An update on the genetic architecture of hyperuricemia and gout.
An update on the genetic architecture of hyperuricemia and gout.
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DOI：
10.1186/s13075-015-0609-2
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发表时间：
2015-04-10
影响因子：
4.9
通讯作者：
Merriman TR
中科院分区：
文献类型：
--
作者：
Merriman TR
全基因组关联研究扫描基因组，寻找与表型相关的常见遗传变异，极大地促进了医学知识的发展。高尿酸血症也不例外，发现了28个基因位点。然而，在高尿酸血症的情况下决定痛风的通路的遗传控制仍然知之甚少。确定高尿酸血症的两条重要途径已被证实(肾脏和肠道尿酸排泄与糖酵解密切相关)。主要的尿酸盐位点为SLC2A9和ABCG2。最近的研究表明，SLC2A9参与肾脏和肠道尿酸的排泄，并参与抗氧化防御。虽然SLC2A9的病因学变异尚未确定，但很明显，SLC2A9基因座存在相当大的遗传复杂性，具有多个统计上独立的遗传变异和局部上位性相互作用。涉及转录控制的染色质区域内或附近的相关遗传变异的位置表明，这一机制(而不是SLC2A9的结构变化)在调节SLC2A9的活性方面是重要的。ABCG2主要参与肾外尿酸排泄不足，病原学变异影响其表达。在其他26个基因座上，在3个(PDZK1、SLC22A11和INHBB)座位上可以识别出可能的致病基因，在另外10个座位上有较强的候选基因。对因果基因的确认将需要结合重新测序、跨祖先作图以及遗传关联数据与表达数据的关联。正如预期的那样，尿酸盐基因座与痛风有关，尽管痛风的影响大小不一致，但需要进行调查。最后，还没有通过临床确诊病例来研究高尿酸血症引起痛风的原因的全基因组相关性研究。在这样的研究中，使用无症状高尿酸血症对照有望提高检测痛风遗传关联的能力。
Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense. Although etiological variants at SLC2A9 are yet to be identified, it is clear that considerable genetic complexity exists at the SLC2A9 locus, with multiple statistically independent genetic variants and local epistatic interactions. The positions of implicated genetic variants within or near chromatin regions involved in transcriptional control suggest that this mechanism (rather than structural changes in SLC2A9) is important in regulating the activity of SLC2A9. ABCG2 is involved primarily in extra-renal uric acid under-excretion with the etiological variant influencing expression. At the other 26 loci, probable causal genes can be identified at three (PDZK1, SLC22A11, and INHBB) with strong candidates at a further 10 loci. Confirmation of the causal gene will require a combination of re-sequencing, trans-ancestral mapping, and correlation of genetic association data with expression data. As expected, the urate loci associate with gout, although inconsistent effect sizes for gout require investigation. Finally, there has been no genome-wide association study using clinically ascertained cases to investigate the causes of gout in the presence of hyperuricemia. In such a study, use of asymptomatic hyperurcemic controls would be expected to increase the ability to detect genetic associations with gout.
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影响因子：
4.9
作者：
Busso N;So A
通讯作者：
So A
影响因子：
16.6
作者：
通讯作者：
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DOI：
10.1073/pnas.78.11.6858
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
AMES, BN;CATHCART, R;HOCHSTEIN, P
通讯作者：
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2.4
作者：
Boffetta, Paolo;Nordenvall, Caroline;Ye, Weimin
通讯作者：
Ye, Weimin
影响因子：
19.6
作者：
Hughes K;Flynn T;de Zoysa J;Dalbeth N;Merriman TR
通讯作者：
Merriman TR