingesting a 64 g fructose solution, as previously described.6 Data were analysed based …

Purpose The precise etiology of autoimmune hepatitis (AIH) remains unknown, although a number of genetic loci have been implicated in the susceptibility of type 1 AIH. The purpose of this study was to test for association of these loci with type 1 AIH in New Zealand Caucasians. Methods 77 AIH patients and 485 healthy controls were genotyped for the SNPs rs2187668 (HLA-DRB*03:01), rs660895 (HLA-DRB*04:01), rs3749971 (HLA-A1-B8-DR3), rs231775 (CLTLA4), rs1800629 (TNF), and rs1800682 (FAS) using predesigned TaqMan SNP genotyping assays. Chi square analysis was used to test for association of allele and genotype with overall AIH, and with severe fibrosis and ALT levels at 6 months. Results Significant risk of AIH was conferred by the minor alleles of rs2187668 (OR = 2.45, 95% CI 1.65-3.61, p FAS SNP rs1800682 was associated with increased risk of severe fibrosis at diagnosis (OR = 2.03, 95% CI 1.05-3.93, p = 0.035) and with incomplete normalization of ALT levels at 6 months post-diagnosis (OR = 3.94, 95% CI 1.62-9.54, p = 0.0015). Conclusions This is the first population-based study to investigate genetic risk loci for type 1 AIH in New Zealand Caucasians. We report significant independent association of HLA-DRB1*03:01 with overall susceptibility to type 1 AIH, as well as FAS with a more aggressive disease phenotype.

Gout is a major health problem in Polynesians and allopurinol, the drug of choice for the management gout, appears to be less effective in Polynesian patients. The uricosuric drug benzbromarone is an alternative treatment but CYP2C9 poor metabolisers (PMs) may be at a heightened risk of benzbromarone-induced hepatotoxicity. The objectives of this study were to determine the frequency of the PM alleles CYP2C9*2 and CYP2C9*3 in New Zealand (NZ) Caucasian and Polynesian gout cohorts; and then to test for novel CYP2C9 polymorphisms in Polynesians.Eight hundred and fifty-two Caucasians (537 controls, 315 gout patients) and 1072 Māori and Pacific Island (Polynesian) people (620 controls, 452 gout patients) were genotyped for CYP2C9*2 and CYP2C9*3. Forty Polynesians were screened for novel CYP2C9 polymorphisms using whole genome sequencing.Frequency of CYP2C9 PM alleles was significantly higher in Caucasians compared to Polynesians (CYP2C9*2: 13.5% versus 3.1%; CYP2C9*3: 5.5% versus 1.6%, P1.2E-11). Within Polynesians, CYP2C9 PM alleles were rarer in Western Polynesians (Samoa, Tonga) than Eastern Polynesians (NZ and Cook Island Maori; CYP2C9*2: 0.6% versus 2.5%; CYP2C9*3: 0.4% versus 2.0%; P0.03). A total of 152 SNPs were found by sequencing. None of these variants were predicted by in silico analysis to significantly impact on CYP2C9 expression or activity.Prospective CYP2C9 genotyping of Caucasian gout patients may be warranted for benzbromarone, whereas the low frequencies of CYP2C9 PM alleles in Polynesians suggests that the CYP2C9 polymorphism may be of little or no relevance to benzbromarone prescribing in this population.

The extent of contribution from common gene copy number (CN) variants in human disease is currently unresolved. Part of the reason for this is the technical difficulty in directly measuring CN variation (CNV) using molecular methods, and the lack of single nucleotide polymorphisms (SNPs) that can tag complex CNV that has arisen multiple times on different SNP haplotypes. One CNV locus implicated in human disease is FCGR. Here we aimed to use next-generation sequencing (NGS) data from the 1000 Genomes Project to assign CN at FCGR3A and FCGR3B and to comprehensively assess the ability of SNPs to tag specific CN variants. A read-depth algorithm was developed (CNVrd) and validated on a subset of HapMap samples using CN assignments that had previously been determined using molecular and microarray methods. At 7 out of 9 other complex loci there was >90% concordance with microarray data. However, given that some prior knowledge of CN is required, the generalizability of CNVrd is limited and should be applied to other complex CNV loci with caution. Subsequently, CN was assigned et FCGR3B using CNVrd in a total of 952 samples from the 1000 Genomes Project, using three classes and SNPs that correlated with duplication were identified. The best tag SNP was observed in the Mexican-American sample set for duplication at FCGR3B. This SNP (rs117435514, r2 = 0.79) also tagged similar duplication in Chinese and Japanese (r2 = 0.35–0.60), but not in Caucasian or African. No tag SNP for duplication at FCGR3A or deletion at FCGR3B was identified in any population. We conclude that it is possible to tag CNV at the FCGR locus, but CN and SNPs have to be characterized and correlated on a population-specific basis.

Recently, the major advances in understanding the genetics of type 1 diabetes have come using the positional cloning approach, both in mouse and human. Construction of congenic mouse strains and, in human, the exploitation of linkage disequilibrium between very closely linked markers and disease-predisposing loci, is enabling fine mapping of these loci.

Objective To investigate the differences in oral health-related quality of life (OHRQoL) and self-reported jaw function between patients with hyperdivergent and normodivergent facial types. Methods Eighty patients with a distinctively hyperdivergent facial type (mandibular plane angle greater than 2 standard deviations, or 42°) and 80 controls were individually matched according to age, sex, ethnicity, and treatment stage. Data were collected using self-report questionnaires such as the Oral Health Impact Profile (OHIP-14) and Jaw Functional Limitation Scale (JFLS-8). Results The mean age of the patients was 17.2 ± 4.6 years (range, 12–9 years), with most (65.0%) being female and of New Zealand European origin (91.3%). Individuals with hyperdivergent facial types had higher overall and social domain scores on the OHIP-14 (p < 0.05) than did the ones with normodivergent facial types. However, the intergroup differences in JFLS-8 scores were not significant (p > 0.05). Conclusions Jaw function appears to be similar in individuals with hyperdivergent and normodivergent facial morphologies. However, those with hyperdivergent facial types are more likely to self-report poorer OHRQoL than are those with normal faces, especially in relation to social aspects.

The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics. Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent–metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling. Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively. The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.

Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76-0.85, P = 7.2 × 10(-14)). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case-control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.

Given the role of CD247 in the response of the T cells, its entailment in autoimmune diseases and in order to better clarify the role of this gene in RA susceptibility, we aimed to analyze CD247 gene variants previously associated with other autoimmune diseases (rs1052237, rs2056626 and rs864537) in a large independent European Caucasian population. However, no evidence of association was found for the analyzed CD247 single-nucleotide polymorphisms (SNPs) with RA and with the presence/absence of anti-cyclic citrullinated polypeptide. We performed a meta-analysis including previously published GWAS data from the rs864537 variant, revealing an overall genome-wide significant association between this CD247 SNP and RA with anti-CCP (OR = 0.90, CI 95% = 0.87-0.93, Poverall = 2.1×10-10). Our results show for first time a GWAS-level association between this CD247 polymorphism and RA risk. © 2013 Teruel et al.

Background Iron homeostasis is a tightly regulated set of biochemical processes. Transferrin and its cell-surface receptor regulate iron uptake and ferritin sequesters free iron and acts as a store for excess iron from intra- and extra-cellular pools. Ferritin has been positively associated with serum urate in the National Health and Nutrition Examination Survey III (NHANES III) [1]. There have been observational and interventional studies suggesting a role for iron as a trigger for gout flares, which may be due to a number of pro-inflammatory activities associated with iron [2, 3]. Consistent with this, genetic variation in the transferrin receptor is associated with gout and with an increased likelihood of self-report of an iron-rich food as a trigger of flares [2]. Genetic variation in the transferrin receptor is associated with gout and with an increased likelihood of self-report of an iron-rich food as a trigger of flares [2]. Objectives To replicate the association of ferritin with serum urate and to test for association of ferritin with gout. Methods For the serum urate association analysis, African-American subjects from the publicly available Jackson Heart Study were included (693 females and 567 males). Subjects who self-reported taking diuretic or urate-lowering medication/s, or who had kidney disease or gout, were excluded. For the gout analysis 93 individuals were included, comprising 60 controls (all males) and 33 gout cases (4 females and 29 males). Linear regression analysis using R 3.2.0 and adjusting for age and body mass index was done to test for association between ferritin and serum urate. An unpaired t test was used to test for association between gout and plasma ferritin. Results A positive association of serum ferritin and urate was found in both males (β=1.02E-04 pmol/L, P =9.6E-03) and females (β=1.95E-04pmol/L, P =7.1E-04) in the Jackson Heart Study. Plasma concentrations of ferritin were elevated in gout cases (Mean±SD; 320.6±167.1 ng/mL) compared to controls (69.45±63.41 ng/mL) ( P –4 ). Conclusions The associations between ferritin and both serum urate and gout implicate iron metabolism in gout. While it is not possible to assign causality from this observational study, the previously reported association of the transferrin receptor with gout [1] is consistent with iron metabolism having a causal role in gout. References Ghio AJ, et al. Free Radic Res. 2005;39(3):337–342. Facchini FS. Rheumatology. 2003;42:1550–1555. Dabbagh AJ, et al. Ann Rheum Dis. 1992;51:516–21. Acknowledgement Research sponsored by Ardea Biosciences/AstraZeneca. Editorial support was provided by PAREXEL and funded by AstraZeneca. Disclosure of Interest T. Fatima: None declared, T. Merriman Grant/research support from: Ardea Biosciences, Inc., C. Iverson Employee of: Ardea Biosciences, Inc., J. Miner Employee of: Ardea Biosciences, Inc.

Background Colonoscopic, endoscopic, and histological studies have demonstrated that intestinal inflammation, similar to the ileo-colitis seen in Crohn9s disease (CD), is a common feature of ankylosing spondylitis (AS). More recently, the existence of a shared genetic basis to CD and AS has been demonstrated [1,2]. Objectives To test whether the association of known CD risk loci with AS is primarily due to the presence of bowel inflammation in AS patients. Methods 286 Caucasian patients fulfilling the modified New York criteria for AS and with no history of inflammatory bowel disease were assessed non-invasively for bowel inflammation using faecal calprotectin and the Dudley Inflammatory Bowel Symptom Questionnaire (DISQ) [3]. All patients and 568 matched healthy controls were genotyped with TaqMan® SNP genotyping assays for the confirmed CD risk loci [2], 1q32 (rs11584383), JAK2 (rs10758669), CDKAL1 (rs6908425), IL12B (rs100454310), ZPBP2 (rs2872507), MUC19/LRRK2 (rs11175593), STAT3 (rs744166), and IL23R (rs1343151, rs10489630, rs11209026). Chi square testing was used to test for association. Results Minor alleles of 1q32 SNP rs11584383 (p=0.002, OR=0.69, 95% CI 0.55–0.87), and IL23R SNPs rs11209026 (p=0.011, OR=0.53, 95% CI 0.32–0.87) and rs1343151 (p=0.027, OR=0.77, 95% CI 0.61–0.97) all conferred protection against AS. However, only the association of 1q32 SNP rs11584383 remained significant after Bonferroni correction for multiple testing (p=0.02). The Cochran9s Q test found no significant difference between ORs after stratification of AS patients by DISQ score and faecal calprotectin (P difference >0.09). Conclusions Previously, the association of CD risk loci with susceptibility to AS has been attributed to the co-occurrence of asymptomatic intestinal inflammation which is well recognised and supports the concept that CD and AS are two extremes of a related genetic and phenotypic disease spectrum. However, our study provides preliminary evidence that the association of the confirmed CD risk locus 1q32 SNP rs11584383 with AS is independent of bowel inflammation. References Parkes M, et al. 2013. Nature reviews Genetics. 14(9):661–673. Danoy P et al. 2010. PLoS genetics. 6(12):e1001195. Stebbings S et al. 2012. Rheumatology. 51(5):858–865. Disclosure of Interest None declared

Background Genetic variants in uric acid transporters that control serum urate levels have been identified in Europeans by genome-wide association studies [1]. However there is no evidence for association with serum urate (or gout) with the organic anion transporters (OAT) 1–3 (SLC22A6, SLC22A7 and SLC22A8) and multi-drug resistance protein 4 (MRP4) encoded by ABCC4; all four transporters have been implicated in uric acid secretion [2]. The Māori and Pacific (Polynesian) population of New Zealand (NZ) has the highest prevalence of gout worldwide and exhibits lower fractional excretion of uric acid (FEUA) than Europeans. Objectives To identify any Polynesian population-specific genetic variants in the SLC22A6–8 and ABCC4 genes associated with gout. Methods All participants had ≥3 self-reported Māori and/or Pacific grandparents. From the total sample set of 1808 individuals, 191 hyperuricaemic (highest urate levels) and 202 normouricaemic (lowest urate levels) individuals were selected and resequenced over a total of 24.3 kb of promoter, exon and 39 and 59 untranslated region DNA within the four genes. Replication genotyping for rs4148500 was done using Taqman over the remaining 1415 individuals. Logistic regression association analysis with gout or hyperuricaemia (≥0.36 mmol/L in women, ≥0.42 mmol/L in men) as outcome, or linear regression with FEUA or serum urate as outcome, was performed adjusting by age, sex and Polynesian ancestry. Results A total of 39 common variants were detected with one in ABCC4 (rs4148500) significantly associated with hyperuricaemia and gout. There were substantial differences in allele frequency between Western (Samoan, Tongan, Niuean, Tokelaun) and Eastern (NZ and Cook Island Māori) Polynesian samples – adjusting for ancestry revealed evidence for association with gout in the resequenced samples (OR=1.62, P=0.012 for rs4148500). The association of rs4148500 with gout was replicated (OR=1.25, P=0.033) and was restricted to males (ORMales=1.43, P=0.001; ORFemales=0.98, P=0.89). The gout risk allele was associated with FEUA in males (b=-0.570, P=0.01) and there was a trend towards association with serum urate in the male controls (b=0.013, P=0.07). The Ensembl database revealed that the variant was monomorphic (for the protective major allele) in Europeans. Conclusions This is the first report of a genetic factor specifically contributing to the increased risk of gout in men of Māori and Pacific ancestry in NZ. Association of ABCC4 with gout and FEUA is consistent with the established role of MRP4 as a unidirectional urinary uric acid efflux pump of uric acid [3]. References Kottgen et al. Nat Genet 2013;45:145 Mandal and Mount. Ann Rev Physiol 2015;77:323 Van Aubel et al. Am J Physiol 2005;288:F327 Acknowledgement The New Zealand Health Research Council, Lottery Health New Zealand, Arthritis New Zealand and the National Institute of Health (United States) are thanked for funding this study. Disclosure of Interest T. Merriman Grant/research support from: ArdeaBio, J. Boocock: None declared, E. Stahl: None declared, M. Cadzow: None declared, A. Phipps-Green: None declared, R. Topless: None declared, J. Harre Hindmarsh: None declared, D. Mount: None declared, L. Stamp: None declared, N. Dalbeth Grant/research support from: Fonterra, ArdeaBio, AstraZeneca, Consultant for: Takeda, Menarini, Teijin, Pfizer, Crealta, Cymabay, H. Choi: None declared, C. Tanner: None declared

Background Mitochondria appear to play a central role in the induction of an NLRP3 inflammatory response, an immune response critical for the development of gouty pathology. Mitochondria are in part self-encoding, possessing a 16.5 kB circular genome which encodes 36 genes. Therefore mitochondrial genetic variation may contribute to susceptibility to gout. Objectives The objective of this study was to test whether mitochondrial genetic variation and copy number among New Zealand Polynesians may be contributing to susceptibility to gout. The Māori and Pacific (Polynesian) populations of New Zealand exhibit a high prevalence of gout (6 and 8%, respectively). Methods 439 whole mitochondrial genomes belonging to Māori and Pacific men from New Zealand (327 cases, 112 controls) were sequenced to explore whether mitochondrial DNA (mtDNA) variation may contribute risk to gout. mtDNA copy number variation was also investigated by looking at relative read depth using Next Generation Sequencing data produced from whole genome sequencing and resequencing of urate loci. Quantitative PCR was undertaken for replication in an extended sample set of 540 Polynesian male and female cases and 530 controls. Results Within Polynesia, there is relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sub-lineages. A lineage-specific heteroplasmy in hypervariable region I was found to associate with a greater than three-fold higher risk of gout among the mitochondrial sequenced sample set (e.g. heteroplasmy at position 16179: OR 3.28, P =0.009; heteroplasmy at position 16181: 3.86, P =9x10 –5 ; heteroplasmy at position 16182: 3.43, P =0.005). Quantitative PCR of mtDNA from the 1070 Polynesian gout cases and controls showed that individuals with gout possess less mtDNA, on average than healthy controls. With each unit increase in ΔCt (which reflects a decrease in mtDNA content), there was a 33% increase in gout risk (OR 1.33, P =0.003). The effect was stronger when looking at those participants who possessed urate levels exceeding 0.40 mmol L –1 (n=422, OR 1.69, P =0.0005). References It is unclear whether the reduced mtDNA copy number in gout is a result of the gouty pathology directly (i.e. the reduced mtDNA copy number is caused by the inflammatory processes underlying gout) or whether the reduced mtDNA copy number contributes to the risk of gout. The latter possibility is supported by the increase in risk using hyperuricemic controls suggesting that reduced mtDNA copy number plays a role in inflammation. Given emerging research is showing that mitochondria play a central role in the induction of the NLRP3 inflammasome, in particular with the co-localisation of the NLRP3 and ASC sub-units, a process essential for the generation of IL-1β, these observations may be significant. Exploring mitochondrial genetic variation may further elucidate the inflammatory processes underlying gout. Acknowledgement The New Zealand Health Research Council, Lottery Health New Zealand, Arthritis New Zealand and the National Institute of Health (United States) are thanked for funding this study. Disclosure of Interest T. Merriman Grant/research support from: ArdeaBio, A. Gosling: None declared, J. Boocock: None declared, N. Dalbeth Grant/research support from: AstraZeneca, Fonterra, ArdeaBio, Consultant for: Menarini, Takeda, Teijin, Pfizer, Crealta, Cymabay, L. Stamp: None declared, E. Stahl: None declared, H. Choi: None declared, L. Matisoo-Smith: None declared

Inhibition of NADH oxidase activity of plasma membranes isolated from a series of human xenografts and cell lines by the antitumor sulfonylurea, N-(4-methylphenylsulfonyl)-N′-(4-chlorophenyl) urea (LY 181984), correlated with the ability of the sulfonylurea to inhibit cell growth. Growth of rat kidney cells either untransformed or transformed with Kirsten-ras (K-ras) were unaffected by the sulfonylurea. Similarly, the NADH oxidase activity of isolated plasma membranes from K-ras transformed cells was unaffected by LY 181984. In contrast, when transformed with Harvey-ras (H-ras), both growth and NADH oxidase activity were inhibited. With the inactive but structurally related LY 181985 (N-4-methylphenyl-sulfonyl)-N′-(phenyl)urea), neither growth nor plasma membrane NADH oxidase activity of either sulfonylurea-susceptible or -resistant tissues or cell lines was inhibited. Both sulfonylureas were inactive with rat liver plasma membranes but NADH oxidase activity of plasma membranes and growth with HeLa cells was inhibited by the active (LY 181984) but not by the inactive (LY 181985) sulfonylurea. The findings suggest a possible correlation between inhibition of plasma membrane NADH oxidase activity by the antitumor sulfonylureas and their oncolytic action.

Objectives. To describe the national demographics, comorbidities and mortality of admissions associated with gout in New Zealand (NZ) from 1999 to 2009 and compare this with English gout admission data from the same period.Methods. The characteristics of all admissions due to or complicated by gout in NZ from 1999 to 2009 were analysed. These findings were then compared with the wider NZ population and the English National Health Service (NHS) gout admission rates from 1999 to 2009.Results. There were 10 241 admissions due to gout (group A) and 34 318 admissions complicated by gout (group B) in NZ from 1999 to 2009. There were 32 741 admissions due to gout in England over the same period. Gout admissions rose at 5.5% per year in NZ and at 7.2% per year in England over the study period. NZ gout patients admitted to hospital were more likely to be Maori or a Pacific Islander and had 3-7 comorbidities. Multiple admissions were common with 1479 NZ gout patients admitted more than once. Comorbidities varied between the NZ groups A and B: hypertension (19-39%), renal disease (16-27%) and diabetes mellitus (20-27%) were common. Heart failure (27.6%) and cardiovascular disease (39.1%) were common in those who had gout complicating their hospital admission. This group also had poorer survival compared with those admitted primarily for gout.Conclusion. This is the first study to describe the epidemiology of admissions associated with gout across an entire country. Admissions are rising in both countries studied and those admitted in NZ have a high rate of comorbidity and re-admission.

Sir, Gout is characterized by inflammatory attacks in joints, triggered by the deposition of crystallized monosodium urate as a result of hyperuricaemia. It is multi-factorial with genetic and environmental predisposition [1]. Two loci encoding urate transporters have been confirmed as associated with gout: SLC2A9 and ABCG2 [2–4].

SummaryBackgroundPulmonary disease is a well recognised and important extra-articular manifestation of rheumatoid arthritis (RA). The objective of this study was to determine the prevalence of airway and parenchymal abnormalities in newly diagnosed patients with RA and to correlate these with clinical measures of RA severity and laboratory tests.Methods60 patients with a new (symptom duration

The IL-23R region is associated with a number of non-infectious inflammatory conditions including inflammatory bowel disease, ankylosing spondylitis and psoriasis,1,–,3 and albeit with less consistent evidence, rheumatoid arthritis (RA).4,–,6 Association of rs1343151 (G→A) with RA, but not rs1004819/rs10489629/rs2201841 , has been reported in European and New Zealand sample sets;5 none of rs3212227/rs6887695/rs7530511 was associated in European and North American sample sets,6 and rs7517847 was not associated in meta-analysed European and New Zealand sample sets.4 Given the immunological evidence pointing to the importance of the Th17–IL-23 axis in inflammation and autoimmunity,7 and the unresolved question of whether or not IL-23R is associated with RA, we further investigated association of IL-23R with RA in white European Caucasian case–control sample sets (cases ascertained …

Contains fulltext : 107808.pdf (Publisher’s version ) (Closed access) There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of /= 2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.

BACKGROUND: Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS: We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS: In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION: Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children. FUNDING: Bill and Melinda Gates Foundation.

Phosphonic acid was more effective in inhibiting the production of sporangia of Phytophthora clandestina in sterile pond water (ED 50 = 1.4 p.p.m.) than it was in inhibiting the growth of mycelium of the fungus on either corn meal agar (ED 50 = 13.8 p.p.m.) or lima bean agar (ED 50 = 236 p.p.m.). Experiments under controlled environmental conditions showed that better control of tap root rot of subterranean clover caused by P. clandestina was achieved by application of potassium phosphonate to a pasteurized soil mixture than by a spray on the foliage alone. However, in a soil from a pasture, foliar sprays were more effective than soil treatments. Application of superphosphate at a rate of 250 kg/ha or higher to the soil reduced the effectiveness of sprays. In three experiments in irrigated pastures a spray of potassium phosphonate at 300 or 313 ml/ha, applied to cotyledons of subterranean clover and to soil, reduced severity of Phytophthora root rot and increased the annual production of dry matter of the legume by 1.96 to 5.11 t/ha in comparison with untreated controls

To the Editor: Histoplasmosis occurs after infection with the dimorphic fungus Histoplasma capsulatum (1–6). Patients become ill after they inhale soil contaminated with H. capsulatum (1,2). Most infections are asymptomatic or result in mild illness not determined to be histoplasmosis (1,2). Symptoms usually develop 3–14 days after exposure and range from self-limited pneumonia to severe disseminated disease requiring antifungal therapy (2,7).

Perianal Crohn's disease (CD) affects around one-quarter of CD patients and represents a distinct disease phenotype. The objective of this study was to investigate a large population-based cohort of inflammatory bowel disease (IBD) patients to identify clinical and genetic risk factors for perianal CD.Data were collected in the Canterbury IBD database, estimated to include 91% of all patients with IBD in Canterbury, New Zealand. Genotyping was performed for selected loci previously demonstrated to be associated with CD. Patients with perianal disease were then compared with both CD patients without perianal disease and healthy controls to assess the presence of potential phenotypic, environmental, and genetic risk factors.Of the 715 CD patients in the database, 190 (26.5%) had perianal disease. In all, 507 patients with genotype data available were analyzed. Perianal disease was associated with younger age at diagnosis (P0.0001), complicated intestinal disease (P0.0001), and ileal disease location (P = 0.002). There was no association with gender, ethnicity, smoking, or breast feeding. Genotype analysis revealed an association with the neutrophil cytosolic factor 4 (NCF4) gene compared with both non-perianal CD patients (odds ratio (OR): 1.47; 95% confidence interval (CI): 1.08-1.99) and healthy controls (OR: 1.47; 95% CI: 1.10-1.95). There was no association identified with other genes, including IBD5 (OR: 0.91; 95% CI: 0.69-1.20), tumor necrosis factor α (OR: 1.04; 95% CI: 0.56-1.85), and IRGM (immunity-related guanosine triphosphatase protein type M) (OR: 1.21; 95% CI: 0.80-1.82).This study suggests that younger age at diagnosis, complicated disease behavior, and ileal disease location are risk factors for perianal CD. In addition, this paper represents the first report of an association of the NCF4 gene with perianal disease.