A common variant of LDL receptor related protein 2 (LRP2) gene is associated with gout susceptibility: a meta-analysis in a Japanese population

Akashi, Akira; Nakayama, Akiyoshi; Kamatani, Yoichiro; Higashino, Toshihide; Shimizu, Seiko; Kawamura, Yusuke; Imoto, Misaki; Naito, Mariko; Hishida, Asahi; Kikuchi, Makoto; Mitsui, Takao; Takada, Tappei; Ichida, Kimiyoshi; Oda, Hiroshi; Shinomiya, Nariyoshi

doi:10.1007/s13577-019-00318-5

Cited by 6 publications

(4 citation statements)

References 33 publications

(51 reference statements)

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“…[17] LRP2 gene polymorphisms in humans have been linked to neural tube defects and cognitive impairment, elevated uric acid and gout, hypercholesterolemia, central adiposity, diabetic nephropathy, hypovitaminosis D and acute coronary syndrome, decreased Abeta amyloid clearance through the choroid plexus in Alzheimer's disease, susceptibility to Alzheimer's disease in Caucasians and ethnic Chinese Han, relapse rate of multiple sclerosis, and gallstone disease. [18][19][20][21][22][23][24][25][26][27] A study of African Americans found a unique missense megalin mutation that protected from end-stage kidney disease in patients with type 2-diabetes mellitus. [28]…”

Section: Megalin Is Essential For Brain Development and Normal Physio...mentioning

confidence: 99%

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Li,

Sheikh-Hamad

2023

Integr Med Nephrol Androl

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Megalin (also known as low density lipoprotein-receptor related protein 2 [LRP2]) is a multi-ligand cell-surface endocytic receptor expressed widely; it is important for the uptake of vitamins, nutrients and hormones. We recently reported the discovery of LRP2/megalin in the mitochondria of many cells and organs. Importantly, megalin traffics the mitochondrial intracrines stanniocalcin-1, TGF-β and angiotensin II from the extracellular milieu to the mitochondria. This transport parallels the retrograde early endosome to Golgi pathway and requires the Rab GTPase Rab32 in the mitochondria, megalin associates with sirtuin family of class III histone deacetylases (Sirt3) and stanniocalcin-1 (Stc1), which are important for anti-oxidant defenses. Deletion of megalin impairs mitochondrial respiration and glycolysis. The interaction between stanniocalcin-1 and megalin is mediated by leucines within the signal peptides of the proteins; and this interaction is essential to the stimulation of mitochondrial respiration and glycolysis by stanniocalcin-1. Our findings suggest that megalin facilitates the regulation of mitochondrial function by extracellular cues.

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Section: Megalin Is Essential For Brain Development and Normal Physio...mentioning

confidence: 99%

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Li,

Sheikh-Hamad

2023

Integr Med Nephrol Androl

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“…It is expressed in numerous tissues, such as proximal renal tubules ( Christensen and Birn, 2002 ). LRP2 SNPs (rs2390793, rs2544390, and rs16856823) are associated with blood uric acid ( Kamatani et al, 2010 ; Kanai et al, 2018 ; Nakatochi et al, 2019b ; Tin et al, 2019b ) and increased gout susceptibility in Japanese ( Akashi et al, 2020 ) and Chinese populations ( Dong et al, 2015 ). However, its variants might lead to renal tubular dysfunction, affecting the renal reabsorption of uric acid ( Kamatani et al, 2010 ; Kanai et al, 2018 ; Nakatochi et al, 2019b ; Tin et al, 2019b ).…”

Section: Association Between Uric Acid Transporter-related Gene Varia...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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“…With clinically defined Japanese gout cases, we have identified several genes through a candidate gene approach [15][16][17][18][19] which are associated with gout. Many urate transporter genes, such as SLC22A12/URAT1 and SLC2A9/GLUT9, whose dysfunctional variants cause renal hypouricemia [20][21][22] are also reported to have an association with gout and hyperuricemia.…”

Section: Supplementary Informationmentioning

confidence: 99%

Both variants of A1CF and BAZ1B genes are associated with gout susceptibility: a replication study and meta-analysis in a Japanese population

et al. 2021

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Gout is a common type of acute arthritis that results from elevated serum uric acid (SUA) levels. Recent genome-wide association studies (GWASs) have revealed several novel single nucleotide polymorphism (SNPs) associated with SUA levels. Of these, rs10821905 of A1CF and rs1178977 of BAZ1B showed the greatest and the second greatest significant effect size for increasing SUA level in the Japanese population, but their association with gout is not clear. We examined their association with gout using 1411 clinically-defined Japanese gout patients and 1285 controls, and meta-analyzed our previous gout GWAS data to investigate any association with gout. Replication studies revealed both SNPs to be significantly associated with gout (P = 0.0366, odds ratio [OR] with 95% confidence interval [CI]: 1.30 [1.02–1.68] for rs10821905 of A1CF, P = 6.49 × 10–3, OR with 95% CI: 1.29 [1.07–1.55] for rs1178977 of BAZ1B). Meta-analysis also revealed a significant association with gout in both SNPs (Pmeta = 3.16 × 10–4, OR with 95% CI: 1.39 [1.17–1.66] for rs10821905 of A1CF, Pmeta = 7.28 × 10–5, OR with 95% CI 1.32 [1.15–1.51] for rs1178977 of BAZ1B). This study shows the first known association between SNPs of A1CF, BAZ1B and clinically-defined gout cases in Japanese. Our results also suggest a shared physiological/pathophysiological background between several populations, including Japanese, for both SUA increase and gout susceptibility. Our findings will not only assist the elucidation of the pathophysiology of gout and hyperuricemia, but also suggest new molecular targets.

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A common variant of LDL receptor related protein 2 (LRP2) gene is associated with gout susceptibility: a meta-analysis in a Japanese population

Cited by 6 publications

References 33 publications

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

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

Both variants of A1CF and BAZ1B genes are associated with gout susceptibility: a replication study and meta-analysis in a Japanese population

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