Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout

Introduction: The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1 beta (IL-1 beta) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1 beta axis for association with gout. Methods: 1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Maori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set. Results: Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P <0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8. Conclusion: There is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1 beta-the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1 beta expression leading to increased production of mature IL-1 beta in gout

The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets

Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism rs2149356 in TLR4 is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Māori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, P = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, P = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion TLR4 SNP rs2143956 associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association

The mechanisms of hyperuricaemia and gout, and its treatment with xanthine oxidoreductase inhibitors.

Hyperuricaemia (serum urate (SU) concentrations ≥ 0.42 mmol/L) is the most important risk factor for gout, a common form of inflammatory arthritis. First choice treatment for gout is the xanthine oxidoreductase (XOR) inhibitor, allopurinol. Febuxostat recently became the second member of this class. Unfortunately, current treatment practices are suboptimal and the prevalence of gout and hyperuricaemia is increasing. The overall aim of the thesis was to examine risk factors for hyperuricaemia and to investigate methods to optimise XOR treatment for gout.The first study aimed to explore the relative influences of factors that increase the risk of hyperuricaemia. Renal, extra-renal, dietary and metabolic factors and male sex were discovered to strongly contribute to the risk of hyperuricaemia. Importantly, no association was found between the fractional clearance of urate and the ABCG2 Q141K genotype, each a marker of renal and intestinal clearance pathways, respectively. Reduced intestinal clearance of urate has a much greater risk of causing hyperuricaemia than previously conceived.The second study aimed to analyse the dose- and concentration-response relationships of allopurinol and its active metabolite, oxypurinol, with SU concentration. An allopurinol dose-response model incorporating a ‘resistant’ concentration of SU adequately described the urate-lowering effect of allopurinol. The dose required to reach a target SU concentration was dependent on the baseline SU concentration but not renal function. From this, a novel nomogram was developed to individualise allopurinol dosage.The final study aimed to examine the dose-response relationship of febuxostat with SU concentration.Again, analogous to the finding with allopurinol, the dose of febuxostat required to reach target SUconcentration was dependent on the baseline SU concentration. By contrast with allopurinol, renal function was an influential covariate that significantly improved this relationship. A ‘resistant’ concentration of SU for febuxostat was identified but was lower than that for allopurinol. As the ‘resistant’ concentration of SU identified in both models lie below the clinical target SU concentration, there is unlikely to be a clinically meaningful difference between these drugs.Overall, the findings from this thesis provide a greater understanding of the mechanisms of hyperuricaemia and how we can individualise XOR inhibitor therapies to optimise treatment of gout

Exploring current and potential roles of Australian community pharmacists in gout management: a qualitative study

Abstract Background Gout is an increasingly prevalent form of inflammatory arthritis. Although effective treatments for gout exist, current management is suboptimal due to low medication adherence rates and treatments that are non-concordant with guidelines. Medications are the mainstay and most effective form of gout management. Thus, there is potential for community pharmacists to play an important primary health care role in gout management, however their current role and their potential to improve management of gout treatment is currently unclear. The purpose of the study is to explore the views of Australian pharmacists on their roles in gout management and to identify factors influencing their involvement in gout management. Methods A convenience sample of community pharmacists were invited to participate using a snowballing recruitment strategy. Semi-structured, face-to-face interviews were conducted with 15 pharmacists of varying age, gender and pharmacy experience. Interviews focused on pharmacists’ experiences of managing gout, interactions with people living with gout and their perceived roles and responsibilities in gout management. Interviews were transcribed verbatim and independently analysed by two reviewers to identify themes. Results The main role of pharmacists reported in gout management was providing patient education. The greatest facilitator to pharmacists involvement in gout management was identified to be pharmacists’ good understanding of gout and its management. Barriers to pharmacists involvement were identified to be difficulties in monitoring adherence to gout medications, low priority given to gout in the pharmacy compared to other chronic health conditions, and lack of specific training and/or continuing education in gout prevention and management. Conclusions Pharmacists can expand their primary health care role in gout management, particularly in the area of ongoing provision of education to people living with gout and in monitoring medication adherence in patients. However, a number of barriers need to be overcome including difficulties in monitoring patient adherence to medications, ensuring a higher priority is given to chronic gout management and providing continuing training to community pharmacists about gout. Implications for pharmacist practice include initiating conversations about medication adherence and education when dispensing medications and undertaking continuing education in gout

Barriers to care in gout : from prescriber to patient

Objective. To explore the understanding of gout and its management by patients and general practitioners (GP), and to identify barriers to optimal gout care. Methods. Semistructured interviews were conducted with 15 GP and 22 patients in Sydney, Australia. Discussions were focused on medication adherence, experiences with gout, and education and perceptions around interventions for gout. Interviews were audio recorded, transcribed verbatim, and analyzed for themes using an analytical framework. Results. Adherence to urate-lowering medications was identified as problematic by GP, but less so by patients with gout. However, patients had little appreciation of the risk of acute attacks related to variable adherence. Patients felt stigmatized that their gout diagnosis was predominantly related to perceptions that alcohol and dietary excess were causal. Patients felt they did not have enough education about gout and how to manage it. A manifestation of this was that uric acid concentrations were infrequently measured. GP were concerned that they did not know enough about managing gout and most were not familiar with current guidelines for management. For example and importantly, the strategies for reducing the risk of acute attacks when commencing urate-lowering therapy (ULT) were not well appreciated by GP or patients. Conclusion. Patients and GP wished to know more about gout and its management. Greater success in establishing and maintaining ULT will require further and better education to substantially benefit patients. Also, given the prevalence, and personal and societal significance of gout, innovative approaches to transforming the management of this eminently treatable disease are needed

Mobile applications to enhance self-management of gout

Background: Gout is an arthritic condition that is characterised by extremely painful, debilitating acute attacks and eventual joint and organ damage if not controlled. Despite the availability of very effective therapies that, if adhered to, will prevent acute attacks and long-term damage, the disorder is increasingly prevalent. There is an urgent need to improve self-management of gout. Objectives: Mobile health (mHealth) applications ('apps'), designed to facilitate management of chronic conditions, present novel opportunities for supporting patient self-management of gout. The aim of this review was to assess features of available gout management apps designed to assist consumers in managing their gout and their consistency with guidelines for gout management. Methods: English-language, smart-device apps designed to assist self-management of gout were identified using search term "gout" and downloaded from Apple and Google Play app stores. To be included in the review, apps had to allow users to monitor their gout disease (e.g. serum uric acid (sUA) tracking, record acute attacks) and/or educate patients about gout. Investigators derived patient-focused recommendations for gout management from contemporary guidelines. Features of reviewed apps were independently assessed by two reviewers for their facilitation of these recommendations. Results: The search identified 57 apps possibly relevant to gout management, of which six met the inclusion criteria. One app incorporated all recommendations for patient-focused gout management from guidelines including monitoring sUA, recording attacks and lifestyle advice. However, the majority of these elements were not functional within the app, and instead required users to manually complete printouts. Conclusions: Currently, only one app exists that includes all recommendations to facilitate patient self-management of gout, however some features can only be actioned manually. Given the lack of progress in achieving better patient outcomes and the promise of mHealth interventions to deliver significant gains, new or updated gout management apps are required to promote successful self-management of this chronic disease.8 page(s

Individualising the dose of allopurinol in patients with gout

Aims: The aims of the study were to: 1) determine if a plasma oxypurinol concentration-response relationship or an allopurinol dose-response relationship best predicts the dose requirements of allopurinol in the treatment of gout; and 2) to construct a nomogram for calculating the optimum maintenance dose of allopurinol to achieve target serum urate (SU) concentrations. Methods: A nonlinear regression analysis was used to examine the plasma oxypurinol concentration- and allopurinol dose-response relationships with serum urate. In 81 patients (205 samples), creatinine clearance (CLCR), concomitant diuretic use and SU concentrations before (UP) and during (UT) treatment were monitored across a range of allopurinol doses (D, 50-700 mg daily). Plasma concentrations of oxypurinol (C) were measured in 47 patients (98 samples). Models (n = 47 patients) and predictions from each relationship were compared using F-tests, r2 values and paired t-tests. The best model was used to construct a nomogram. Results: The final plasma oxypurinol concentration-response relationship (UT=UP-C*(UP-UR)/(ID50+C), r2 = 0.64) and allopurinol dose-response relationship (UT=UP-D*(UP-UR)/(ID50+D), r2 = 0.60) did not include CLCR or diuretic use as covariates. There was no difference (P = 0.87) between the predicted SU concentrations derived from the oxypurinol concentration- and allopurinol dose-response relationships. The nomogram constructed using the allopurinol dose-response relationship for all recruited patients (n = 81 patients) required pretreatment SU as the predictor of allopurinol maintenance dose. Conclusions: Plasma oxypurinol concentrations, CLCR and diuretic status are not required to predict the maintenance dose of allopurinol. Using the nomogram, the maintenance dose of allopurinol estimated to reach target concentrations can be predicted from UP

Additional file 1: of Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout

Association power curves. Figure presenting the power of the genetic association analysis. (PPTX 161 kb