Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

Boocock, James; Leask, Megan; Okada, Yukinori; Matsuo, Hirotaka; Kawamura, Yusuke; Shi, Yongyong; Li, Changgui; Mount, David B.; Mandal, A. K.; Wang, Weiqing; Cadzow, Murray; Gosling, Anna L.; Major, Tanya J; Horsfield, Julia A.; Choi, Hyon K.; Fadason, Tayaza; O’Sullivan, Justin M.; Stahl, Eli A.; Merriman, Tony R.

doi:10.1093/hmg/ddaa013

Cited by 43 publications

(20 citation statements)

References 80 publications

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“…Thus, it is reasonable to hypothesise that rs10011796 marks an effect that influences gene expression. This is consistent with the presence of an expression QTL (regulatory) effect independent of rs2231142 in the ABCG2 urate GWAS signal [47]. The rs10011796 C-allele (that associates with reduced serum urate and risk of gout) does associate with reduced ABCG2 and increased PPM1K-DT (a long non-coding RNA 100 kb downstream of ABCG2) expression (www.gtex.org).…”

Section: Discussionsupporting

confidence: 72%

“…The molecular mechanism driving the non-additive interaction between ABCG2 SNPs rs2231142 and rs10011796 is unclear. Given that rs10011796 is a noncoding intronic variant outside any known Encode regulatory motif features (www.encodeproject.org), it is likely that rs10011796 is in linkage disequilibrium with the causal variant, rather than the causal variant itself, although other intronic variants in ABCG2 have been associated with ABCG2 expression [46,47]. The majority of common phenotype associations identified by GWAS are expression quantitative trait loci [48], influencing gene expression and transcript stability, and these variants can therefore modify the penetrance of coding variants [49].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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 − 21 and OR meta = 1.85, P = 1.3E − 03 , respectively). There was evidence for an effect of 141K in determining HU in European (OR = 1.56, P = 1.7E − 18 ) but not in Polynesian (OR meta = 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 − 06 ), however significantly weaker than ABCG2 rs2231142 141K (P Het = 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 − 06 ). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian (P meta = 2.5E − 03 ). Conclusion: These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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show abstract

“…Thus, it is reasonable to hypothesise that rs10011796 marks an effect that influences gene expression. This is consistent with the presence of an expression QTL (regulatory) effect independent of rs2231142 in the ABCG2 urate GWAS signal (47). The rs10011796 C-allele (that associates with reduced serum urate and risk of gout) does associate with reduced ABCG2 and increased PPM1K-DT (a long non-coding RNA 100kb downstream of ABCG2) expression (www.gtex.org).…”

Section: Discussionsupporting

confidence: 72%

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

Wrigley

Phipps‐Green

Topless

et al. 2020

Preprint

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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 1,699 European gout cases and 14,350 normourciemic (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 -21 and OR meta =1.85, P =1.3E -03 , respectively). There was evidence for an effect of 141K in determining HU in European (OR=1.56, P =1.7E -18 ) but not in Polynesian (OR meta =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 -06 ), however significantly weaker than ABCG2 rs2231142 141K ( P Het =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 -06 ). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian ( P meta = 2.5E -03 ). Conclusion These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

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“…MLXIPL encodes a Myc/Max/Mad superfamily basic helixloop-helix leucine zipper transcription factor that forms a heterodimeric complex. That binds and activates the (Boocock et al, 2020). MLXIPL is primarily associated with cellular carbohydrate metabolism and glycolytic processes.…”

Section: Gckr MLX Interacting Protein (Mlxip) and Mlx Interacting Pro...mentioning

confidence: 99%

Trends in the Contribution of Genetic Susceptibility Loci to Hyperuricemia and Gout and Associated Novel Mechanisms

Zhao

Guo

Schrodi

et al. 2022

Front. Cell Dev. Biol.

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Hyperuricemia and gout are complex diseases mediated by genetic, epigenetic, and environmental exposure interactions. The incidence and medical burden of gout, an inflammatory arthritis caused by hyperuricemia, increase every year, significantly increasing the disease burden. Genetic factors play an essential role in the development of hyperuricemia and gout. Currently, the search on disease-associated genetic variants through large-scale genome-wide scans has primarily improved our understanding of this disease. However, most genome-wide association studies (GWASs) still focus on the basic level, whereas the biological mechanisms underlying the association between genetic variants and the disease are still far from well understood. Therefore, we summarized the latest hyperuricemia- and gout-associated genetic loci identified in the Global Biobank Meta-analysis Initiative (GBMI) and elucidated the comprehensive potential molecular mechanisms underlying the effects of these gene variants in hyperuricemia and gout based on genetic perspectives, in terms of mechanisms affecting uric acid excretion and reabsorption, lipid metabolism, glucose metabolism, and nod-like receptor pyrin domain 3 (NLRP3) inflammasome and inflammatory pathways. Finally, we summarized the potential effect of genetic variants on disease prognosis and drug efficacy. In conclusion, we expect that this summary will increase our understanding of the pathogenesis of hyperuricemia and gout, provide a theoretical basis for the innovative development of new clinical treatment options, and enhance the capabilities of precision medicine for hyperuricemia and gout treatment.

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Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

Cited by 43 publications

References 80 publications

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

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

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

Trends in the Contribution of Genetic Susceptibility Loci to Hyperuricemia and Gout and Associated Novel Mechanisms

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