Evaluate the effects of serum urate level on bone mineral density: a genome-wide gene–environment interaction analysis in UK Biobank cohort

Yao, Yao; Chu, Xuan; Ma, Mei; Ye, Jing; Wen, Yan; Li, Ping; Cheng, Bolun; Cheng, Shiqiang; Zhang, Lu; Liu, Li; Qi, Xin; Liang, Chujun; Kafle, Om Prakash; Wu, Cuiyan; Wang, Sen; Wang, Xi; Ning, Yujie; Zhang, Feng

doi:10.1007/s12020-021-02760-8

Cited by 7 publications

(4 citation statements)

References 51 publications

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“…With regard to SLC2A9 and serum urate, 59 publications have been deposited in the GWAS Catalog up until March 11, 2023, with two studies 44,45 reporting on GEIs (interaction effects between genes and serum urate on bone mineral density and type 2 diabetes mellitus). In the literature, 17,[46][47][48][49] several studies have also reported/reviewed SLC2A9 interactions involving thiazides/diuretics.…”

Section: Discussionmentioning

confidence: 99%

Genetic Determinants of Thiazide‐Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances – A Genome‐Wide Evaluation of the UK Biobank

Asiimwe,

Walker,

Sofat

et al. 2024

Clin Pharma and Therapeutics

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Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide‐use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self‐reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene–environment interaction (GEI) tests on the significant (P < 2.5 × 10−9) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at P = 0.05 divided by the number of vQTL SNPs tested for GEIs. The vQTL analysis identified eight statistically significant SNPs for blood glucose (5 SNPs) and serum urate (3 SNPs), with none being identified for the urinary biomarkers. Two of the SNPs (1 glucose SNP: CDKAL1 intron rs35612982, GEI P = 6.24 × 10−3; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10−4) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the SLC2A9‐mediated interaction having been previously reported. In conclusion, we used a two‐stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide‐associated biochemical abnormalities. Understanding how environmental exposures (including medications such as thiazides) and genetics interact, is an important step toward precision medicine and improved patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Genetic Determinants of Thiazide‐Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances – A Genome‐Wide Evaluation of the UK Biobank

Asiimwe,

Walker,

Sofat

et al. 2024

Clin Pharma and Therapeutics

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“…The possible pathophysiological associations of gout leading to incident osteoporosis are elusive and may involve genetic, lifestyle, and environmental factors and other undefined vital factors. Recently, a large genome-wide association study demonstrated that significant genetic variants related to urate are positively associated with bone mineral density, where some genes overlap between men and women [ 36 ]. These findings highlight the presence of genetic susceptibility to osteoporosis in patients with gout depending on sex [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a large genome-wide association study demonstrated that significant genetic variants related to urate are positively associated with bone mineral density, where some genes overlap between men and women [ 36 ]. These findings highlight the presence of genetic susceptibility to osteoporosis in patients with gout depending on sex [ 36 ]. Gout and osteoporosis appear to overlap for some risk factors, including increased age, postmenopausal women, comorbidities, smoking, low physical activity, alcohol drinking, hyperglycemia, and high triglyceride level [ 4 , 22 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Potential Association of Osteoporosis and Not Osteoporotic Fractures in Patients with Gout: A Longitudinal Follow-Up Study

et al. 2022

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Health issues associated with gout and increased occurrence of osteoporosis or fractures have been raised; however, the results are elusive. Herein, we explored the possible link between gout and incident osteoporosis/osteoporotic fractures based on long-term follow-up nationwide data. This study enrolled 16,305 patients with gout and 65,220 controls who were matched by propensity score at a 1:4 ratio on the basis of sex, age, income, and residence from the Korean National Health Insurance Service-Health Screening Cohort database (2002–2015). A Cox proportional hazard model was employed to identify the relevance between gout and incident osteoporosis/fractures, following adjustment for various covariates. In the follow-up period, osteoporosis developed in 761 individuals with gout and 2805 controls (incidence rates: 8.0 and 7.3/1000 person-years, respectively), and each osteoporotic fracture in the distal radius (2.8 vs. 2.7/1000 person-years), hip (1.3 vs. 1.3/1000 person-years), and spine (4.5 vs. 4.5/1000 person-years) occurred in gout and control groups, respectively. After adjustment, the gout group presented an 11% higher development of osteoporosis (95% confidence interval = 1.02–1.20) than the controls (p = 0.011). Subgroup analyses maintained the augment of incident osteoporosis in sufferers with gout, particularly in either men or <60 years. However, no such relevance was identified between gout and incident osteoporotic fractures at any site. In conclusion, gout may result in a slightly elevated likelihood of developing osteoporosis, and not osteoporotic fractures, in the Korean population.

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“…Some insight on how RPTPδ may influence a process like osteogenesis may ultimately come from investigations on the interplay of genetic and environmental factors that determine bone mineral density. Recent studies point to a protective role of uric acid against bone loss, and an interaction effect of serum urate levels and rs10977015 in PTPRD on bone mineral density was suggested using data from the United Kingdom Biobank cohort ( Yao et al, 2021 ). Similarly, in a search for genetic components that may associate with circulating glycine levels in the risk to develop coronary artery disease in women, PTPRD was among the twelve loci that linked to glycine metabolism but the latter could not be tied to coronary artery disease risk ( Jia et al, 2019 ).…”

Section: Documented Genetic Variabilitymentioning

confidence: 99%

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

Hendriks

Cruchten

Pulido

2023

Front. Cell Dev. Biol.

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Protein tyrosine phosphatases, together with protein tyrosine kinases, control many molecular signaling steps that control life at cellular and organismal levels. Impairing alterations in the genes encoding the involved proteins is expected to profoundly affect the quality of life—if compatible with life at all. Here, we review the current knowledge on the effects of germline variants that have been reported for genes encoding a subset of the protein tyrosine phosphatase superfamily; that of the thirty seven classical members. The conclusion must be that the newest genome research tools produced an avalanche of data that suggest ‘guilt by association’ for individual genes to specific disorders. Future research should face the challenge to investigate these accusations thoroughly and convincingly, to reach a mature genotype-phenotype map for this intriguing protein family.

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Evaluate the effects of serum urate level on bone mineral density: a genome-wide gene–environment interaction analysis in UK Biobank cohort

Cited by 7 publications

References 51 publications

Genetic Determinants of Thiazide‐Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances – A Genome‐Wide Evaluation of the UK Biobank

Genetic Determinants of Thiazide‐Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances – A Genome‐Wide Evaluation of the UK Biobank

Potential Association of Osteoporosis and Not Osteoporotic Fractures in Patients with Gout: A Longitudinal Follow-Up Study

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

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