Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes

被引:141
作者
Matsuo, Hirotaka [1 ]
Yamamoto, Ken [2 ]
Nakaoka, Hirofumi [3 ]
Nakayama, Akiyoshi [1 ,4 ]
Sakiyama, Masayuki [1 ,5 ]
Chiba, Toshinori [1 ]
Takahashi, Atsushi [6 ]
Nakamura, Takahiro [6 ,7 ]
Nakashima, Hiroshi [8 ]
Takada, Yuzo [9 ]
Danjoh, Inaho [10 ,11 ]
Shimizu, Seiko [1 ]
Abe, Junko [1 ]
Kawamura, Yusuke [1 ]
Terashige, Sho [1 ]
Ogata, Hiraku [1 ]
Tatsukawa, Seishiro [1 ]
Yin, Guang [12 ,13 ]
Okada, Rieko [12 ]
Morita, Emi [12 ]
Naito, Mariko [12 ]
Tokumasu, Atsumi [14 ]
Onoue, Hiroyuki [15 ]
Iwaya, Keiichi [16 ]
Ito, Toshimitsu [17 ]
Takada, Tappei [18 ]
Inoue, Katsuhisa [19 ]
Kato, Yukio [20 ]
Nakamura, Yukio [10 ]
Sakurai, Yutaka [8 ]
Suzuki, Hiroshi [18 ]
Kanai, Yoshikatsu [21 ]
Hosoya, Tatsuo [22 ,23 ]
Hamajima, Nobuyuki [24 ]
Inoue, Ituro [3 ]
Kubo, Michiaki [25 ]
Ichida, Kimiyoshi [26 ]
Ooyama, Hiroshi [14 ]
Shimizu, Toru [27 ]
Shinomiya, Nariyoshi [1 ]
机构
[1] Natl Def Med Coll, Dept Integrat Physiol & Bionano Med, 3-2 Namiki, Tokorozawa, Saitama 3598513, Japan
[2] Kurume Univ, Sch Med, Dept Med Chem, Kurume, Fukuoka 830, Japan
[3] Natl Inst Genet, Div Human Genet, Dept Integrated Genet, Mishima, Shizuoka 411, Japan
[4] Japan Air Self Def Force, Iwo To Air Base Grp, Med Grp, Headquarters, Tokyo, Japan
[5] Natl Def Med Coll, Dept Dermatol, Tokorozawa, Saitama 3598513, Japan
[6] RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan
[7] Natl Def Med Coll, Math Lab, Tokorozawa, Saitama 3598513, Japan
[8] Natl Def Med Coll, Dept Prevent Med & Publ Hlth, Tokorozawa, Saitama 3598513, Japan
[9] Natl Def Med Coll, Cent Res Inst, Tokorozawa, Saitama 3598513, Japan
[10] RIKEN, BioResource Ctr, Cell Engn Div, Tsukuba, Ibaraki, Japan
[11] Tohoku Univ, Tohoku Med Megabank Org, Dept Integrat Genom, Sendai, Miyagi 980, Japan
[12] Nagoya Univ, Grad Sch Med, Dept Prevent Med, Nagoya, Aichi 4648601, Japan
[13] Seinan Jo Gakuin Univ, Fac Hlth & Welf, Dept Nutr Sci, Fukuoka, Japan
[14] Ryougoku East Gate Clin, Tokyo, Japan
[15] Natl Def Med Coll, Dept Internal Med, Tokorozawa, Saitama 3598513, Japan
[16] Natl Def Med Coll, Dept Pathol, Tokorozawa, Saitama 3598513, Japan
[17] Self Def Forces Cent Hosp, Dept Internal Med, Tokyo, Japan
[18] Tokyo Univ Hosp, Dept Pharm, Tokyo 113, Japan
[19] Tokyo Univ Pharm & Life Sci, Sch Pharm, Dept Biopharmaceut, Tokyo, Japan
[20] Kanazawa Univ, Fac Pharm, Kanazawa, Ishikawa, Japan
[21] Osaka Univ, Grad Sch Med, Dept Pharmacol, Div Biosyst Pharmacol, Osaka, Japan
[22] Jikei Univ, Sch Med, Dept Internal Med, Div Kidney & Hypertens, Tokyo, Japan
[23] Jikei Univ, Sch Med, Dept Pathophysiol & Therapy Chron Kidney Dis, Tokyo, Japan
[24] Nagoya Univ, Grad Sch Med, Dept Healthcare Adm, Nagoya, Aichi 4648601, Japan
[25] RIKEN, Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan
[26] Tokyo Univ Pharm & Life Sci, Dept Pathophysiol, Tokyo, Japan
[27] Midorigaoka Hosp, Osaka, Japan
基金
日本学术振兴会;
关键词
RESISTANCE PROTEIN TRANSPORTER; GLUCOKINASE-REGULATORY-PROTEIN; URIC-ACID; GENETIC-LOCI; CORNICHON PROTEINS; URATE TRANSPORTER; FASTING GLUCOSE; COMMON; METAANALYSIS; VARIANTS;
D O I
10.1136/annrheumdis-2014-206191
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 < 5.0x10(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p = 1.9x10(-12); OR = 1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p = 1.6x10(-23); OR = 1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p = 6.4x10(-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 = 4.8x10(-4)] for urate clearance and r = 0.96 [p = 5.0x10(-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.
引用
收藏
页码:652 / 659
页数:8
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