Population Heterogeneity in the Genetic Control of Serum Urate

Merriman, Tony R.

doi:10.1016/j.semnephrol.2011.08.005

Cited by 30 publications

(23 citation statements)

References 38 publications

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“…In contrast, there was marginal evidence for association of rs2544390 with gout risk in European Caucasian, but in an opposing direction (OR = 0.79, P Unadjusted = 0.02). Heterogeneity (allelic and genetic) is also evident in gene associations with gout between among South East Asian, Polynesian and European Caucasian at SLC2A9 and ABCG2 (reviewed in [20]). If the association in European Caucasian were to be confirmed this would allow the inference that rs2544390 is not causal.…”

Section: Discussionmentioning

confidence: 99%

Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption

et al. 2013

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IntroductionThe T allele of a single nucleotide polymorphism (SNP: rs2544390) in lipoprotein receptor-related protein 2 (LRP2) is associated with higher serum urate and risk of gout in Japanese individuals. SNP rs2544390 also interacts with alcohol consumption in determining hyperuricemia in this population. We investigated the association of rs2544390 with gout, and interaction with all types of alcohol consumption in European and New Zealand (NZ) Māori and Pacific subjects, and a Māori study cohort from the East Coast region of NZ’s North Island.MethodsRs2544390 was genotyped by Taqman®. From NZ a total of 1205 controls and 1431 gout cases clinically ascertained were used. Publicly available genotype and serum urate data were utilized from the Atherosclerosis Risk in Communities (ARIC) study and the Framingham Heart Study (FHS). Alcohol consumption data were obtained by consumption frequency questions in all study cohorts. Multivariate adjusted logistic regression was done using STATA.ResultsThe T allele of rs2544390 was associated with increased risk of gout in the combined Māori and Pacific Island cohort (OR = 1.20, P = 0.009), and associated with gout in the European subjects, but with a protective effect (OR = 0.79, PUnadjusted = 0.02). Alcohol consumption was positively associated with risk of gout in Māori and Pacific subjects (0.2% increased risk/g/week, P = 0.004). There was a non-additive interaction between any alcohol intake and the risk of gout in the combined Māori and Pacific cohorts (PInteraction = 0.001), where any alcohol intake was associated with a 4.18-fold increased risk in the CC genotype group (P = 6.6x10-5), compared with a 1.14-fold increased risk in the CT/TT genotype group (P = 0.40). These effects were not observed in European subjects.ConclusionsAssociation of the T-allele with gout risk in the Māori and Pacific subjects was consistent with this allele increasing serum urate in Japanese individuals. The non-additive interaction in the Māori and Pacific subjects showed that alcohol consumption over-rides any protective effect conferred by the CC genotype. Further exploration of the mechanism underlying this interaction should generate new understanding of the biological role of alcohol in gout, in addition to strengthening the evidence base for reduction of alcohol consumption in the management of gout.

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Section: Discussionmentioning

confidence: 99%

Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption

et al. 2013

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“…SLC2A9 rs11942223 and ABCG2 rs2231142 were selected as variants consistently associated with gout in many populations, including Polynesian populations (reviewed in [9]). ABCG2 rs10011796 was selected as an additional gout-associated ABCG2 SNP [8], noting that this SNP has also been associated with allopurinol response in a USA study population [19].…”

Section: Methodsmentioning

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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“…Sequence variation within SLC2A9 is also much higher than average for human genes (91), with almost 25 nonsynonymous coding SNPs within the gene. There is also substantial heterogeneity in the genetics of SLC2A9 in various human populations, with consistent association between SLC2A9 and SUA but different associations for the same SNP within different populations (109). These observations are reflected in the heterogeneous effect of coding SNPs.…”

Section: The Glut9 Urate Transportermentioning

confidence: 99%

The Molecular Physiology of Uric Acid Homeostasis

Mandal

Mount²

2015

Annu. Rev. Physiol.

427

331

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Uric acid, generated from the metabolism of purines, has proven and emerging roles in human disease. Serum uric acid is determined by production and the net balance of reabsorption or secretion by the kidney and intestine. A detailed understanding of epithelial absorption and secretion of uric acid has recently emerged, aided in particular by the results of genome-wide association studies of hyperuricemia. Novel genetic and regulatory networks with effects on uric acid homeostasis have also emerged. These developments promise to lead to a new understanding of the various diseases associated with hyperuricemia and to novel, targeted therapies for hyperuricemia.

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Population Heterogeneity in the Genetic Control of Serum Urate

Cited by 30 publications

References 38 publications

Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption

Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption

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

The Molecular Physiology of Uric Acid Homeostasis

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