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Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.
Ann Rheum Dis. 2016 Apr; 75(4):652-9.AR

Abstract

OBJECTIVE

Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only.

METHODS

A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls.

RESULTS

Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10(-12); OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10(-23); OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10(-9); OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10(-4)] for urate clearance and r=0.96 [p=5.0×10(-4)] for urinary urate excretion).

CONCLUSIONS

Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

Links

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Authors+Show Affiliations

Matsuo H
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Yamamoto K
Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
Nakaoka H
Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan.
Nakayama A
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan Medical Group, Headquarters, Iwo-to Air Base Group, Japan Air Self-Defense Force, Tokyo, Japan.
Sakiyama M
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan Department of Dermatology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Chiba T
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Takahashi A
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan.
Nakamura T
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Saitama, Japan.
Nakashima H
Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan.
Takada Y
The Central Research Institute, National Defense Medical College, Tokorozawa, Saitama, Japan.
Danjoh I
Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
Shimizu S
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Abe J
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Kawamura Y
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Terashige S
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Ogata H
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Tatsukawa S
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Yin G
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan Department of Nutritional Sciences, Faculty of Health and Welfare, Seinan Jo Gakuin University, Fukuoka, Japan.
Okada R
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Morita E
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Naito M
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Tokumasu A
Ryougoku East Gate Clinic, Tokyo, Japan.
Onoue H
Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
Iwaya K
Department of Pathology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Ito T
Department of Internal Medicine, Self-Defense Forces Central Hospital, Tokyo, Japan.
Takada T
Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
Inoue K
Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Kato Y
Faculty of Pharmacy, Kanazawa University, Kanazawa, Ishikawa, Japan.
Nakamura Y
Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
Sakurai Y
Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan.
Suzuki H
Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
Kanai Y
Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Hosoya T
Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan.
Hamajima N
Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Inoue I
Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan.
Kubo M
Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan.
Ichida K
Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Ooyama H
Ryougoku East Gate Clinic, Tokyo, Japan.
Shimizu T
Midorigaoka Hospital, Osaka, Japan.
Shinomiya N
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.

MeSH

ATP Binding Cassette Transporter, Subfamily G, Member 2ATP-Binding Cassette TransportersAdaptor Proteins, Signal TransducingAdultAgedAsian PeopleCardiac MyosinsCase-Control StudiesEgg ProteinsGenetic Predisposition to DiseaseGenome-Wide Association StudyGlucose Transport Proteins, FacilitativeGoutHumansHyperuricemiaJapanMaleMembrane ProteinsMiddle AgedMyosin Light ChainsNeoplasm ProteinsPolymorphism, Single NucleotideUric Acid

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25646370

Citation

Matsuo, Hirotaka, et al. "Genome-wide Association Study of Clinically Defined Gout Identifies Multiple Risk Loci and Its Association With Clinical Subtypes." Annals of the Rheumatic Diseases, vol. 75, no. 4, 2016, pp. 652-9.
Matsuo H, Yamamoto K, Nakaoka H, et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis. 2016;75(4):652-9.
Matsuo, H., Yamamoto, K., Nakaoka, H., Nakayama, A., Sakiyama, M., Chiba, T., Takahashi, A., Nakamura, T., Nakashima, H., Takada, Y., Danjoh, I., Shimizu, S., Abe, J., Kawamura, Y., Terashige, S., Ogata, H., Tatsukawa, S., Yin, G., Okada, R., ... Shinomiya, N. (2016). Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Annals of the Rheumatic Diseases, 75(4), 652-9. https://doi.org/10.1136/annrheumdis-2014-206191
Matsuo H, et al. Genome-wide Association Study of Clinically Defined Gout Identifies Multiple Risk Loci and Its Association With Clinical Subtypes. Ann Rheum Dis. 2016;75(4):652-9. PubMed PMID: 25646370.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. AU - Matsuo,Hirotaka, AU - Yamamoto,Ken, AU - Nakaoka,Hirofumi, AU - Nakayama,Akiyoshi, AU - Sakiyama,Masayuki, AU - Chiba,Toshinori, AU - Takahashi,Atsushi, AU - Nakamura,Takahiro, AU - Nakashima,Hiroshi, AU - Takada,Yuzo, AU - Danjoh,Inaho, AU - Shimizu,Seiko, AU - Abe,Junko, AU - Kawamura,Yusuke, AU - Terashige,Sho, AU - Ogata,Hiraku, AU - Tatsukawa,Seishiro, AU - Yin,Guang, AU - Okada,Rieko, AU - Morita,Emi, AU - Naito,Mariko, AU - Tokumasu,Atsumi, AU - Onoue,Hiroyuki, AU - Iwaya,Keiichi, AU - Ito,Toshimitsu, AU - Takada,Tappei, AU - Inoue,Katsuhisa, AU - Kato,Yukio, AU - Nakamura,Yukio, AU - Sakurai,Yutaka, AU - Suzuki,Hiroshi, AU - Kanai,Yoshikatsu, AU - Hosoya,Tatsuo, AU - Hamajima,Nobuyuki, AU - Inoue,Ituro, AU - Kubo,Michiaki, AU - Ichida,Kimiyoshi, AU - Ooyama,Hiroshi, AU - Shimizu,Toru, AU - Shinomiya,Nariyoshi, Y1 - 2015/02/02/ PY - 2014/7/1/received PY - 2015/1/6/accepted PY - 2015/2/4/entrez PY - 2015/2/4/pubmed PY - 2016/7/22/medline KW - Arthritis KW - Gene Polymorphism KW - Gout SP - 652 EP - 9 JF - Annals of the rheumatic diseases JO - Ann Rheum Dis VL - 75 IS - 4 N2 - OBJECTIVE: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. METHODS: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. RESULTS: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10(-12); OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10(-23); OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10(-9); OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10(-4)] for urate clearance and r=0.96 [p=5.0×10(-4)] for urinary urate excretion). CONCLUSIONS: Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics. SN - 1468-2060 UR - https://www.unboundmedicine.com/medline/citation/25646370/Genome_wide_association_study_of_clinically_defined_gout_identifies_multiple_risk_loci_and_its_association_with_clinical_subtypes_ DB - PRIME DP - Unbound Medicine ER -