Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.
Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.
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DOI：
10.1161/circgenetics.113.000264
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Böger RH
中科院分区：
文献类型：
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作者：
Lüneburg N;Lieb W;Zeller T;Chen MH;Maas R;Carter AM;Xanthakis V;Glazer NL;Schwedhelm E;Seshadri S;Ikram MA;Longstreth WT Jr;Fornage M;König IR;Loley C;Ojeda FM;Schillert A;Wang TJ;Sticht H;Kittel A;König J;Benjamin EJ;Sullivan LM;Bernges I;Anderssohn M;Ziegler A;Gieger C;Illig T;Meisinger C;Wichmann HE;Wild PS;Schunkert H;Psaty BM;Wiggins KL;Heckbert SR;Smith N;Lackner K;Lunetta KL;Blankenberg S;Erdmann J;Munzel T;Grant PJ;Vasan RS;Böger RH
二甲基精氨酸（DMA）通过抑制NO合酶（不对称二甲基精氨酸，ADMA）和细胞对L-精氨酸的摄取（ADMA和对称二甲基精氨酸，SDMA）来干扰一氧化氮（NO）的形成。在前瞻性临床研究中，ADMA已被描述为心血管风险标志物，而SDMA是肾功能的新标志物，与缺血性卒中后的全因死亡率相关。本研究的目的是阐明这些生物标志物的个体间变异性的环境和遗传贡献。本研究包括对3个充分表征的基于人群的队列（FHS（n=2992）、GHS（n=4354）和MONICA/KORA F3（n=581））进行全基因组关联分析，并确定了与ADMA、L-精氨酸和SDMA个体间变异性相关的重复基因座（DDAH 1、MED 23、Arg 1和AGXT 2）。实验性计算机模拟和体外研究证实了所鉴定的AGXT 2变体的功能意义。对利兹卒中研究的384例患者进行的临床结果分析表明，血浆SDMA、AGXT 2变异体水平升高与各种心脏代谢风险因素之间存在相关性。在利兹研究中，AGXT 2变异与卒中后生存率无关，在CHARGE研究中，AGXT 2变异与卒中事件无关。这些GWAS支持DDAH 1和MED 23/Arg 1分别在调节ADMA和L-精氨酸代谢中的重要性，并确定了AGXT 2对SDMA的新的肾脏调节途径。AGXT 2变异可能解释SDMA、肾功能和预后之间的部分致病联系。AGXT 2变异与中风之间的关联尚不清楚，需要进一步研究。
Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and L-arginine uptake into the cell (ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a cardiovascular risk marker whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterise the environmental and genetic contributions to inter-individual variability of these biomarkers. This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (FHS (n=2992), GHS (n=4354) and MONICA/KORA F3 (n=581)) and identified replicated loci (DDAH1, MED23, Arg1 and AGXT2) associated with the inter-individual variability in ADMA, L-arginine and SDMA. Experimental in-silico and in-vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants and various cardiometabolic risk factors. AGXT2 variants were not associated with post-stroke survival in the Leeds study, nor were they associated with incident stroke in the CHARGE consortium. These GWAS support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and L-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.