Publications by authors named "Amanda Phipps-Green"

43 Publications

Association of low-level environmental exposure to cadmium and lead with gout flare using a cohort study design.

Chemosphere 2021 Apr 27;280:130648. Epub 2021 Apr 27.

Institute of Metabolic Diseases, Qingdao University, Qingdao, 266071, China; Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, China; Medical Research Center, The Affiliated Hospital of Qingdao University, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, China. Electronic address:

Cadmium (Cd) and lead (Pb) are toxic heavy metals with endocrine-disrupting properties. We investigated the associations of low-level environmental exposure to Cd/Pb and gout status (intercritical gout, gout flare and combined gout) in a cohort study. We measured by ICP-MS the levels of Cd and Pb in blood (Cd-B and Pb-B) and urine (Cd-U and Pb-U) from 408 participants with blood and 346 participants with urine samples recruited from a hospital gout clinic. The median levels of Cd-B and Pb-B (in μg/L) in the gout flare group were 0.87 (range 0.41-2.49) and 31.54 (25.38-41.46), respectively, and the median levels of Cd-U and Pb-U in the gout flare group were 1.05 (0.69-1.91) and 3.86 (3.49-4.44), respectively. These medians were significantly higher than those in the control or intercritical groups (P < 0.05). For Cd-B in tertile 2 (T2) and Cd-U in tertile 3, Cd levels were significantly associated with gout flare status compared to the reference tertile 1 (OR = 4.3, P = 0.041 and OR = 25.1, P = 0.002, respectively) after adjustment under Model 3. For Pb-U, the risk of gout flare status was significantly higher in T2 (OR = 51.0, P = 0.002) compared to the T1 under Model 3. Our results show that median levels of Cd-B, Pb-B, Cd-U and Pb-U in the gout flare group were significantly higher than participants without gout or with gout but in the intercritical period. We provide evidence that the risk of gout flare status is associated with increased Cd levels, and that blood and urine levels of Cd are a risk factor for gout flare status.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130648DOI Listing
April 2021

Gout, Rheumatoid Arthritis, and the Risk of Death Related to Coronavirus Disease 2019: An Analysis of the UK Biobank.

ACR Open Rheumatol 2021 Apr 15. Epub 2021 Apr 15.

University of Otago, Dunedin, New Zealand, and University of Alabama at Birmingham.

Objectives: The objectives for this study were to assess whether gout and/or rheumatoid arthritis (RA) are risk factors for coronavirus disease 2019 (COVID-19) diagnosis and to assess whether gout and/or RA are risk factors for death from COVID-19.

Methods: We used data from the UK Biobank. Multivariable-adjusted logistic regression was employed in the following analyses: analysis A, to test for association between gout and/or RA and COVID-19 diagnosis (n = 473,139); analysis B, to test for association between gout and/or RA and death from COVID-19 in a case-control cohort of people who died of or survived COVID-19 (n = 2059); analysis C, to test for association between gout and/or RA and death from COVID-19 in the entire UK Biobank cohort (n = 473,139).

Results: RA, but not gout, was associated with COVID-19 diagnosis in analysis A. Neither RA nor gout was associated with risk of death in the group diagnosed with COVID-19 in analysis B. However, RA was associated with risk of death related to COVID-19 by using the UK Biobank cohort in analysis C, independent of comorbidities and other measured risk factors (odds ratio [OR] 1.9; 95% confidence interval CI 1.2-3.0). Gout was not associated with death related to COVID-19 in the same UK Biobank analysis (OR 1.2; 95% CI 0.8-1.7).

Conclusion: RA is a risk factor for death from COVID-19 by using the UK Biobank cohort. These findings require replication in larger data sets that also allow for inclusion of a wider range of factors.
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http://dx.doi.org/10.1002/acr2.11252DOI Listing
April 2021

Genetic Polymorphisms on , and in Young Adults: Lack of Association With Alcohol Consumption.

Front Psychiatry 2020 7;11:549429. Epub 2020 Dec 7.

Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Risk behaviors for young adults such as alcohol use are associated with increased risk of morbidity and mortality. Patterns of risk behavior may be genetically determined and vary between genders. Previous studies in both young adults and heavy drinking adult samples have demonstrated that some genotypes, such as A118G, Val158Met and Taq1A and C52IT, may predict addictive behaviors including alcohol consumption and impulsivity, although results have been mixed. This study aimed to investigate the predictive relationship of these four single nucleotide polymorphisms (SNPs) prospectively on student patterns of drinking using a micro-longitudinal daily diary design in a sample of 628 young adults ages 18-25 of predominantly of European ethnicity. Linear mixed models were used to examine the effect of SNPs on the number of drinks per drinking session with gender as a moderating variable. There were no main effects for genotype on alcohol consumption, nor for gender × genotype for any of the SNPs. There was a trend for an effect of the Taq1A on the number of drinks per drinking day and for the interaction of gender and Taq1A on the number of drinks per drinking day. These findings suggest that the Taq1A A118G, C521T, or Val158Met polymorphisms, are not associated with alcohol consumption in young adults, although there may be a relationship between Taq1A and alcohol consumption in young adult males.
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http://dx.doi.org/10.3389/fpsyt.2020.549429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750453PMC
December 2020

Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects.

J Hum Genet 2021 Feb 10;66(2):161-169. Epub 2020 Aug 10.

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.
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http://dx.doi.org/10.1038/s10038-020-0821-zDOI Listing
February 2021

The ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion.

Nat Commun 2020 06 2;11(1):2767. Epub 2020 Jun 2.

Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.

The pathophysiological nature of the common ABCG2 gout and hyperuricemia associated variant Q141K (rs2231142) remains undefined. Here, we use a human interventional cohort study (ACTRN12615001302549) to understand the physiological role of ABCG2 and find that participants with the Q141K ABCG2 variant display elevated serum urate, unaltered FEUA, and significant evidence of reduced extra-renal urate excretion. We explore mechanisms by generating a mouse model of the orthologous Q140K Abcg2 variant and find male mice have significant hyperuricemia and metabolic alterations, but only subtle alterations of renal urate excretion and ABCG2 abundance. By contrast, these mice display a severe defect in ABCG2 abundance and function in the intestinal tract. These results suggest a tissue specific pathobiology of the Q141K variant, support an important role for ABCG2 in urate excretion in both the human kidney and intestinal tract, and provide insight into the importance of intestinal urate excretion for serum urate homeostasis.
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http://dx.doi.org/10.1038/s41467-020-16525-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265540PMC
June 2020

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout.

Arthritis Res Ther 2020 03 12;22(1):45. Epub 2020 Mar 12.

Department of Biochemistry, University of Otago, Box 56, Dunedin, New Zealand.

Background: The ABCG2 Q141K (rs2231142) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is ~ 60% that of SLC2A9, yet the effect size on gout is greater. We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls.

Methods: We analysed 1699 European gout cases and 14,350 normouricemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables.

Results: In Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR = 1.85, P = 3.8E and OR = 1.85, P = 1.3E, respectively). There was evidence for an effect of 141K in determining HU in European (OR = 1.56, P = 1.7E) but not in Polynesian (OR = 1.49, P = 0.057). For SLC2A9 rs11942223, the T allele associated with gout in the presence of HU in European (OR = 1.37, P = 4.7E), however significantly weaker than ABCG2 rs2231142 141K (P = 0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and rs10011796. Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian (P = 0.009) and 2.6-fold in European (P = 9.9E). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian (P = 2.5E).

Conclusion: These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.
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http://dx.doi.org/10.1186/s13075-020-2136-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069001PMC
March 2020

Do Serum Urate-associated Genetic Variants Influence Gout Risk in People Taking Diuretics? Analysis of the UK Biobank.

J Rheumatol 2020 11 1;47(11):1704-1711. Epub 2020 Feb 1.

R.K. Narang, MBChB, G. Gamble, MSc, N. Dalbeth, FRACP, Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland;

Objective: The aim of this study was to determine whether serum urate (SU)-associated genetic variants differ in their influence on gout risk in people taking a diuretic compared to those not taking a diuretic.

Methods: This research was conducted using the UK Biobank Resource (n = 359,876). Ten SU-associated single-nucleotide polymorphisms (SNP) were tested for their association with gout according to diuretic use. Gene-diuretic interactions for gout association were tested using a genetic risk score (GRS) and individual SNP by logistic regression adjusting for relevant confounders.

Results: After adjustment, use of a loop diuretic was positively associated with prevalent gout (OR 2.34, 95% CI 2.08-2.63), but thiazide diuretics were inversely associated with prevalent gout (OR 0.60, 95% CI 0.55-0.66). Compared with a lower GRS (< mean), a higher GRS (≥ mean) was positively associated with gout in those not taking diuretics (OR 2.63, 2.49-2.79), in those taking loop diuretics (OR 2.04, 95% CI 1.65-2.53), in those taking thiazide diuretics (OR 2.70, 2.26-3.23), and in those taking thiazide-like diuretics (OR 2.11, 95% CI 1.37-3.25). No nonadditive gene-diuretic interactions were observed.

Conclusion: In people taking diuretics, SU-associated genetic variants contribute strongly to gout risk, with a similar effect to that observed in those not taking a diuretic. These findings suggest that the contribution of genetic variants is not restricted to people with "primary" gout, and that genetic variants can play an important role in gout susceptibility in the presence of other risk factors.
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http://dx.doi.org/10.3899/jrheum.191005DOI Listing
November 2020

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

Rheumatology (Oxford) 2020 09;59(9):2544-2549

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, AucklandNew Zealand.

Objective: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout.

Methods: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed.

Results: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83).

Conclusion: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.
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http://dx.doi.org/10.1093/rheumatology/kez685DOI Listing
September 2020

Differential DNA Methylation of Networked Signaling, Transcriptional, Innate and Adaptive Immunity, and Osteoclastogenesis Genes and Pathways in Gout.

Arthritis Rheumatol 2020 05 23;72(5):802-814. Epub 2020 Mar 23.

University of California, San Diego and San Diego VAMC.

Objective: In gout, autoinflammatory responses to urate crystals promote acute arthritis flares, but the pathogeneses of tophi, chronic synovitis, and erosion are less well understood. Defining the pathways of epigenomic immunity training can reveal novel pathogenetic factors and biomarkers. The present study was undertaken to seminally probe differential DNA methylation patterns utilizing epigenome-wide analyses in patients with gout.

Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from a San Diego cohort of patients with gout (n = 16) and individually matched healthy controls (n = 14). PBMC methylome data were processed with ChAMP package in R. ENCODE data and Taiji data analysis software were used to analyze transcription factor (TF)-gene networks. As an independent validation cohort, whole blood DNA samples from New Zealand Māori subjects (n = 13 patients with gout, n = 16 control subjects without gout) were analyzed.

Results: Differentially methylated loci clearly separated gout patients from controls, as determined by hierarchical clustering and principal components analyses. IL23R, which mediates granuloma formation and cell invasion, was identified as one of the multiple differentially methylated gout risk genes. Epigenome-wide analyses revealed differential methylome pathway enrichment for B and T cell receptor signaling, Th17 cell differentiation and interleukin-17 signaling, convergent longevity regulation, circadian entrainment, and AMP-activated protein kinase signaling, which are pathways that impact inflammation via insulin-like growth factor 1 receptor, phosphatidylinositol 3-kinase/Akt, NF-κB, mechanistic target of rapamycin signaling, and autophagy. The gout cohorts overlapped for 37 (52.9%) of the 70 TFs with hypomethylated sequence enrichment and for 30 (78.9%) of the 38 enriched KEGG pathways identified via TFs. Evidence of shared differentially methylated gout TF-gene networks, including the NF-κB activation-limiting TFs MEF2C and NFATC2, pointed to osteoclast differentiation as the most strongly weighted differentially methylated pathway that overlapped in both gout cohorts.

Conclusion: These findings of differential DNA methylation of networked signaling, transcriptional, innate and adaptive immunity, and osteoclastogenesis genes and pathways suggest that they could serve as novel therapeutic targets in the management of flares, tophi, chronic synovitis, and bone erosion in patients with gout.
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http://dx.doi.org/10.1002/art.41173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323903PMC
May 2020

Population-specific factors associated with fractional excretion of uric acid.

Arthritis Res Ther 2019 11 12;21(1):234. Epub 2019 Nov 12.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1023, New Zealand.

Background: Reduced renal clearance of uric acid is a major contributor to hyperuricemia. The aim of this study was to examine clinical and genetic variables associated with fractional excretion of uric acid (FEUA).

Methods: Participants (with and without gout) in the Genetics of Gout in Aotearoa study with available genotyping and FEUA data were included (n = 1713). Ten FEUA-associated loci detected within a genome-wide association study for serum urate in a European population were analysed. A polygenic score for FEUA was calculated in each ancestry group to model the cumulative effects of the genetic variants on FEUA. Associations between FEUA and both clinical variables and polygenic score were tested using linear regression models.

Results: The mean (SD) FEUA was 5.13 (2.70) % in Eastern Polynesian participants, 4.70 (5.89) % in Western Polynesian participants, and 5.89 (2.73) % in New Zealand European participants. Although association with FEUA was observed for SLC2A9 rs11942223 in New Zealand European participants (P = 2.39 × 10), this association was not observed in Eastern or Western Polynesian participants. The polygenic score was positively associated with FEUA in all ancestry groups. In New Zealand European participants, body mass index, diuretic use, polygenic score, and male sex were associated with FEUA and explained 22% of FEUA variance in the regression model. In Eastern and Western Polynesian participants, the tested variables explained 10% and 4% of FEUA variance respectively.

Conclusions: Both clinical and genetic variables contribute to renal clearance of uric acid. SLC2A9 exerts effects on FEUA variance in people of European ancestry, but not in those of Polynesian ancestry. There is a large unexplained variance in FEUA, particularly in people of Polynesian ancestry.
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http://dx.doi.org/10.1186/s13075-019-2016-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852918PMC
November 2019

mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy?

Ann Rheum Dis 2019 05 27;78(5):663-671. Epub 2019 Feb 27.

Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: Gout is the most common inflammatory arthritis worldwide, and patients experience a heavy burden of cardiovascular and metabolic diseases. The inflammation is caused by the deposition of monosodium urate (MSU) crystals in tissues, especially in the joints, triggering immune cells to mount an inflammatory reaction. Recently, it was shown that MSU crystals can induce mechanistic target of rapamycin (mTOR) signalling in monocytes encountering these crystals in vitro. The mTOR pathway is strongly implicated in cardiovascular and metabolic disease. We hypothesised that inhibiting this pathway in gout might be a novel avenue of treatment in these patients, targeting both inflammation and comorbidities.

Methods: We used a translational approach starting from ex vivo to in vitro and back to in vivo.

Results: We show that ex vivo immune cells from patients with gout exhibit higher expression of the mTOR pathway, which we can mimic in vitro by stimulating healthy immune cells (B lymphocytes, monocytes, T lymphocytes) with MSU crystals. Monocytes are the most prominent expressers. By using live imaging, we demonstrate that monocytes, on encountering MSU crystals, initiate cell death and release a wide array of proinflammatory cytokines. By inhibiting signalling with metformin or rapamycin, a reduction of cell death and release of inflammatory mediators was observed. Consistent with this, we show that patients with gout who are treated with the mTOR inhibitor metformin have a lower frequency of gout attacks.

Conclusions: We propose mTOR inhibition as a novel therapeutic target of interest in gout treatment.
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http://dx.doi.org/10.1136/annrheumdis-2018-214656DOI Listing
May 2019

The Oxytocin Receptor Gene () Variant rs53576 Is Not Related to Emotional Traits or States in Young Adults.

Front Psychol 2018 11;9:2548. Epub 2018 Dec 11.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

To understand the genetic underpinnings of emotion, researchers have studied genetic variants in the oxytocin system, a hormone and neurotransmitter important to socio-emotional functioning. The oxytocin receptor gene () variant rs53576 has been associated with emotional traits such as positive affect and related constructs such as optimism and self-esteem. Individuals carrying the A allele (AG and AA genotypes) of rs53576 have been found to score lower in these traits when compared to GG homozygotes, although not always. Given recent mixed evidence regarding this polymorphism, replication of these associations is critical. Using a cross-sectional design, the present study tested the association between rs53576 and a wide variety of emotional traits and states in a sample of 611 young adults ages 18 - 25 of various ethnicities (European, Asian, Māori/Pacific Islander, other). Participants completed standard trait measures of positive and negative affect, depressive symptoms, life engagement, psychological well-being, optimism, and self-esteem. They also completed state measures of positive and negative affect and life engagement for 13-days using Internet daily diaries. Controlling for ethnicity and gender, variation at the variant rs53576 obtained from blood samples was not related to any of the emotional traits or states. This null finding occurred despite measuring emotions in "near to real time" using daily diaries and having sufficient power to detect a medium effect size difference between homozygous genotype groups. These findings suggest that variation at the rs53576 locus may not be as involved in emotional differences as initial studies suggested.
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http://dx.doi.org/10.3389/fpsyg.2018.02548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297827PMC
December 2018

A non-coding genetic variant maximally associated with serum urate levels is functionally linked to HNF4A-dependent PDZK1 expression.

Hum Mol Genet 2018 11;27(22):3964-3973

Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

The precise molecular mechanisms by which urate-associated genetic variants affect urate levels are unknown. Here, we tested for functional linkage of the maximally associated genetic variant rs1967017 at the PDZK1 locus to elevated PDZK1 expression. We performed expression quantitative trait loci (eQTL) and likelihood analyses and gene expression assays. Zebrafish were used to evaluate tissue-specific gene expression. Luciferase assays in HEK293 and HepG2 cells measured the effect of rs1967017 on transcription amplitude. Probabilistic Annotation Integrator analysis revealed rs1967017 as most likely to be causal and rs1967017 was an eQTL for PDZK1 in the intestine. The region harboring rs1967017 was capable of directly driving green fluorescent protein expression in the kidney, liver and intestine of zebrafish embryos, consistent with a conserved ability to confer tissue-specific expression. Small interfering RNA depletion of HNF4A reduced endogenous PDZK1 expression in HepG2 cells. Luciferase assays showed that the T allele of rs1967017 gains enhancer activity relative to the urate-decreasing C allele, with T allele enhancer activity abrogated by HNF4A depletion. HNF4A physically binds the rs1967017 region, suggesting direct transcriptional regulation of PDZK1 by HNF4A. Computational prediction of increased motif strength, together with our functional assays, suggests that the urate-increasing T allele of rs1967017 strengthens a binding site for the transcription factor HNF4A. Our and other data predict that the urate-raising T allele of rs1967017 enhances HNF4A binding to the PDZK1 promoter, thereby increasing PDZK1 expression. As PDZK1 is a scaffold protein for many ion channel transporters, increased expression can be predicted to increase activity of urate transporters and alter excretion of urate.
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http://dx.doi.org/10.1093/hmg/ddy295DOI Listing
November 2018

Response to: 'The reference levels of serum urate for clinically evident incident gout' by Chen and Ding.

Ann Rheum Dis 2019 05 21;78(5):e42. Epub 2018 Mar 21.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

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http://dx.doi.org/10.1136/annrheumdis-2018-213372DOI Listing
May 2019

Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis.

Ann Rheum Dis 2018 07 20;77(7):1048-1052. Epub 2018 Feb 20.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

Objectives: To provide estimates of the cumulative incidence of gout according to baseline serum urate.

Methods: Using individual participant data from four publicly available cohorts (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, and both the Original and Offspring cohorts of the Framingham Heart Study), the cumulative incidence of clinically evident gout was calculated according to baseline serum urate category. Cox proportional hazards modelling was used to evaluate the relation of baseline urate categories to risk of incident gout.

Results: This analysis included 18 889 participants who were gout-free at baseline, with mean (SD) 11.2 (4.2) years and 212 363 total patient-years of follow-up. The cumulative incidence at each time point varied according to baseline serum urate concentrations, with 15-year cumulative incidence (95% CI) ranging from 1.1% (0.9 to 1.4) for <6 mg/dL to 49% (31 to 67) for ≥10 mg/dL. Compared with baseline serum urate <6 mg/dL, the adjusted HR for baseline serum urate 6.0-6.9 mg/dL was 2.7, for 7.0-7.9 mg/dL was 6.6, for 8.0-8.9 mg/dL was 15, for 9.0-9.9 mg/dL was 30, and for ≥10 mg/dL was 64.

Conclusions: Serum urate level is a strong non-linear concentration-dependent predictor of incident gout. Nonetheless, only about half of those with serum urate concentrations ≥10mg/dL develop clinically evident gout over 15 years, implying a role for prolonged hyperuricaemia and additional factors in the pathogenesis of gout.
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http://dx.doi.org/10.1136/annrheumdis-2017-212288DOI Listing
July 2018

The impact of diuretic use and ABCG2 genotype on the predictive performance of a published allopurinol dosing tool.

Br J Clin Pharmacol 2018 05 20;84(5):937-943. Epub 2018 Feb 20.

Department of Medicine, University of Otago, Christchurch, New Zealand.

Aim: This research aims to evaluate the predictive performance of a published allopurinol dosing tool.

Methods: Allopurinol dose predictions were compared to the actual dose required to achieve serum urate (SU) <0.36 mmol l using mean prediction error. The influence of patient factors on dose predictions was explored using multilinear regression.

Results: Allopurinol doses were overpredicted by the dosing tool; however, this was minimal in patients without diuretic therapy (MPE 63 mg day , 95% CI 40-87) compared to those receiving diuretics (MPE 295 mg day , 95% CI 260-330, P < 0.0001). ABCG2 genotype (rs2231142, G>T) had an important impact on the dose predictions (MPE 201, 107, 15 mg day for GG, GT and TT, respectively, P < 0.0001). Diuretic use and ABCG2 genotype explained 53% of the variability in prediction error (R  = 0.53, P = 0.0004).

Conclusions: The dosing tool produced acceptable maintenance dose predictions for patients not taking diuretics. Inclusion of ABCG2 genotype and a revised adjustment for diuretics would further improve the performance of the dosing tool.
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http://dx.doi.org/10.1111/bcp.13516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903228PMC
May 2018

Influence of genetic variants on renal uric acid handling in response to frusemide: an acute intervention study.

RMD Open 2017 11;3(1):e000424. Epub 2017 Apr 11.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

Objectives: Genetic variation in the renal urate transporters (GLUT9) and (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 or 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<0.001) and then decreased (mean (SD) change from baseline -1.5% (2.1%) at 180 min, p<0.001). A very small increase in serum urate was observed over the study period (mean (SD) change from baseline 0.007 (0.01) mmol/L at 180 min, p<0.001). The presence of the urate-lowering and gout-protective alleles for ( and ) and () did not significantly alter the FEUA following a frusemide load. At both 60 and 180 min, change in fractional excretion of sodium was independently associated with change in FEUA (standardised β≥0.40, p<0.001).

Conclusions: The tested variants in and do not influence acute changes in renal handling of uric acid in response to frusemide.

Trial Registration Number: ACTRN12614000871640; Results.
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http://dx.doi.org/10.1136/rmdopen-2016-000424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611711PMC
April 2017

Population-Specific Resequencing Associates the ATP-Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Māori and Pacific Men.

Arthritis Rheumatol 2017 07 31;69(7):1461-1469. Epub 2017 May 31.

University of Otago, Dunedin, New Zealand.

Objective: There is no evidence for a genetic association between organic anion transporters 1-3 (SLC22A6, SLC22A7, and SLC22A8) and multidrug resistance protein 4 (MRP4; encoded by ABCC4) with the levels of serum urate or gout. The Māori and Pacific (Polynesian) population of New Zealand has the highest prevalence of gout worldwide. The aim of this study was to determine whether any Polynesian population-specific genetic variants in SLC22A6-8 and ABCC4 are associated with gout.

Methods: All participants had ≥3 self-reported Māori and/or Pacific grandparents. Among the total sample set of 1,808 participants, 191 hyperuricemic and 202 normouricemic individuals were resequenced over the 4 genes, and the remaining 1,415 individuals were used for replication. Regression analyses were performed, adjusting for age, sex, and Polynesian ancestry. To study the functional effect of nonsynonymous variants of ABCC4, transport assays were performed in Xenopus laevis oocytes.

Results: A total of 39 common variants were detected, with an ABCC4 variant (rs4148500) significantly associated with hyperuricemia and gout. This variant was monomorphic for the urate-lowering allele in Europeans. There was evidence for an association of rs4148500 with gout in the resequenced samples (odds ratio [OR] 1.62 [P = 0.012]) that was replicated (OR 1.25 [P = 0.033]) and restricted to men (OR 1.43 [P = 0.001] versus OR 0.98 [P = 0.89] in women). The gout risk allele was associated with fractional excretion of uric acid in male individuals (β = -0.570 [P = 0.01]). A rare population-specific allele (P1036L) with predicted strong functional consequence reduced the uric acid transport activity of ABCC4 by 30%.

Conclusion: An association between ABCC4 and gout and fractional excretion of uric acid is consistent with the established role of MRP4 as a unidirectional renal uric acid efflux pump.
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http://dx.doi.org/10.1002/art.40110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984252PMC
July 2017

Population-specific association between ABCG2 variants and tophaceous disease in people with gout.

Arthritis Res Ther 2017 03 7;19(1):43. Epub 2017 Mar 7.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd, Grafton, Auckland, New Zealand.

Background: Tophi contribute to musculoskeletal disability, joint damage and poor health-related quality of life in people with gout. The aim of this study was to examine the role of SLC2A9 and ABCG2 variants in tophaceous disease in people with gout.

Methods: Participants (n = 1778) with gout fulfilling the 1977 American Rheumatism Association (ARA) classification criteria, who were recruited from primary and secondary care, attended a detailed study visit. The presence of palpable tophi was recorded. SLC2A9 rs11942223, ABCG2 rs2231142 and ABCG2 rs10011796 were genotyped. Data were analysed according to tophus status.

Results: Compared to participants without tophi, those with tophi were older, had longer disease duration and higher serum creatinine, and were more likely to be of Māori or Pacific (Polynesian) ancestry. SLC2A9 rs11942223 was not associated with tophi. However, the risk alleles for both ABCG2 single nucleotide polymorphisms (SNPs) were present more frequently in those with tophi (OR (95% CI) 1.24 (1.02-1.51) for rs2231142 and 1.33 (1.01-1.74) for rs10011796, p < 0.05 for both). The effect of rs2231142 was limited to participants of Māori or Pacific ancestry (OR 1.50 (1.14-1.99), p = 0.004), with a significant effect observed in those of Western Polynesian ancestry only (OR 1.71 (1.07-2.72), p = 0.017). The rs10011796 risk allele was strongly associated with tophi in the Western Polynesian group (OR 3.76 (1.61-8.77), p = 0.002), but not in the Eastern Polynesian group (OR 0.87 (0.52-1.46), p = 0.60) nor in the non-Polynesian group (OR 1.16 (0.81-1.66), p = 0.32). The ABCG2 associations persisted in the Western Polynesian group after adjusting for serum urate, creatinine, and disease duration, and when including both ABCG2 variants in the regression models.

Conclusions: Variation in ABCG2 function may play a role in the development of tophaceous disease in some populations with high prevalence of severe gout.
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http://dx.doi.org/10.1186/s13075-017-1254-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341474PMC
March 2017

Replication of association of the apolipoprotein A1-C3-A4 gene cluster with the risk of gout.

Rheumatology (Oxford) 2016 08 18;55(8):1421-30. Epub 2016 Apr 18.

Department of Biochemistry, University of Otago, Dunedin, New Zealand

Objective: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout.

Methods: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Māori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C).

Results: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10).

Conclusion: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.
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http://dx.doi.org/10.1093/rheumatology/kew057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854033PMC
August 2016

Clinical and genetic features of diuretic-associated gout: a case-control study.

Rheumatology (Oxford) 2016 07 17;55(7):1172-6. Epub 2016 Mar 17.

Department of Medicine, University of Auckland, Auckland,

Objective: Hyperuricaemia and gout are well-recognized complications of diuretic use. The aim of this study was to examine the clinical and genetic features of diuretic-associated gout.

Methods: Participants (n = 1365) fulfilling the 1977 ARA gout classification criteria, recruited from primary and secondary care, attended a study visit that included a detailed clinical assessment. Use of diuretic therapy was recorded during the study visit, and was confirmed by electronic dispensing data [n = 426 (31.2%) on diuretics]. Gout-associated single nucleotide polymorphisms were genotyped. Clinical and genetic features of diuretic-associated gout were analysed using a case-control study design (diuretics vs no diuretics).

Results: In the diuretic group there were more women, higher rates of comorbid conditions, higher BMI and lower estimated glomerular filtration rate compared with those not taking diuretics. Gout disease duration, frequency of gout flares and presence of tophi were similar in the two groups. Patients on diuretics had higher age of gout presentation and higher recorded serum urate. The ABCG2 rs2231142 risk allele was present less frequently in the diuretic group (36.1%) compared with those not on diuretics (47.6%, P = 1.2 × 10(-4)). The differences in ABCG2 were observed in both men and women with gout.

Conclusion: Diuretic-associated gout represents a medically complex condition. Although age of gout onset is later and serum urate concentrations are higher in those on diuretics, other clinical features of gout are similar. The observed differences in the ABCG2 risk allele frequency suggest that some genetic factors play a less dominant role in diuretic-associated gout compared with primary gout.
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http://dx.doi.org/10.1093/rheumatology/kew018DOI Listing
July 2016

Hyperuricaemia: contributions of urate transporter ABCG2 and the fractional renal clearance of urate.

Ann Rheum Dis 2016 07 1;75(7):1363-6. Epub 2015 Dec 1.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

Objective: To investigate the contributions towards hyperuricaemia of known risk factors, focusing on fractional (renal) clearance of urate (FCU) and variation in the ATP-binding cassette transporter, sub-family G 2 (ABCG2) gene.

Methods: The contributions of age, sex, ancestry, Q141K genotype for ABCG2, FCU, sugar-sweetened beverage and alcohol consumption, metabolic syndrome disorders and measures of renal function to the risk of hyperuricaemia were evaluated by comparing hyperuricaemic (serum urate≥0.42 mmol/L, n=448) with normouricaemic (serum urate<0.42 mmol/L, n=344) participants using stepwise logistic regression. Model performance was evaluated using the area under the receiver operator characteristic curve (AUROC).

Results: ABCG2 genotype, FCU, male sex, body mass index, serum triglyceride concentrations, estimated glomerular filtration rate and consumption of alcohol were the best predictors of hyperuricaemia (AUROC 0.90, 81% accuracy). Homozygosity in the 141K variant for ABCG2 conferred an adjusted OR of 10.5 for hyperuricaemia (95% CI 2.4 to 46.2). For each 1% decrease of FCU, the adjusted OR increased by 51% (OR 1.51, 95% CI 1.37 to 1.66). There was no association between ABCG2 genotype and FCU (r=0.02, p=0.83).

Conclusions: The ABCG2 141K variant and the FCU contribute strongly but independently to hyperuricaemia. These findings provide further evidence for a significant contribution of ABCG2 to extra-renal (gut) clearance of urate.
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http://dx.doi.org/10.1136/annrheumdis-2015-208111DOI Listing
July 2016

Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout.

Rheumatol Int 2016 Feb 26;36(2):255-61. Epub 2015 Sep 26.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

The Arg64 allele of variant rs4994 (Trp64Arg) in the β3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Māori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman(®). Māori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (β = 0.036, P = 0.004, P Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.
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http://dx.doi.org/10.1007/s00296-015-3370-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653370PMC
February 2016

Body mass index modulates the relationship of sugar-sweetened beverage intake with serum urate concentrations and gout.

Arthritis Res Ther 2015 Sep 22;17:263. Epub 2015 Sep 22.

Department of Biochemistry, Division of Health Sciences, University of Otago, 710 Cumberland Street, Dunedin, 9016, New Zealand.

Introduction: Both sugar-sweetened beverage (SSB) intake and body mass index (BMI) are associated with elevated serum urate concentrations and gout risk. The aim of this study was to determine whether the associations of SSB intake with serum urate and gout are moderated by BMI.

Method: The effects of chronic SSB intake on serum urate and gout status were analysed in a large cross-sectional population study. The effects of an acute fructose load on serum urate and fractional excretion of uric acid (FEUA) were examined over 180 minutes in a short-term intervention study. In all analyses, the responses were compared in those with BMI <25 mg/kg(2) (low BMI) and ≥25 mg/kg(2) (high BMI).

Results: In the serum urate analysis (n = 12,870), chronic SSB intake was associated with increased serum urate in the high BMI group, but not in the low BMI group (P difference = 3.6 × 10(-3)). In the gout analysis (n = 2578), chronic high SSB intake was associated with gout in the high BMI group, but not in the low BMI group (P difference = 0.012). In the acute fructose loading study (n = 76), serum urate was increased in the high BMI group at baseline and throughout the observation period (PBMI group <0.0001), but there were similar acute serum urate increases in both BMI groups in response to the fructose load (P interaction = 0.99). The baseline FEUA was similar between the two BMI groups. However, following the fructose load, FEUA responses in the BMI groups differed (P interaction <0.0001), with increased FEUA at 120 minutes and 180 minutes in the low BMI group and reduced FEUA at 60 minutes in the high BMI group.

Conclusions: These data suggest that BMI influences serum urate and gout risk in response to chronic SSB intake, and renal tubular uric acid handling in response to an acute fructose load. In addition to many other health benefits, avoidance of SSBs may be particularly important in those with overweight/obesity to prevent hyperuricaemia and reduce gout risk.

Trials Registration: Australian Clinical Trials Registry ACTRN12610001036000 . Registered 24 November 2010.
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http://dx.doi.org/10.1186/s13075-015-0781-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578754PMC
September 2015

Gout Is a Chronic Inflammatory Disease in Which High Levels of Interleukin-8 (CXCL8), Myeloid-Related Protein 8/Myeloid-Related Protein 14 Complex, and an Altered Proteome Are Associated With Diabetes Mellitus and Cardiovascular Disease.

Arthritis Rheumatol 2015 Dec;67(12):3303-13

University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: The frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients.

Methods: We studied 330 gout patients from 3 independent cohorts and compared them with 144 healthy individuals and 276 disease controls. We measured circulating levels of interleukin-8 (IL-8)/CXCL8, IL-1β, IL-6, IL-10, IL-12, and tumor necrosis factor, after which we performed proteome-wide analysis in a selection of samples to identify proteins that were possibly prognostic for the development of comorbidities. Replication analysis was performed specifically for myeloid-related protein 8 (MRP-8)/MRP-14 complex.

Results: Compared to healthy controls and disease control patients, patients with gouty arthritis (n = 48) had significantly higher mean levels of CXCL8 (P < 0.001), while other cytokines were almost undetectable. Similarly, patients with intercritical gout showed high levels of CXCL8. CXCL8 was independently associated with diabetes mellitus in patients with intercritical gout (P < 0.0001). Proteome-wide analysis in gouty arthritis (n = 18) and intercritical gout (n = 39) revealed MRP-8 and MRP-14 as the proteins with the greatest differential expression between low and high levels of CXCL8 and also showed a positive correlation of MRP8/MRP14 complex with CXCL8 levels (R(2)  = 0.49, P < 0.001). These findings were replicated in an independent cohort. The proteome of gout patients with high levels of CXCL8 was associated with diabetes mellitus (odds ratio 16.5 [95% confidence interval 2.8-96.6]) and CVD (odds ratio 3.9 [95% confidence interval 1.0-15.3]).

Conclusion: Circulating levels of CXCL8 are increased during both the acute and intercritical phases of gout, and they coincide with a specific circulating proteome that is associated with risk of diabetes mellitus and CVD. Further research focused on the roles of CXCL8 and MRP8/MRP14 complex in patients with gout is warranted.
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http://dx.doi.org/10.1002/art.39318DOI Listing
December 2015

Modulation of genetic associations with serum urate levels by body-mass-index in humans.

PLoS One 2015 26;10(3):e0119752. Epub 2015 Mar 26.

Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom.

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374966PMC
March 2016

Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts.

PLoS One 2014 10;9(3):e88991. Epub 2014 Mar 10.

Department of Biochemistry, University of Otago, Otago, New Zealand.

Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.

Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.

Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.

Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively.

Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088991PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948621PMC
March 2016

Influence of the ABCG2 gout risk 141 K allele on urate metabolism during a fructose challenge.

Arthritis Res Ther 2014 Jan 30;16(1):R34. Epub 2014 Jan 30.

Introduction: Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic response to fructose loading.

Methods: Healthy volunteers (n = 74) provided serum and urine samples immediately before and 30, 60, 120 and 180 minutes after ingesting a 64 g fructose solution. Data were analyzed based on the presence or absence of the ABCG2 141 K gout risk allele.

Results: The 141 K risk allele was present in 23 participants (31%). Overall, serum urate (SU) concentrations during the fructose load were similar in those with and without the 141 K allele (PSNP = 0.15). However, the 141 K allele was associated with a smaller increase in SU following fructose intake (PSNP <0.0001). Those with the 141 K allele also had a smaller increase in serum glucose following the fructose load (PSNP = 0.002). Higher fractional excretion of uric acid (FEUA) at baseline and throughout the fructose load was observed in those with the 141 K risk allele (PSNP <0.0001). However, the change in FEUA in response to fructose was not different in those with and without the 141 K risk allele (PSNP = 0.39). The 141 K allele effects on serum urate and glucose were more pronounced in Polynesian participants and in those with a body mass index ≥25 kg/m².

Conclusions: In contrast to the predicted responses for a hyperuricemia/gout risk allele, the 141 K allele is associated with smaller increases in SU and higher FEUA following a fructose load. The results suggest that ABCG2 interacts with extra-renal metabolic pathways in a complex manner to regulate SU and gout risk.

Clinical Trials Registration: The study was registered by the Australian Clinical Trials Registry (ACTRN12610001036000).
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http://dx.doi.org/10.1186/ar4463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978630PMC
January 2014

Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects.

Arthritis Res Ther 2013 ;15(6):R220

Introduction: There is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Māori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets.

Methods: A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata.

Results: A haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38, P = 6.1 × 10-4; OR = 0.91, P = 0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR = 0.28, P = 6.0 × 10-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR = 0.98, P = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51, P = 0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80, P = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63, P = 0.028) but risk in European Caucasian samples (OR = 1.33, P = 0.039).

Conclusions: Our analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data.
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http://dx.doi.org/10.1186/ar4417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978909PMC
November 2014