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Masayuki Sakiyama - One of the best experts on this subject based on the ideXlab platform.
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Independent effects of ADH1B and ALDH2 common dysfunctional variants on Gout risk.
Scientific reports, 2017Co-Authors: Masayuki Sakiyama, Akiyoshi Nakayama, Hirotaka Matsuo, Sayo Kawai, Airi Akashi, Seiko Shimizu, Toshihide Higashino, Makoto Kawaguchi, Mariko Naito, Hiroshi NakashimaAbstract:Gout is caused by hyperuricemia, with alcohol consumption being an established risk factor. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are crucial enzymes for alcohol metabolism. We recently performed a genome-wide association study of Gout and a subsequent fine-mapping study which identified rs671 of ALDH2 as a Gout locus. However, the association between Gout and common variants of ADH1B has hitherto remained unreported, prompting us to investigate the association between Gout and common dysfunctional variants of ADH1B (rs1229984) and ALDH2 (rs671). We used 1,048 clinically defined Gout cases and 1,334 controls of Japanese male. The “His carrier” (His/His or His/Arg) of rs1229984 (His48Arg) of ADH1B significantly increased Gout risk (P = 4.3 × 10−4, odds ratio = 1.76), as did the “non-Lys carrier (Glu/Glu)” of rs671 (Glu504Lys) of ALDH2. Furthermore, common variants of ADH1B and ALDH2 are independently associated with Gout. Our findings likewise suggest that genotyping these variants can be useful for the evaluation of Gout risk.
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gwas of clinically defined Gout and subtypes identifies multiple susceptibility loci that include urate transporter genes
Annals of the Rheumatic Diseases, 2017Co-Authors: Akiyoshi Nakayama, Yu Toyoda, Hirofumi Nakaoka, Masayuki Sakiyama, Yukinori Okada, Aasma Shaukat, Yoichiro Kamatani, Ken Yamamoto, Takahiro NakamuraAbstract:Objective A genome-wide association study (GWAS) of Gout and its subtypes was performed to identify novel Gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined Gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of Gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p −8 ): urate transporter genes ( SLC22A12 and SLC17A1 ) and HIST1H2BF-HIST1H4E for all Gout cases, and NIPAL1 and FAM35A for the renal underexcretion Gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with Gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with Gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with Gout at a genome-wide level of significance (p meta =3.58×10 −8 ). Conclusions Our findings including novel Gout risk loci provide further understanding of the molecular pathogenesis of Gout and lead to a novel concept for the therapeutic target of Gout/hyperuricaemia.
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Identification of rs671, a common variant of ALDH2, as a Gout susceptibility locus.
Scientific reports, 2016Co-Authors: Masayuki Sakiyama, Akiyoshi Nakayama, Hirofumi Nakaoka, Ken Yamamoto, Takahiro Nakamura, Hirotaka Matsuo, Sayo Kawai, Rieko Okada, Hiroshi Ooyama, Toru ShimizuAbstract:Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between Gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be Gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected and genotyping of 1,048 male Gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with Gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with Gout (P = 1.7 × 10−18, odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with Gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine Gout-associated SNP in the MYL2-CUX2 locus and that “A” allele (Lys) of rs671 plays a protective role in the development of Gout.
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Common variant of ALPK1 is not associated with Gout: a replication study
Human Cell, 2015Co-Authors: Toshinori Chiba, Akiyoshi Nakayama, Masayuki Sakiyama, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Kenji Wakai, Shino Suma, Yutaka Sakurai, Toru ShimizuAbstract:Gout is one of the most kinds of common inflammatory arthritis as a consequence of hyperuricemia. Alpha-protein kinase 1 ( ALPK1 ) gene locates in a Gout-susceptibility locus on chromosome 4q21–31, and encodes ALPK1 protein which plays a pivotal role in the phosphorylation of myosin 1. In the previous genetic study of Taiwanese populations, 3 single nucleotide polymorphisms (SNPs), rs11726117, rs231247 and rs231253, in ALPK1 gene were reported to have a significant association with Gout. However, no replication study has been performed to confirm this association. Therefore, we first conducted a replication study with clinically defined Gout patients in a different population. Linkage disequilibrium (LD) analyzes of the 3 SNPs in ALPK1 revealed that these SNPs are in strong LD in a Japanese population. Among the 3 SNPs of ALPK1 , rs11726117 (M861T) is the only missense SNP. Therefore, rs11726117 was genotyped in a Japanese population of 903 clinically defined Gout cases and 1,302 controls, and was evaluated for a possible association with Gout. The minor allele frequencies of rs11726117 were 0.26 and 0.25 in the case and control groups, respectively. The association analysis has not detected a significant association between rs11726117 and Gout susceptibility in a Japanese population ( p = 0.44). Because ABCG2 , a major causative gene for Gout, also locates in the Gout-susceptibility locus on chromosome 4q, these findings suggest that among genes in a Gout-susceptibility locus, not ALPK1 but ABCG2 could be important as a Gout-susceptible gene.
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A common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload Gout, but not with all Gout susceptibility
Human Cell, 2013Co-Authors: Akiyoshi Nakayama, Takahiro Nakamura, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Takuya Shimizu, Hiraku Ogata, Yuzo Takada, Toshinori Chiba, Masayuki SakiyamaAbstract:Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, Gout patients can be divided into those with renal overload (ROL) Gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) Gout. Recent genome-wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 ( MCT9/SLC16A9 ) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and Gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL Gout ( p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all Gout cases ( p = 0.10), non-ROL Gout cases ( p = 0.83), and RUE Gout cases ( p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL Gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of Gout as well as the physiological roles of MCT9.
Akiyoshi Nakayama - One of the best experts on this subject based on the ideXlab platform.
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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
Human Cell, 2020Co-Authors: Airi Akashi, Akiyoshi Nakayama, Yoichiro Kamatani, Seiko Shimizu, Toshihide Higashino, Mariko Naito, Yusuke Kawamura, Misaki Imoto, Asahi Hishida, Makoto KawaguchiAbstract: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 ( p _meta = 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.
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Independent effects of ADH1B and ALDH2 common dysfunctional variants on Gout risk.
Scientific reports, 2017Co-Authors: Masayuki Sakiyama, Akiyoshi Nakayama, Hirotaka Matsuo, Sayo Kawai, Airi Akashi, Seiko Shimizu, Toshihide Higashino, Makoto Kawaguchi, Mariko Naito, Hiroshi NakashimaAbstract:Gout is caused by hyperuricemia, with alcohol consumption being an established risk factor. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are crucial enzymes for alcohol metabolism. We recently performed a genome-wide association study of Gout and a subsequent fine-mapping study which identified rs671 of ALDH2 as a Gout locus. However, the association between Gout and common variants of ADH1B has hitherto remained unreported, prompting us to investigate the association between Gout and common dysfunctional variants of ADH1B (rs1229984) and ALDH2 (rs671). We used 1,048 clinically defined Gout cases and 1,334 controls of Japanese male. The “His carrier” (His/His or His/Arg) of rs1229984 (His48Arg) of ADH1B significantly increased Gout risk (P = 4.3 × 10−4, odds ratio = 1.76), as did the “non-Lys carrier (Glu/Glu)” of rs671 (Glu504Lys) of ALDH2. Furthermore, common variants of ADH1B and ALDH2 are independently associated with Gout. Our findings likewise suggest that genotyping these variants can be useful for the evaluation of Gout risk.
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gwas of clinically defined Gout and subtypes identifies multiple susceptibility loci that include urate transporter genes
Annals of the Rheumatic Diseases, 2017Co-Authors: Akiyoshi Nakayama, Yu Toyoda, Hirofumi Nakaoka, Masayuki Sakiyama, Yukinori Okada, Aasma Shaukat, Yoichiro Kamatani, Ken Yamamoto, Takahiro NakamuraAbstract:Objective A genome-wide association study (GWAS) of Gout and its subtypes was performed to identify novel Gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined Gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of Gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p −8 ): urate transporter genes ( SLC22A12 and SLC17A1 ) and HIST1H2BF-HIST1H4E for all Gout cases, and NIPAL1 and FAM35A for the renal underexcretion Gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with Gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with Gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with Gout at a genome-wide level of significance (p meta =3.58×10 −8 ). Conclusions Our findings including novel Gout risk loci provide further understanding of the molecular pathogenesis of Gout and lead to a novel concept for the therapeutic target of Gout/hyperuricaemia.
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Identification of rs671, a common variant of ALDH2, as a Gout susceptibility locus.
Scientific reports, 2016Co-Authors: Masayuki Sakiyama, Akiyoshi Nakayama, Hirofumi Nakaoka, Ken Yamamoto, Takahiro Nakamura, Hirotaka Matsuo, Sayo Kawai, Rieko Okada, Hiroshi Ooyama, Toru ShimizuAbstract:Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between Gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be Gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected and genotyping of 1,048 male Gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with Gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with Gout (P = 1.7 × 10−18, odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with Gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine Gout-associated SNP in the MYL2-CUX2 locus and that “A” allele (Lys) of rs671 plays a protective role in the development of Gout.
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Common variant of ALPK1 is not associated with Gout: a replication study
Human Cell, 2015Co-Authors: Toshinori Chiba, Akiyoshi Nakayama, Masayuki Sakiyama, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Kenji Wakai, Shino Suma, Yutaka Sakurai, Toru ShimizuAbstract:Gout is one of the most kinds of common inflammatory arthritis as a consequence of hyperuricemia. Alpha-protein kinase 1 ( ALPK1 ) gene locates in a Gout-susceptibility locus on chromosome 4q21–31, and encodes ALPK1 protein which plays a pivotal role in the phosphorylation of myosin 1. In the previous genetic study of Taiwanese populations, 3 single nucleotide polymorphisms (SNPs), rs11726117, rs231247 and rs231253, in ALPK1 gene were reported to have a significant association with Gout. However, no replication study has been performed to confirm this association. Therefore, we first conducted a replication study with clinically defined Gout patients in a different population. Linkage disequilibrium (LD) analyzes of the 3 SNPs in ALPK1 revealed that these SNPs are in strong LD in a Japanese population. Among the 3 SNPs of ALPK1 , rs11726117 (M861T) is the only missense SNP. Therefore, rs11726117 was genotyped in a Japanese population of 903 clinically defined Gout cases and 1,302 controls, and was evaluated for a possible association with Gout. The minor allele frequencies of rs11726117 were 0.26 and 0.25 in the case and control groups, respectively. The association analysis has not detected a significant association between rs11726117 and Gout susceptibility in a Japanese population ( p = 0.44). Because ABCG2 , a major causative gene for Gout, also locates in the Gout-susceptibility locus on chromosome 4q, these findings suggest that among genes in a Gout-susceptibility locus, not ALPK1 but ABCG2 could be important as a Gout-susceptible gene.
Hirotaka Matsuo - One of the best experts on this subject based on the ideXlab platform.
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Gout.
Nature reviews. Disease primers, 2019Co-Authors: Nicola Dalbeth, Hyon K Choi, Hirotaka Matsuo, Leo A B Joosten, Puja P Khanna, Fernando Perez-ruiz, Lisa K StampAbstract:Gout is a chronic disease caused by monosodium urate (MSU) crystal deposition. Gout typically presents as an acute, self-limiting inflammatory monoarthritis that affects the joints of the lower limb. Elevated serum urate level (hyperuricaemia) is the major risk factor for MSU crystal deposition and development of Gout. Although traditionally considered a disorder of purine metabolism, altered urate transport, both in the gut and the kidneys, has a key role in the pathogenesis of hyperuricaemia. Anti-inflammatory agents, such corticosteroids, NSAIDs and colchicine, are widely used for the treatment of Gout flare; recognition of the importance of NLRP3 inflammasome activation and bioactive IL-1β release in initiation of the Gout flare has led to the development of anti-IL-1β biological therapy for Gout flares. Sustained reduction in serum urate levels using urate-lowering therapy is vital in the long-term management of Gout, which aims to dissolve MSU crystals, suppress Gout flares and resolve tophi. Allopurinol is the first-line urate-lowering therapy and should be started at a low dose, with gradual dose escalation. Low-dose anti-inflammatory therapies can reduce Gout flares during initiation of urate-lowering therapy. Models of care, such as nurse-led strategies that focus on patient engagement and education, substantially improve clinical outcomes and now represent best practice for Gout management.
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Independent effects of ADH1B and ALDH2 common dysfunctional variants on Gout risk.
Scientific reports, 2017Co-Authors: Masayuki Sakiyama, Akiyoshi Nakayama, Hirotaka Matsuo, Sayo Kawai, Airi Akashi, Seiko Shimizu, Toshihide Higashino, Makoto Kawaguchi, Mariko Naito, Hiroshi NakashimaAbstract:Gout is caused by hyperuricemia, with alcohol consumption being an established risk factor. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are crucial enzymes for alcohol metabolism. We recently performed a genome-wide association study of Gout and a subsequent fine-mapping study which identified rs671 of ALDH2 as a Gout locus. However, the association between Gout and common variants of ADH1B has hitherto remained unreported, prompting us to investigate the association between Gout and common dysfunctional variants of ADH1B (rs1229984) and ALDH2 (rs671). We used 1,048 clinically defined Gout cases and 1,334 controls of Japanese male. The “His carrier” (His/His or His/Arg) of rs1229984 (His48Arg) of ADH1B significantly increased Gout risk (P = 4.3 × 10−4, odds ratio = 1.76), as did the “non-Lys carrier (Glu/Glu)” of rs671 (Glu504Lys) of ALDH2. Furthermore, common variants of ADH1B and ALDH2 are independently associated with Gout. Our findings likewise suggest that genotyping these variants can be useful for the evaluation of Gout risk.
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Identification of rs671, a common variant of ALDH2, as a Gout susceptibility locus.
Scientific reports, 2016Co-Authors: Masayuki Sakiyama, Akiyoshi Nakayama, Hirofumi Nakaoka, Ken Yamamoto, Takahiro Nakamura, Hirotaka Matsuo, Sayo Kawai, Rieko Okada, Hiroshi Ooyama, Toru ShimizuAbstract:Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between Gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be Gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected and genotyping of 1,048 male Gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with Gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with Gout (P = 1.7 × 10−18, odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with Gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine Gout-associated SNP in the MYL2-CUX2 locus and that “A” allele (Lys) of rs671 plays a protective role in the development of Gout.
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Common variant of ALPK1 is not associated with Gout: a replication study
Human Cell, 2015Co-Authors: Toshinori Chiba, Akiyoshi Nakayama, Masayuki Sakiyama, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Kenji Wakai, Shino Suma, Yutaka Sakurai, Toru ShimizuAbstract:Gout is one of the most kinds of common inflammatory arthritis as a consequence of hyperuricemia. Alpha-protein kinase 1 ( ALPK1 ) gene locates in a Gout-susceptibility locus on chromosome 4q21–31, and encodes ALPK1 protein which plays a pivotal role in the phosphorylation of myosin 1. In the previous genetic study of Taiwanese populations, 3 single nucleotide polymorphisms (SNPs), rs11726117, rs231247 and rs231253, in ALPK1 gene were reported to have a significant association with Gout. However, no replication study has been performed to confirm this association. Therefore, we first conducted a replication study with clinically defined Gout patients in a different population. Linkage disequilibrium (LD) analyzes of the 3 SNPs in ALPK1 revealed that these SNPs are in strong LD in a Japanese population. Among the 3 SNPs of ALPK1 , rs11726117 (M861T) is the only missense SNP. Therefore, rs11726117 was genotyped in a Japanese population of 903 clinically defined Gout cases and 1,302 controls, and was evaluated for a possible association with Gout. The minor allele frequencies of rs11726117 were 0.26 and 0.25 in the case and control groups, respectively. The association analysis has not detected a significant association between rs11726117 and Gout susceptibility in a Japanese population ( p = 0.44). Because ABCG2 , a major causative gene for Gout, also locates in the Gout-susceptibility locus on chromosome 4q, these findings suggest that among genes in a Gout-susceptibility locus, not ALPK1 but ABCG2 could be important as a Gout-susceptible gene.
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A common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload Gout, but not with all Gout susceptibility
Human Cell, 2013Co-Authors: Akiyoshi Nakayama, Takahiro Nakamura, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Takuya Shimizu, Hiraku Ogata, Yuzo Takada, Toshinori Chiba, Masayuki SakiyamaAbstract:Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, Gout patients can be divided into those with renal overload (ROL) Gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) Gout. Recent genome-wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 ( MCT9/SLC16A9 ) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and Gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL Gout ( p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all Gout cases ( p = 0.10), non-ROL Gout cases ( p = 0.83), and RUE Gout cases ( p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL Gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of Gout as well as the physiological roles of MCT9.
Takahiro Nakamura - One of the best experts on this subject based on the ideXlab platform.
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gwas of clinically defined Gout and subtypes identifies multiple susceptibility loci that include urate transporter genes
Annals of the Rheumatic Diseases, 2017Co-Authors: Akiyoshi Nakayama, Yu Toyoda, Hirofumi Nakaoka, Masayuki Sakiyama, Yukinori Okada, Aasma Shaukat, Yoichiro Kamatani, Ken Yamamoto, Takahiro NakamuraAbstract:Objective A genome-wide association study (GWAS) of Gout and its subtypes was performed to identify novel Gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined Gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of Gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p −8 ): urate transporter genes ( SLC22A12 and SLC17A1 ) and HIST1H2BF-HIST1H4E for all Gout cases, and NIPAL1 and FAM35A for the renal underexcretion Gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with Gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with Gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with Gout at a genome-wide level of significance (p meta =3.58×10 −8 ). Conclusions Our findings including novel Gout risk loci provide further understanding of the molecular pathogenesis of Gout and lead to a novel concept for the therapeutic target of Gout/hyperuricaemia.
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Identification of rs671, a common variant of ALDH2, as a Gout susceptibility locus.
Scientific reports, 2016Co-Authors: Masayuki Sakiyama, Akiyoshi Nakayama, Hirofumi Nakaoka, Ken Yamamoto, Takahiro Nakamura, Hirotaka Matsuo, Sayo Kawai, Rieko Okada, Hiroshi Ooyama, Toru ShimizuAbstract:Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between Gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between MYL2 and CUX2 on chromosome 12. However, other genes around rs2188380 could possibly be Gout susceptibility genes. Therefore, we performed a fine-mapping study of the MYL2-CUX2 region. From 8,595 SNPs in the MYL2-CUX2 region, 9 tag SNPs were selected and genotyping of 1,048 male Gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with Gout after Bonferroni correction. rs671 (Glu504Lys) of ALDH2 had the most significant association with Gout (P = 1.7 × 10−18, odds ratio = 0.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with Gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of ALDH2, is a genuine Gout-associated SNP in the MYL2-CUX2 locus and that “A” allele (Lys) of rs671 plays a protective role in the development of Gout.
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A common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload Gout, but not with all Gout susceptibility
Human Cell, 2013Co-Authors: Akiyoshi Nakayama, Takahiro Nakamura, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Takuya Shimizu, Hiraku Ogata, Yuzo Takada, Toshinori Chiba, Masayuki SakiyamaAbstract:Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, Gout patients can be divided into those with renal overload (ROL) Gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) Gout. Recent genome-wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 ( MCT9/SLC16A9 ) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and Gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL Gout ( p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all Gout cases ( p = 0.10), non-ROL Gout cases ( p = 0.83), and RUE Gout cases ( p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL Gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of Gout as well as the physiological roles of MCT9.
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a common missense variant of monocarboxylate transporter 9 mct9 slc16a9 gene is associated with renal overload Gout but not with all Gout susceptibility
Human Cell, 2013Co-Authors: Akiyoshi Nakayama, Takahiro Nakamura, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Takuya Shimizu, Hiraku Ogata, Yuzo Takada, Toshinori Chiba, Masayuki SakiyamaAbstract:Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, Gout patients can be divided into those with renal overload (ROL) Gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) Gout. Recent genome-wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 (MCT9/SLC16A9) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and Gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL Gout (p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all Gout cases (p = 0.10), non-ROL Gout cases (p = 0.83), and RUE Gout cases (p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL Gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of Gout as well as the physiological roles of MCT9.
Hyon K Choi - One of the best experts on this subject based on the ideXlab platform.
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risk of Gout flares after vaccination a prospective case cross over study
Annals of the Rheumatic Diseases, 2019Co-Authors: Chio Yokose, Tuhina Neogi, Robert Terkeltaub, Yuqing Zhang, Clara Chen, Christine E Chaisson, David J Hunter, Natalie Mccormick, Hyon K ChoiAbstract:Objectives The recombinant zoster vaccine (RZV) containing a strong non-aluminium adjuvant is associated with increased risk of Gout flares, presumably via NLRP3 inflammasome activation. We tested the possibility that other vaccines may also be associated with Gout flares. Methods We conducted an online case-crossover study of patients with Gout to examine the association between vaccination and Gout flares. We collected information through the Internet on exposures to potential risk factors, including vaccinations, during 2-day hazard periods prior to Gout flare and 2-day control periods without a flare. Conditional logistic regression was used to adjust for covariates. Results There were 517 participants with Gout (mean age 55 years, 79% male) who experienced Gout flares during follow-up. There were 28 vaccinations during 990 hazard periods and 21 vaccinations during 1407 control periods. Vaccination was associated with twofold higher odds of Gout flare (adjusted OR 1.99; 95% CI 1.01 to 3.89). Conclusion Our findings suggest vaccines other than RZV are associated with increased odds of Gout flares, potentially through a shared pathogenetic mechanism like NLRP3 inflammasome. However, the absolute magnitude of increased odds of Gout flares with vaccinations remains small and must be interpreted within the context of the overwhelming benefits of vaccinations.
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Gout.
Nature reviews. Disease primers, 2019Co-Authors: Nicola Dalbeth, Hyon K Choi, Hirotaka Matsuo, Leo A B Joosten, Puja P Khanna, Fernando Perez-ruiz, Lisa K StampAbstract:Gout is a chronic disease caused by monosodium urate (MSU) crystal deposition. Gout typically presents as an acute, self-limiting inflammatory monoarthritis that affects the joints of the lower limb. Elevated serum urate level (hyperuricaemia) is the major risk factor for MSU crystal deposition and development of Gout. Although traditionally considered a disorder of purine metabolism, altered urate transport, both in the gut and the kidneys, has a key role in the pathogenesis of hyperuricaemia. Anti-inflammatory agents, such corticosteroids, NSAIDs and colchicine, are widely used for the treatment of Gout flare; recognition of the importance of NLRP3 inflammasome activation and bioactive IL-1β release in initiation of the Gout flare has led to the development of anti-IL-1β biological therapy for Gout flares. Sustained reduction in serum urate levels using urate-lowering therapy is vital in the long-term management of Gout, which aims to dissolve MSU crystals, suppress Gout flares and resolve tophi. Allopurinol is the first-line urate-lowering therapy and should be started at a low dose, with gradual dose escalation. Low-dose anti-inflammatory therapies can reduce Gout flares during initiation of urate-lowering therapy. Models of care, such as nurse-led strategies that focus on patient engagement and education, substantially improve clinical outcomes and now represent best practice for Gout management.
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the dietary approaches to stop hypertension dash diet western diet and risk of Gout in men prospective cohort study
BMJ, 2017Co-Authors: Gary C Curhan, Hyon K Choi, Sharan K Rai, Teresa T Fung, Sarah F KellerAbstract:Objective To prospectively examine the relation between the Dietary Approaches to Stop Hypertension (DASH) and Western diets and risk of Gout (ie, the clinical endpoint of hyperuricemia) in men. Design Prospective cohort study. Setting The Health Professionals Follow-up Study. Participants 44 444 men with no history of Gout at baseline. Using validated food frequency questionnaires, each participant was assigned a DASH dietary pattern score (based on high intake of fruits, vegetables, nuts and legumes, low fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats) and a Western dietary pattern score (based on high intake of red and processed meats, French fries, refined grains, sweets, and desserts). Main outcome measure Risk of incident Gout meeting the preliminary American College of Rheumatology survey criteria for Gout, adjusting for potential confounders, including age, body mass index, hypertension, diuretic use, and alcohol intake. Results During 26 years of follow-up, 1731 confirmed cases of incident Gout were documented. A higher DASH dietary pattern score was associated with a lower risk for Gout (adjusted relative risk for extreme fifths 0.68, 95% confidence interval 0.57 to 0.80, P value for trend <0.001). In contrast, a higher Western dietary pattern score was associated with an increased risk for Gout (1.42, 1.16 to 1.74, P=0.005). Conclusion The DASH diet is associated with a lower risk of Gout, suggesting that its effect of lowering uric acid levels in individuals with hyperuricemia translates to a lower risk of Gout. Conversely, the Western diet is associated with a higher risk of Gout. The DASH diet may provide an attractive preventive dietary approach for men at risk of Gout.
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cherry consumption and decreased risk of recurrent Gout attacks
Arthritis & Rheumatism, 2012Co-Authors: Yuqing Zhang, Tuhina Neogi, Clara Chen, Christine E Chaisson, David J Hunter, Hyon K ChoiAbstract:Gout is an excruciatingly painful inflammatory arthritis caused by the crystallization of uric acid within joints. The prevalence of Gout in the US was estimated to be 3.9% of US adults based on the National Health and Nutrition Examination Survey 2007-2008, which translates into 8.3 million US adults (1, 2). While the pathophysiology of Gout is well-characterized and efficacious pharmacological regimens are available, many patients with Gout continue to experience recurrent Gout attacks (3, 4). Such attacks cause tremendous pain and suffering and are a major cause of morbidity. Over the past few decades, cherries have garnered considerable public attention and interest from both patients and investigators as potentially effective options in the prevention and management of Gout. Small experimental studies in healthy human subjects and animals have demonstrated that cherry consumption lowers serum uric acid levels (5, 6). Others have reported that cherry products contain high levels of anthocyanins (7-9) that possess anti-inflammatory and antioxidant properties (8, 10-12). Furthermore, some cherry producers have claimed that cherry products have the potential to reduce the pain associated with Gout (13) and some patients use cherries as a strategy to avoid and/or treat Gout attacks (14). However, to our knowledge, no study has assessed whether consumption of cherries lowers the risk of Gout attacks, as reflected in warning letters sent to various cherry-based product manufacturers by the Food and Drug Administration about the lack of sufficient data regarding their claims of disease-related benefits of cherry products (13). To help address this relevant knowledge gap, we analyzed 633 Gout patients who were prospectively recruited from across the United States in an online Gout study (15). In this study, we used a case-crossover design to quantify the relative risk of Gout attack after cherry intake as compared with no cherry intake and its potential modification by allopurinol use and major Gout risk factors.
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purine rich foods intake and recurrent Gout attacks
Annals of the Rheumatic Diseases, 2012Co-Authors: Yuqing Zhang, Hyon K Choi, Clara Chen, Christine E Chaisson, David J Hunter, Tuhina NeogiAbstract:Objective To examine and quantify the relation between purine intake and the risk of recurrent Gout attacks among Gout patients. Methods The authors conducted a case-crossover study to examine associations of a set of putative risk factors with recurrent Gout attacks. Individuals with Gout were prospectively recruited and followed online for 1 year. Participants were asked about the following information when experiencing a Gout attack: the onset date of the Gout attack, clinical symptoms and signs, medications (including antiGout medications), and presence of potential risk factors (including daily intake of various purine-containing food items) during the 2-day period prior to the Gout attack. The same exposure information was also assessed over 2-day control periods. Results This study included 633 participants with Gout. Compared with the lowest quintile of total purine intake over a 2-day period, OR of recurrent Gout attacks were 1.17, 1.38, 2.21 and 4.76, respectively, with each increasing quintile (p for trend <0.001). The corresponding OR were 1.42, 1.34, 1.77 and 2.41 for increasing quintiles of purine intake from animal sources (p for trend <0.001), and 1.12, 0.99, 1.32 and 1.39 from plant sources (p=0.04), respectively. The effect of purine intake persisted across subgroups by sex, use of alcohol, diuretics, allopurinol, NSAIDs and colchicine. Conclusions The study fi ndings suggest that acute purine intake increases the risk of recurrent Gout attacks by almost fi vefold among Gout patients. Avoiding or reducing amount of purine-rich foods intake, especially of animal origin, may help reduce the risk of Gout attacks.
