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

McKinney, Cushla; Stamp, Lisa K.; Dalbeth, Nicola; Topless, Ruth; Day, Richard O.; Kannangara, Diluk R. W.; Williams, Kenneth M.; Janssen, Matthijs; Jansen, T.L.Th.A.; Joosten, Leo A. B.; Radstake, Timothy R D J; Riches, Philip L.; Tausche, Anne‐Kathrin; Lioté, Frédéric; So, Alexander; Merriman, Tony R.

doi:10.1186/s13075-015-0802-3

Cited by 59 publications

(62 citation statements)

References 59 publications

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“…This study identified that CARD8 rs2043211 was not associated with increased gout risk, which is in contrast to the known difference of genetic distribution of this SNP in the Chinese and European gout population (67). As far as we know, this study is the first to determine genetic association between the P2X7R SNP and gout patients, revealing that P2X7R polymorphism did not increase the risk of gout in our study population.…”

Section: Discussioncontrasting

confidence: 79%

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Genetic Association for P2X7R rs3751142 and CARD8 rs2043211 Polymorphisms for Susceptibility of Gout in Korean Men: Multi-Center Study

Lee

Oh³

et al. 2016

J Korean Med Sci

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The aim of this study was to determine the association between P2X7R rs3751142 and CARD8 rs2043211 polymorphisms and gout susceptibility in male Korean subjects. This study enrolled a total of 242 male patients with gout and 280 healthy controls. The polymorphisms of two individual genes including rs3751142(C>A) in the P2X7R gene and rs2043211(A>T) in the CARD8 gene were assessed using Taq-Man analysis. Statistical analyses were performed using the Chi-square test, Kruskal-Wallis test, and logistic regression analyses. A difference in genotypic frequency of the P2X7R rs3751142 and CARD8 rs2043211 genes was not detected between gout and control patients. Clinical parameters including age, onset age, disease duration, body mass index, and serum uric acid levels were not different among the three genotypes for either P2X7R or CARD8 (P > 0.05 for all). A pair-wise comparison of P2X7R rs3751142 and CARD8 rs2043211 genotype combinations revealed that subjects with the CA P2X7R rs3751142 genotype and the TT CARD8 rs2043211 genotype had a trend toward a higher risk of gout compared to the CC/AA combination (P = 0.056, OR = 2.618, 95% CI 0.975 - 7.031). In conclusion, this study revealed that genetic variability of the P2X7R rs3751142 and CARD8 rs2043211 genes might, in part, be associated with susceptibility for gout.

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Section: Discussioncontrasting

confidence: 79%

“…Although the precise pathogenic mechanism of gout has not been clearly determined, several crucial proteins such as the purinergic receptor P2X ligand-gated ion channel 7 ( P2X7R ) (345) and caspase activation and recruitment domain 8 ( CARD8 ) (67) proteins are known to be responsible for the pathogenesis of gout.…”

Section: Introductionmentioning

confidence: 99%

Genetic Association for P2X7R rs3751142 and CARD8 rs2043211 Polymorphisms for Susceptibility of Gout in Korean Men: Multi-Center Study

Lee

Oh³

et al. 2016

J Korean Med Sci

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“…Previous studies have identified polymorphisms in the NALP3 inflammasome, TLR-4, CARD8, IL-1β, IL-18, and CD14 genes to be associated with gout [30–35]. A cross sectional study examining genetic association in European and Maori New Zealanders and Caucasian controls found a significant multiplicative interaction between polymorphisms in the CARD8 and IL-1β genes and gout, further supporting the role of a pro-inflammatory genotype in gout pathogenesis [33]. Thus, further studies are required to understand if these genetic changes explain the propensity for developing recurrent gout attacks, and for gout attacks to be triggered by pro-inflammatory dietary and lifestyle factors.…”

Section: Discussionmentioning

confidence: 81%

Triggers of acute attacks of gout, does age of gout onset matter? A primary care based cross-sectional study

et al. 2017

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ObjectivesTo determine the proportion of people with gout who self-report triggers of acute attacks; identify the commonly reported triggers, and examine the disease and demographic features associated with self-reporting any trigger(s) of acute attacks of gout.MethodsIndividuals with gout were asked to fill a questionnaire enquiring about triggers that precipitated their acute gout attacks. Binary logistic regression was used to compute odds ratio (OR) and 95% confidence intervals (CI) to examine the association between having ≥1 self-reported trigger of acute gout and disease and demographic risk factors and to adjust for covariates. All statistical analyses were performed using STATA.Results550 participants returned completed questionnaires. 206 (37.5%) reported at least one trigger of acute attacks, and less than 5% reported >2 triggers. Only 28.73% participants reported that their most recent gout attack was triggered by dietary or lifestyle risk factors. The most frequently self-reported triggers were alcohol intake (14.18%), red-meat or sea-food consumption (6%), dehydration (4.91%), injury or excess activity (4.91%), and excessively warm or cold weather (4.36% and 5.45%). Patients who had onset of gout before the age of 50 years were significantly more likely to identify a trigger for precipitating their acute gout attacks (aOR (95%CI) 1.73 (1.12–2.68) after adjusting for covariates.ConclusionMost people with gout do not identify any triggers for acute attacks, and identifiable triggers are more common in those with young onset gout. Less than 20% people self-reported acute gout attacks from conventionally accepted triggers of gout e.g. alcohol, red-meat intake, while c.5% reported novel triggers such as dehydration, injury or physical activity, and weather extremes.

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“…A variant in TLR4 , that likely influences TLR4 expression, has been associated with gout in two studies 97,98. Two SNPs in NLRP3-related genes have been associated with gout 99–101. The first one is a nonsense variation in the caspase recruitment domain-containing protein 8 (CARD8, rs2043211 ), a negative regulator of the NLRP3 inflammasome.…”

Section: Mechanistic Aspects Of Abcg2 In Inflammationmentioning

confidence: 99%

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

Cleophas¹,

Joosten²,

Stamp³

et al. 2017

PGPM

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As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance.

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

Cited by 59 publications

References 59 publications

Genetic Association for P2X7R rs3751142 and CARD8 rs2043211 Polymorphisms for Susceptibility of Gout in Korean Men: Multi-Center Study

Genetic Association for P2X7R rs3751142 and CARD8 rs2043211 Polymorphisms for Susceptibility of Gout in Korean Men: Multi-Center Study

Triggers of acute attacks of gout, does age of gout onset matter? A primary care based cross-sectional study

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

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