Tin A, Balakrishnan P, Beaty T H, Boerwinkle E, Hoogeveen R C, Young J H, Kao W H L
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Human Genetics Center, University of Texas School of Public Health, Houston, TX, USA.
Diabet Med. 2016 Jul;33(7):968-75. doi: 10.1111/dme.12971. Epub 2015 Oct 30.
To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes.
We conducted a genome-wide association study of log-transformed plasma lactate levels in 6901 European-American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects.
The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele β=0.08; P=1.8×10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele β=0.06; P=1.6×10(-9) ). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01).
We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes-related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism.
研究循环乳酸水平的遗传影响，循环乳酸水平是与糖尿病相关的氧化能力标志物。
我们对社区动脉粥样硬化风险研究中6901名欧美参与者的血浆乳酸水平进行对数转换后，开展了全基因组关联研究。对于在欧美参与者中达到全基因组显著性的区域，我们在非裔美国受试者中进行了候选区域分析，并测试了二甲双胍使用与欧美受试者血浆乳酸指数单核苷酸多态性之间的相互作用。
欧美受试者的全基因组关联研究确定了两个全基因组显著性位点，即GCKR（rs1260326，T等位基因β=0.08；P=1.8×10⁻⁴⁷）和PPP1R3B/LOC157273（rs9987289，A等位基因β=0.06；P=1.6×10⁻⁹）。这两个位点的指数单核苷酸多态性解释了欧美受试者中对数转换后血浆乳酸水平变异的3.3%。在非裔美国受试者中，基于区域显著性阈值，GCKR处的指数单核苷酸多态性与血浆乳酸相关，但PPP1R3B/LOC157273处的则不相关。二甲双胍的使用似乎增强了欧美受试者中PPP1R3B/LOC157273处指数单核苷酸多态性与血浆乳酸之间的关联（相互作用P=0.01）。
我们确定GCKR和PPP1R3B/LOC157273为血浆乳酸的两个全基因组显著性位点。这两个位点均与其他糖尿病相关表型有关。这些发现增进了我们对乳酸代谢遗传控制的理解。
