Twenty-eight loci that influence serum urate levels: analysis of association with gout

Phipps‐Green, Amanda; Merriman, ME; Topless, Ruth; Altaf, Sara; Montgomery, Grant W.; Franklin, Christopher S.; Jones, Gregory T.; Rij, AM van; White, Douglas; Stamp, LK; Dalbeth, Nicola; Merriman, TR

doi:10.1136/annrheumdis-2014-205877

Cited by 128 publications

(123 citation statements)

References 29 publications

(54 reference statements)

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“…We and other groups [5][6][7][8][9] recently reported gout/ hyperuricaemia to have relatively strong genetic risk factors. More recently, and for the first time, we performed a GWAS with only clinically defined Japanese male gout cases in which 16 single nucleotide polymorphisms (SNPs) were replicated, and five gout-risk loci were identified including two novel loci (MYL2-CUX2 and CNIH-2).…”

Section: Introductionmentioning

confidence: 64%

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

et al. 2016

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ObjectiveA genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.MethodsPutative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study.ResultsIn addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10−8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (pmeta=3.58×10−8).ConclusionsOur findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

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Section: Introductionmentioning

confidence: 64%

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

et al. 2016

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“…Variants in two genes, ABCG2 and SLC2A9 , are consistently associated with hyperuricaemia and prevalent gout in many different populations [8–10]. …”

Section: Introductionmentioning

confidence: 99%

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

Phipps‐Green

Stamp

et al. 2017

Arthritis Res Ther

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BackgroundTophi 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.MethodsParticipants (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.ResultsCompared 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.ConclusionsVariation in ABCG2 function may play a role in the development of tophaceous disease in some populations with high prevalence of severe gout.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1254-8) contains supplementary material, which is available to authorized users.

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“…It also reduces hyperuricemia caused by thiazides and hence is a useful agent in hypertensive patients developing gout. 6 Amlodipine, a calcium channel blocker, at a dose of 5-10 mg/day is also found to be useful in reducing urate levels in patients with cyclosporine-induced hyperuricemia. Fenofibrate, a drug widely used for control of dyslipidemia, is also found to have moderate uricosuric action.…”

Section: Treatmentmentioning

confidence: 99%

“…Twenty-eight genetic loci are associated with serum urate levels in Europeans but newer loci have also been detected in recent studies. 6 The major gout-causing genes identified are SLC2A9 and ABCG2, the urate transport genes and SLC17A1, which encodes sodiumdependent phosphate transporter 1, a renal transporter of uric acid. 7 Gout often presents as severe monoarthritis of acute onset in lower limb joints such as the first metatarsophalangeal (MTP) joint or ankle.…”

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confidence: 99%

Gout: an Asia‐Pacific update

Paul

James

2017

Int J of Rheum Dis

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Even though, Hippocrates recognized gout as an affection of older men and a product of high living long back in 5th century BC, this painful condition promises to accompany humanity to the 21st century. The incidence is progressively rising and females are also affected in the modern era. There are also regional and ethnic variations in the incidence, the genetics of which is being studied. The recommended best therapy for the acute attacks and long term prophylaxis has improved remarkably in the recent years. However, patients are often treated inadequately and risk factors for their disease are not well explored in daily practice. Although well designed long term studies of current and newer treatment are welcomed, educating doctors especially the primary care physicians who manage majority of gout cases, in optimizing the currently available management options would improve the present care.Key words: disease aetiology and pathogenesis -human, gout, metabolic and crystal arthropathies drug treatment, metabolic and crystal arthropathies epidemiology, metabolic and crystal arthropathies inflammasome.

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Twenty-eight loci that influence serum urate levels: analysis of association with gout

Abstract: We provide the first evidence for association with gout at four loci (IGF1R, PDZK1, MAF, HLF). Understanding why there is lack of correlation between urate and gout effect sizes will be important in understanding the aetiology of gout.

Cited by 128 publications

References 29 publications

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

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

Gout: an Asia‐Pacific update

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