Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude
Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude
复制标题
DOI：
10.1073/pnas.1906171116
复制
发表时间：
2019-11-26
影响因子：
11.1
通讯作者：
Bigham, Abigail W.
中科院分区：
文献类型：
--
作者：
Brutsaert, Tom D.;Kiyamu, Melisa;Bigham, Abigail W.
高地土著安第斯人已经居住在海拔数千年。它们在高海拔地区表现出较高的有氧代谢能力（VO（2）max），这可能是遗传适应缺氧的反映。先前用于自然选择的全基因组（GW）扫描已经提名Egl-9同源物1基因（EGLN 1）作为候选基因。编码的蛋白质EGLN 1/PHD 2是一种O-2传感器，控制缺氧诱导因子-α（HIF-α）的水平，该因子调节细胞对缺氧的反应。通过对429名秘鲁盖丘亚族和94名美国低地参考者的总样本进行GW关联和协方差分析，我们确定了5个EGLN 1 SNP 5与低氧时较高的VO（2）max（L.min（-1）和mL.min（-1）.kg（-1））相关（rs 1769793、rs 2064766、rs 2437150、rs 2491403、rs 479200）。对于这些SNP 5中的4个，与来自1000个基因组计划的25个不同的低地比较群体相比，克丘亚族具有最高频率的有利（高VO（2）max）等位基因。基因型效应是实质性的，高与低VO（2）max基因型类别的差异接近11%（例如，对于rs 1769793 SNP基因型，TT = 34.2 mL.min（-1）.kg（-1）vs. CC = 30.5 mL.min（-1）.kg（-1））。为了防止虚假的关联，我们控制了人群分层。在2002年收集的一个独立的安第斯样本中，EGLN 1 SNP rs 1769793的发现得到了复制。这些发现结合了之前关于安第斯山脉EGLN 1自然选择的报道，并支持了这样的假设：自然选择增加了EGLN 1因果变异的频率，该变异增强了秘鲁克丘亚人在高海拔运动期间O-2的输送或使用。
Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO(2)max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O-2 sensor that controls levels of the Hypoxia Inducible Factor-alpha (HIF-alpha), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNP5 associated with higher VO(2)max (L.min(-1) and mL.min(-l).kg(-1)) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNP5, Quechua had the highest frequency of the advantageous (high VO(2)max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO(2)max genotype categories differing by similar to 11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL.min(-l).kg(-1) vs. CC = 30.5 mL.min(-l).kg(-1)). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O-2 delivery or use during exercise at altitude in Peruvian Quechua.