Effects of multiple genetic loci on the pathogenesis from serum urate to gout

Zheng, Dong; Zhou, Jingru; Jiang, Shuai; Li, Yuan; Zhao, Dongbao; Yang, Chengde; Ma, Yanyun; Wang, Yi; He, Hua‐Jun; Ji, Hengdong; Yang, Yajun; Wang, Xiaofeng; Xu, Xiufeng; Pang, Yafei; Zou, Hejian; Jin, Li; Wang, Jiucun

doi:10.1038/srep43614

Cited by 56 publications

(77 citation statements)

References 37 publications

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“…Furthermore, 4332 individuals with no history of gout were selected from the Taizhou Longitudinal Study (Wang et al 2009). Those subjects were divided into subgroups based on their smoking status recorded in questionnaires, and body mass index (BMI) values according to the categories of the World Health Organization (WHO) (Yang et al 2016; Dong et al 2017b). Smoking status contained non-smoker, former smoker and current smoker.…”

Section: Methodsmentioning

confidence: 99%

“…RNA was isolated from blood cells of 58 male healthy subjects. Detail information of experimental approaches for DNA and RNA had been described in our previous study (Dong et al 2017b). Genotyping of SNPs in PKD2 (rs2725215 and rs2728121) and ABCG2 (rs2231137 and rs1481012) was processed by SNaPshot.…”

Section: Methodsmentioning

confidence: 99%

“…Uric acid is the end breakdown product of purine complex in human beings and high uric acid levels in the blood (hyperuricemia) leads to the deposition of monosodium urate (MSU) crystals in the joints and tissues, which plays a predominant role in the development of gout (Dehghan et al 2008; Yang et al 2010; Köttgen et al 2012; Perez-Ruiz et al 2014; Dong et al 2017b). Gout is one acute inflammatory arthritis (Dong and Wang 2015; Dong et al 2017a) and affects a large number of individuals in many countries (Zhu et al 2011; Dong et al 2015a).…”

Section: Introductionmentioning

confidence: 99%

“…Nowadays, several loci in different genes have been identified to affect serum urate concentration and gout risk (Köttgen et al 2012; Merriman 2015). However, those loci only explained a fraction of heredity of serum urate/gout and some of them contribute differently to the pathogenesis from elevated serum urate to hyperuricemia to gout (Köttgen et al 2012; Dong et al 2017b). And epistasis had been proved to affect complex traits and played important roles in various biological functions (Cordell 2002; Phillips 2008).…”

Section: Introductionmentioning

confidence: 99%

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PKD2 influence uric acid levels and gout risk by interacting with ABCG2

Zheng

Zhou

Jiang

et al. 2018

Preprint

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Background: Uric acid is the final product of purine metabolism and elevated serum urate levels can cause gout. Conflicting results were reported for the effect of PKD2 on serum urate levels and gout risk. Therefore, our study attempted to state the important role of PKD2 in influencing the pathogenesis of gout.Method: SNPs in PKD2 (rs2725215 and rs2728121) and ABCG2 (rs2231137 and rs1481012) were tested in approximately 5,000 Chinese individuals. Results:Two epistatic interactions between loci in PKD2 (rs2728121) and ABCG2 (rs1481012 and rs2231137) showed distinct contributions to uric acid levels with P int values of 0.018 and 0.004, respectively, and the associations varies by gender and BMI. The SNP pair of rs2728121 and rs1481012 justly played roles in uric acid in females (P int = 0.006), while the other pair did in males (P int = 0.017). Regarding BMI, the former SNP pair merely contributed in overweigh subjects (P int = 0.022) and the latter one did in both normal and overweigh individuals (P int = 0.013 and 0.047, respectively). Furthermore, the latter SNP pair was also associated with gout pathology (P int = 0.001), especially in males (P int = 0.001). Finally, functional analysis showed potential epistatic interactions in those genes region and PKD2 mRNA expression had a positive correlation with ABCG2's (r = 0.743, P = 5.83e-06). Conclusion:Our study for the first time identified that epistatic interactions between PKD2 and ABCG2 influenced serum urate concentrations and gout risk, and PKD2 might affect the pathogenesis from elevated serum urate to hyperuricemia to gout by modifying ABCG2.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PKD2 influence uric acid levels and gout risk by interacting with ABCG2

Zheng

Zhou

Jiang

et al. 2018

Preprint

Self Cite

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“…Therefore the regulation of PDZK1 levels would be expected to contribute to urate homeostasis, making understanding of the molecular mechanisms that control PDZK1 expression important. This is particularly important in the context of reports of association of PDZK1 with gout in multiple ancestral groups (8,16,17) and the established role of renal and gut under-excretion of uric acid as a cause of gout (18,19). Given that a urate GWAS association signal maps to a small region (<10 kb) immediately upstream of the transcription start site of PDZK1 (4,20), our aim was to use in vivo and in vitro approaches to understand if variants in proximity to PDZK1 control serum urate levels by modulating transcription of this gene.…”

Section: Introductionmentioning

confidence: 99%

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

Ketharnathan

Leask

Boocock

et al. 2018

Preprint

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Several dozen genetic variants associate with serum urate levels, but the precise molecular mechanisms by which they affect serum urate 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 locus (eQTL) and likelihood analyses followed by gene expression assays. Zebrafish were used to determine the ability of rs1967017 to direct tissue-specific gene expression. Luciferase assays in HEK293 and HepG2 cells measured the effect of rs1967017 on transcription amplitude. PAINTOR 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. The urate-increasing T-allele of rs1967017 strengthens a binding site for the transcription factor HNF4A. siRNA 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.With other reports our 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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Impact of Clinical Association Between Gout and Dementia: A Nationwide Population‐Based Cohort Study in Korea

Kim

Yim

Choi

et al. 2022

Arthritis Care & Research

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Objective. Hyperuricemia might have neuroprotective or neurodegenerative effects on dementia via oxidative stress or inflammatory response regulation. Few studies have explored the association of hyperuricemia or gout with dementia. This retrospective cohort study aimed to investigate the association between gout and dementia in Korea.Methods. Altogether, 5,052 gout patients and 25,260 age-and sex-matched controls were selected from the National Health Insurance Service (NHIS)-National Sample Cohort database. The incidence and risk of dementia were evaluated by reviewing the NHIS record. We also performed a subgroup analysis according to age group (age <65 or ≥65 years) using the standard age of 65 years for elderly and nonelderly groups and sex.Results. During follow-up, 81 and 558 participants in the gout and control cohorts developed dementia, respectively. The mean follow-up duration was 4.38 years in gout patients and 4.94 years in controls. Gout patients had a hazard ratio (HR) of 0.79 for overall dementia (95% confidence interval [95% CI] 0.62-1.00) and significantly lower Alzheimer's disease risk (HR 0.73 [95% CI 0.54-0.98]) after adjusting for age, sex, household income, and comorbidities. In subgroup analysis stratified by age and sex, the inverse association between gout and the risk of overall dementia (HR 0.71 [95% CI 0.52-0.97]) and Alzheimer's disease (HR 0.67 [95% CI 0.46-0.97]) were observed in the elderly male group. On the other hand, age-and sex-adjusted analysis showed that the HR for vascular dementia of gout patients was 2.31 (95% CI 1.02-5.25) in the nonelderly male group.Conclusion. Gout decreased the risk of incident Alzheimer's disease-type dementia, especially in elderly patients. The association between gout and dementia risk may differ according to age and disease duration.

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Effects of multiple genetic loci on the pathogenesis from serum urate to gout

Cited by 56 publications

References 37 publications

PKD2 influence uric acid levels and gout risk by interacting with ABCG2

PKD2 influence uric acid levels and gout risk by interacting with ABCG2

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

Impact of Clinical Association Between Gout and Dementia: A Nationwide Population‐Based Cohort Study in Korea

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