tetano
Editor, Senior Moderator
Natl Sci Rev
. 2022 Jul 1;9(9):nwac118.
doi: 10.1093/nsr/nwac118. eCollection 2022 Sep.
Lineage-specific positive selection on ACE2 contributes to the genetic susceptibility of COVID-19
Yuwen Pan[SUP] 1 [/SUP], Panhong Liu[SUP] 2 [/SUP], Fang Wang[SUP] 3 [/SUP], Peng Wu[SUP] 4 5 [/SUP], Fanjun Cheng[SUP] 6 [/SUP], Xin Jin[SUP] 7 [/SUP], Shuhua Xu[SUP] 8 9 10 11 12 [/SUP]
Affiliations
Abstract
The Angiotensin-Converting Enzyme-2 (ACE2) gene, located on Xp22.2, attracts a great deal of attention because the protein it encodes is believed to be the functional cellular receptor for the new coronavirus (SARS-CoV-2). However, recent studies are controversial, especially concerning the intrinsic link between ACE2 diversity and COVID-19 susceptibility. Here, we conduct a population genetic study on ACE2 in 6354 individuals representing 210 present-day populations and 5329 individuals of ancient or archaic groups. We dissected the genetic architecture of ACE2 and identified two major haplogroups (hg) in East Asians, i.e. ACE2-hg1 (43%) and ACE2-hg2 (53%), while other populations harbor more diverse ACE2-hgs. Accordingly, there was a significant loss of ACE2 common variations in East Asians in contrast to the X-chromosome-wide and genome-wide patterns. Notably, association analysis between ACE2-hgs and COVID-19 severity in 1229 Han Chinese individuals with various levels of COVID-19 severity showed a higher risk of ACE2-hg1 (odds ratio = 1.56, P < 0.01) and a lower risk of ACE2-hg2 (odds ratio = 0.65, P < 0.01). Interestingly, ACE2-hg1 is in strong linkage disequilibrium with rs1849863-C, which is an assumed risk factor of elevated plasma ACE2 level and is related to a higher risk of COVID-19 severity, hospitalization and infection. Strikingly, remarkable signatures of positive selection were detected, especially on ACE2-hg2, and were traced back to 100 000 years ago (but rose to a strong level during the Bronze Age, 5000∼3000 years ago, in East Asians). The selection pressures could have stemmed from multiple sources, but pre-COVID-19 viral epidemics and pandemics might have been potential driving forces, which consequently contributed to the genetic susceptibility to COVID-19 within and between populations.
Keywords: ACE2; COVID-19; East Asia; genetic diversity; genetic susceptibility; natural selection.
. 2022 Jul 1;9(9):nwac118.
doi: 10.1093/nsr/nwac118. eCollection 2022 Sep.
Lineage-specific positive selection on ACE2 contributes to the genetic susceptibility of COVID-19
Yuwen Pan[SUP] 1 [/SUP], Panhong Liu[SUP] 2 [/SUP], Fang Wang[SUP] 3 [/SUP], Peng Wu[SUP] 4 5 [/SUP], Fanjun Cheng[SUP] 6 [/SUP], Xin Jin[SUP] 7 [/SUP], Shuhua Xu[SUP] 8 9 10 11 12 [/SUP]
Affiliations
- PMID: 36199986
- PMCID: PMC9529360
- DOI: 10.1093/nsr/nwac118
Abstract
The Angiotensin-Converting Enzyme-2 (ACE2) gene, located on Xp22.2, attracts a great deal of attention because the protein it encodes is believed to be the functional cellular receptor for the new coronavirus (SARS-CoV-2). However, recent studies are controversial, especially concerning the intrinsic link between ACE2 diversity and COVID-19 susceptibility. Here, we conduct a population genetic study on ACE2 in 6354 individuals representing 210 present-day populations and 5329 individuals of ancient or archaic groups. We dissected the genetic architecture of ACE2 and identified two major haplogroups (hg) in East Asians, i.e. ACE2-hg1 (43%) and ACE2-hg2 (53%), while other populations harbor more diverse ACE2-hgs. Accordingly, there was a significant loss of ACE2 common variations in East Asians in contrast to the X-chromosome-wide and genome-wide patterns. Notably, association analysis between ACE2-hgs and COVID-19 severity in 1229 Han Chinese individuals with various levels of COVID-19 severity showed a higher risk of ACE2-hg1 (odds ratio = 1.56, P < 0.01) and a lower risk of ACE2-hg2 (odds ratio = 0.65, P < 0.01). Interestingly, ACE2-hg1 is in strong linkage disequilibrium with rs1849863-C, which is an assumed risk factor of elevated plasma ACE2 level and is related to a higher risk of COVID-19 severity, hospitalization and infection. Strikingly, remarkable signatures of positive selection were detected, especially on ACE2-hg2, and were traced back to 100 000 years ago (but rose to a strong level during the Bronze Age, 5000∼3000 years ago, in East Asians). The selection pressures could have stemmed from multiple sources, but pre-COVID-19 viral epidemics and pandemics might have been potential driving forces, which consequently contributed to the genetic susceptibility to COVID-19 within and between populations.
Keywords: ACE2; COVID-19; East Asia; genetic diversity; genetic susceptibility; natural selection.