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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.

ABSTRACT: Gout, which results from elevated serum uric acid (SUA), is a common form of arthritis that is induced by urate crystals. A single nucleotide polymorphism, rs2544390, of LDL receptor related protein 2 (LRP2/Megalin), has previously been reported to be associated with SUA by a genome-wide association study in a Japanese population. However, it was controversial as to whether rs2544390 is associated with gout in a Japanese population, since previous studies with Japanese populations have reported an association between gout and rs2544390 both with and without significance. This prompted us to investigate the association between gout and rs2544390 of LRP2. Using 1208 clinically diagnosed gout patients and 1223 controls in a Japanese male population, our results showed that while rs2544390 did not show a significant association with gout susceptibility in the present study (p?=?0.0793, odds ratio [OR] with 95% confidential interval [CI] 1.11 [0.99-1.24]). However, a meta-analysis using previous studies on Japanese populations revealed a significant association with gout (pmeta?=?0.0314, OR with 95% CI 1.09 [1.01-1.18]). We have therefore for the first time confirmed a positive association between rs2544390 and gout with only a Japanese male population. Our study provides clues to a better understanding of the pathogenesis of gout and has the potential to lead to novel therapeutic strategies against gout using LRP2 as a molecular target.

SUBMITTER: Akashi A

PROVIDER: S-EPMC7080676 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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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.

Akashi Airi A Nakayama Akiyoshi A Kamatani Yoichiro Y Higashino Toshihide T Shimizu Seiko S Kawamura Yusuke Y Imoto Misaki M Naito Mariko M Hishida Asahi A Kawaguchi Makoto M Takao Mikiya M Matsuo Michinori M Takada Tappei T Ichida Kimiyoshi K Ooyama Hiroshi H Shinomiya Nariyoshi N Matsuo Hirotaka H

Human cell 20200124 2

Gout, which results from elevated serum uric acid (SUA), is a common form of arthritis that is induced by urate crystals. A single nucleotide polymorphism, rs2544390, of LDL receptor related protein 2 (LRP2/Megalin), has previously been reported to be associated with SUA by a genome-wide association study in a Japanese population. However, it was controversial as to whether rs2544390 is associated with gout in a Japanese population, since previous studies with Japanese populations have reported ...[more]

PMID: 31975031

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Project description:BackgroundGout is a common disease resulting from hyperuricemia which causes acute arthritis. A recent genome-wide association study (GWAS) of gout identified three new loci for gout in Han Chinese: regulatory factor X3 (RFX3), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), and breast carcinoma amplified sequence 3 (BCAS3). The lack of any replication studies of these three loci using other population groups prompted us to perform a replication study with Japanese clinically defined gout cases and controls.MethodsWe genotyped the variants of RFX3 (rs12236871), KCNQ1 (rs179785) and BCAS3 (rs11653176) in 723 Japanese clinically defined gout cases and 913 controls by TaqMan method. rs179785 of KCNQ1 is also evaluated by direct sequencing because of difficulties of its genotyping by TaqMan method.ResultsAlthough the variants of RFX3 and BCAS3 were clearly genotyped by TaqMan method, rs179785 of KCNQ1 was not, because rs179785 (A/G) of KCNQ1 is located at the last nucleotide ("A") of the 12-bp deletion variant (rs200562977) of KCNQ1. Therefore, rs179785 and rs200562977 of KCNQ1 were genotyped by direct sequencing in all samples. Moreover, by direct sequencing with the same primers, we were able to evaluate the genotypes of rs179784 of KCNQ1 which shows strong linkage disequilibrium with rs179785 (D' = 1.0 and r 2 = 0.99). rs11653176, a common variant of BCAS3, showed a significant association with gout (P = 1.66 × 10- 3; odds ratio [OR] = 0.80); the direction of effect was the same as that seen in the previous Han Chinese GWAS. Two variants of KCNQ1 (rs179785 and rs179784) had a nominally significant association (P = 0.043 and 0.044; OR = 0.85 and 0.86, respectively), but did not pass the significance threshold for multiple hypothesis testing using the Bonferroni correction. On the other hand, rs200562977 of KCNQ1 and rs12236871 of RFX3 did not show any significant association with gout.ConclusionBCAS3 is a coactivator of estrogen receptor alpha, and the influence of estrogen to serum uric acid level is well known. Our present replication study, as did the previous gout GWAS, demonstrated the common variant of BCAS3 to be associated with gout susceptibility.

Dataset Information

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

Publications

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

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