Zhou Jingqi, Sun Yitang, Huang Weishan, Ye Kaixiong
Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, USA.
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
J Gerontol A Biol Sci Med Sci. 2021 Jul 13;76(8):e147-e154. doi: 10.1093/gerona/glab035.
The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown.
To identify intermediate traits associated with the 3p21.31 locus, we first performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310 999 European individuals from the UK Biobank. For genes potentially regulated by the COVID-19 risk variant, we examined associations between their expression and the polygenic score (PGS) of 1263 complex traits in a meta-analysis of 31 684 blood samples. For the prioritized blood cell traits, we tested their associations with age and sex in the same UK Biobank sample.
Our PheWAS highlighted multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07 × 10-8, 4.09 × 10-13), eosinophil count and percentage (p = 5.73 × 10-3, 2.20 × 10-3), and neutrophil percentage (p = 3.23 × 10-3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73 × 10-21, 5.08 × 10-19); CCR2 with monocytes (p = 2.40 × 10-10); and CCR1 with monocytes and neutrophil (p = 1.78 × 10-6, 7.17 × 10-5). Additionally, we found that almost all examined white blood cell traits are significantly different across age and sex groups.
Our findings suggest that altered blood cell traits, especially those of monocyte, eosinophil, and neutrophil, may represent the mechanistic links between the genetic locus 3p21.31 and severe COVID-19. They may also underlie the increased risk of severe COVID-19 in older adults and men.
基因位点3p21.31与重症2019冠状病毒病（COVID-19）相关，但潜在的病理生理机制尚不清楚。
为了确定与3p21.31位点相关的中间性状，我们首先在英国生物银行的310999名欧洲个体中，对923种表型进行了全表型组关联研究（PheWAS）。对于可能受COVID-19风险变异调控的基因，我们在对31684份血液样本的荟萃分析中，检查了它们的表达与1263种复杂性状的多基因评分（PGS）之间的关联。对于优先考虑的血细胞性状，我们在同一个英国生物银行样本中测试了它们与年龄和性别的关联。
我们的PheWAS突出显示了多种血细胞性状与COVID-19风险变异相关，包括单核细胞计数和百分比（p = 1.07×10⁻⁸，4.09×10⁻¹³）、嗜酸性粒细胞计数和百分比（p = 5.73×10⁻³，2.20×10⁻³）以及中性粒细胞百分比（p = 3.23×10⁻³）。PGS分析揭示了候选基因的表达与特定血细胞的遗传预测计数之间存在正相关：CCR3与嗜酸性粒细胞和嗜碱性粒细胞（p = 5.73×10⁻²¹，5.08×10⁻¹⁹）；CCR2与单核细胞（p = 2.40×10⁻¹⁰）；CCR1与单核细胞和中性粒细胞（p = 1.78×10⁻⁶，7.17×10⁻⁵）。此外，我们发现几乎所有检测的白细胞性状在年龄和性别组之间存在显著差异。
我们的研究结果表明，血细胞性状的改变，尤其是单核细胞、嗜酸性粒细胞和中性粒细胞的性状改变，可能代表了基因位点3p21.31与重症COVID-19之间的机制联系。它们也可能是老年人和男性患重症COVID-19风险增加的基础。
