deCODE genetics/Amgen Inc., Reykjavik, Iceland.
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Commun Biol. 2020 Apr 23;3(1):189. doi: 10.1038/s42003-020-0921-5.
Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (Effect = -1.61 SD, CI = [-1.98, -1.35]; Effect = 0.63 SD, CI = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.
血红蛋白是人类中重要的携氧分子，其水平受到细胞内铁和氧感应机制的调节。为了寻找与血红蛋白浓度相关的新型变异，我们使用来自冰岛和英国的 684122 人的组合数据集，进行了血红蛋白浓度的全基因组关联研究。值得注意的是，我们在 ACO1 基因座发现了七个与血红蛋白浓度降低或升高相关的新型变异，其中六个为罕见编码变异，一个为常见变异。在这些变异中，错义突变 Cys506Ser 和无义突变 Lys334Ter 分别只存在于 8 代和 10 代的家系中，且在研究中具有最大的两种效应（效应值=-1.61SD，置信区间[-1.98，-1.35]；效应值=0.63SD，置信区间[0.36，0.91]）。我们还发现 Cys506Ser 与持续性贫血风险增加相关（比值比=17.1，P=2×10）。在这项研究中观察到的强烈双向作用表明，ACO1 作为一种已知的铁感应分子，是血红蛋白浓度的主要体内平衡调节剂。
