Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.
Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.
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DOI：
10.1016/s0140-6736(08)61343-4
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发表时间：
2008-12-06
期刊：
影响因子：
168.9
通讯作者：
Fox, Caroline S.
中科院分区：
文献类型：
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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.
高尿酸血症是一种高度可遗传的特征，是痛风的关键风险因素。我们的目标是发现与血清尿酸(UA)和痛风相关的新基因。在弗雷明翰心脏研究(FHS；n=7699)和鹿特丹研究(RS；n=4148)中，对血清UA进行了全基因组关联研究(GWAS)。在白人(n=11024)和黑人(n=3843)社区动脉粥样硬化风险研究参与者中复制了全基因组显著的SNPs。用痛风评估这些SNPs的关联性；用Meta分析结合白人的结果。FHS中的3个基因座和RS中的2个基因座对UA具有全基因组意义。错义SNP分别为：SLC2A9错义SNP rs16890979(p=7.0x10−168[白人]；2.9×10−18[黑人])；错义SNP rs2 231142(p=2.5×10−60[白人]；9.8×10−4[黑人])；SLC17A3 rs1165205(p=3.3×10−2 6[白人]；0.33[黑人])。在白人中，所有SNP与痛风存在方向一致的关联：rs16890979(每T等位基因OR0.58，95%CI0.53-0.63，p=1.2×10−31)、rs2231142(每T等位基因OR=1.74，1.51-1.99，p=3.3×10−15)和rs1165205(OR=每T等位基因0.85，0.77-0.94，p=0.002)。在ARIC黑人中，rs2231142与痛风存在方向一致的关联(OR=1.71，1.06-2.77，p=0.028)。在每项研究中，由三个座位的高危等位基因组成的可加性遗传风险得分(0~6)显示出与尿酸(从272~351FHS，269~386μμ/L，303~426μ摩尔/L[ARIC白色])和痛风(患病率2~13%[FHS]，2~8%[RS]，1~18%[ARIC白色])的分级关联。我们发现了三个与UA和痛风相关的遗传位点(其中两个是新发现的，包括ABCG2中的一个候选功能变异Q141K)。根据在肾尿酸盐处理中可能起作用的基因进行的评分显示，痛风的风险梯度很大。
Hyperuricemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes related to serum uric acid (UA) and gout. Genome-wide association studies (GWAS) were conducted for serum UA in the Framingham Heart Study (FHS; n=7699) and the Rotterdam Study (RS; n=4148). Genome-wide significant SNPs were replicated among white (n=11024) and black (n=3843) Atherosclerosis Risk in Communities (ARIC) Study participants. The association of these SNPs was evaluated with gout; results in whites were combined using meta-analysis. Three loci in FHS and two in the RS showed genome-wide significance with UA. Top SNPs in each locus were: missense SNP rs16890979 in SLC2A9 (p=7.0×10−168 [whites]; 2.9×10−18 [blacks]), missense SNP rs2231142 in ABCG2 (p=2.5×10−60 [whites]; 9.8×10−4 [blacks]), and rs1165205 in SLC17A3 (p=3.3×10−26 [whites]; 0.33 [blacks]). All SNPs showed direction-consistent association with gout in whites: rs16890979 (OR 0.58 per T allele, 95% CI 0.53–0.63, p=1.2×10−31), rs2231142 (OR=1.74 per T allele, 1.51–1.99, p=3.3×10−15), and rs1165205 (OR=0.85 per T allele, 0.77–0.94, p=0.002). In ARIC blacks, rs2231142 showed a direction-consistent association with gout (OR=1.71, 1.06–2.77, p=0.028). An additive genetic risk score (0–6) comprised of high risk alleles at the three loci showed graded associations in each study across scores with UA (from 272–351 μmol/l [FHS], 269–386 μmol/l [RS], and 303–426 μmol/l [ARIC whites]) and gout (prevalence 2–13% [FHS], 2–8% [RS], 1–18% [ARIC whites]). We identified three genetic loci (two novel including a candidate functional variant Q141K in ABCG2) related to UA and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk gradient for gout.