GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.
GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.
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DOI：
10.1136/annrheumdis-2016-209632
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发表时间：
2017-05
影响因子：
27.4
通讯作者：
Eurogout Consortium
中科院分区：
文献类型：
--
作者：
Nakayama A;Nakaoka H;Yamamoto K;Sakiyama M;Shaukat A;Toyoda Y;Okada Y;Kamatani Y;Nakamura T;Takada T;Inoue K;Yasujima T;Yuasa H;Shirahama Y;Nakashima H;Shimizu S;Higashino T;Kawamura Y;Ogata H;Kawaguchi M;Ohkawa Y;Danjoh I;Tokumasu A;Ooyama K;Ito T;Kondo T;Wakai K;Stiburkova B;Pavelka K;Stamp LK;Dalbeth N;Eurogout Consortium;Sakurai Y;Suzuki H;Hosoyamada M;Fujimori S;Yokoo T;Hosoya T;Inoue I;Takahashi A;Kubo M;Ooyama H;Shimizu T;Ichida K;Shinomiya N;Merriman TR;Matsuo H;Eurogout Consortium
进行痛风及其亚型的全基因组关联研究（GWAS）以鉴定新的痛风位点，包括那些亚型特异性的位点。使用1961个单核苷酸多态性（SNP）的定制芯片，用1396个病例和1268个对照复制了来自日本男性的945例临床定义的痛风病例和1213名对照的GWAS的推定因果关联信号。我们还首先进行了痛风亚型的GWAS。用高加索人和新西兰波利尼西亚人样本进行复制，以进一步验证本研究中鉴定的基因座。除了我们之前报道的5个基因座，在全基因组显著性水平（p<5.0×10−8）下还发现了其他易感基因座：尿酸盐转运蛋白基因（SLC 22 A12和SLC 17 A1）和HIST 1H 2BF-HIST 1H 4 E适用于所有痛风病例，NIPAL 1和FAM 35 A适用于肾排泄不足型痛风亚型。虽然NIPAL 1编码镁转运蛋白，但功能分析未检测到尿酸盐通过NIPAL 1转运，表明与尿酸盐处理间接相关。在人肾脏中的定位分析揭示了NIPAL 1和FAM 35 A主要在远端小管中的表达，这表明远端肾单位参与了人类的尿酸盐处理。临床确诊的男性痛风患者和高加索人和波利尼西亚人祖先的对照也进行了基因分型，所有病例中FAM 35 A与痛风相关。对这三个群体的荟萃分析显示，FAM 35 A与痛风在全基因组水平上具有显著性（pmeta=3.58×10−8）。我们的研究结果包括新的痛风风险位点提供了进一步了解痛风的分子发病机制，并导致痛风/高尿酸血症的治疗靶点的新概念。
A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. 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. In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10−8): 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 (pmeta=3.58×10−8). 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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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
64.8
作者：
Enomoto, A;Kimura, H;Endou, H
通讯作者：
Endou, H
影响因子：
5.8
作者：
Beitz, E
通讯作者：
Beitz, E
DOI：
10.1016/0197-2456(86)90046-2
发表时间：
1986-09-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
DERSIMONIAN, R;LAIRD, N
通讯作者：
LAIRD, N
影响因子：
168.9
作者：
Dehghan, Abbas;Kottgen, Anna;Yang, Qiong;Hwang, Shih Jen;Kao, W. H. Linda;Rivadeneira, Fernando;Boerwinkle, Eric;Levy, Daniel;Hofman, Albert;Astor, Brad C.;Benjamin, Emelia J.;van Duijn, Cornelia M.;Witteman, Jacqueline C.;Coresh, Josef;Fox, Caroline S.
通讯作者：
Fox, Caroline S.