The numbers of cases of and deaths from COVID-19 in East Asian countries are obviously lower than those in other parts of the world (677.9 cases and 12.6 deaths per 1 million population in Japan, 4521 cases and 133.2 deaths per 1 million population in the world) [1]. Basic research has shown that angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are crucial for SARS-CoV-2 infection. Recent studies have indicated that the genetic diversity of ACE2 and TMPRSS2 variants across races might affect these functions and the susceptibility, symptoms and outcome of SARS-CoV-2 infection [[2], [3], [4], [5]]. Therefore, understanding racial differences in ACE2 and TMPRSS2 gene variants underlying the potential severity of COVID-19 is important.
We analyzed the coding variants of ACE2 and TMPRSS2 and their allele frequencies (AFs) in 350 Japanese patients with advanced-stage lung cancer using whole-exome sequencing data in a study that was part of the International Lung Cancer Genome Screening Project in East Asia (LC-SCRUM-Asia). In addition, we compared the observed genetic variants and their AFs with those of other Japanese cohorts and other ethnic populations using publicly available genomic databases: dbSNP, GnomAD and TOPMed.
In our Japanese lung cancer cohort, 9 and 7 variants were found in ACE2 and TMPRSS2, respectively (Table 1 ). All the variants except for two intron variants near exons were missense changes. Silent amino acid changes were excluded from the analysis. The AFs of c. 439 + 4G > A in ACE2 (rs2285666) and c.589 G > A in TMPRSS2 (rs12329760) were much higher in East Asians (0.5281 and 0.4172, respectively) in both our cohort and another Japanese cohort (The Tohoku Medical Megabank Project database) than in Caucasians (0.3692 and 0.1722, respectively). On the other hand, c.23 G > T in TMPRSS2 (rs75603675) was more frequent in Caucasians than in East Asians (0.2845 vs. 0.0141, respectively). The AFs of other variants were similar among the compared populations. The above-mentioned variants with significant AF differences might be associated with the differences in disease severity of COVID-19 between East Asians and Caucasians.
Table 1.
Coding variants of ACE2 and TMPRSS2 in Japanese lung cancer patients and racial comparisons of AFs.
| Gene | Position | dbSNP rs# | Amino acid change | CDS | Japanese lung cancer patients (LC-SCRUM-Asia) |
Genome database (freq.) |
|||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Zygosity |
Total (N = 350) |
||||||||||||||||||
| Hetero |
Homo |
ToMMo (JPN) |
GnomAD |
TOPMed | ExAC | ||||||||||||||
| N | freq. | N | freq. | N | freq. | AFR | AMR | ASJ | EAS | NFE | Whole | ||||||||
| ACE2 | chrX: 15618865 | - | p.E57G | c.170A > G | 1 | 0.0029 | - | - | 1 | 0.0029 | - | - | - | - | - | - | - | - | - |
| chrX: 15610348 | rs2285666 | Intron Variant | c.439 + 4G > A | 51 | 0.1457 | 152 | 0.4343 | 203 | 0.5800 | 0.4973 | 0.2204 | 0.3692 | 0.2590 | 0.5281 | 0.1991 | 0.2324 | 0.2503 | 0.1770 | |
| chrX: 15609946 | - | p.Y158C | c.473A > G | 1 | 0.0029 | - | - | 1 | 0.0029 | - | - | - | - | - | - | - | - | - | |
| chrX: 15603621 | - | p.V293F | c.877 G > T | 1 | 0.0029 | - | - | 1 | 0.0029 | - | - | - | - | - | - | - | - | - | |
| chrX: 15596236 | - | p.S425A | c.1273 T > G | - | - | 1 | 0.0029 | 1 | 0.0029 | - | - | - | - | - | - | - | - | - | |
| chrX: 15593829 | rs191860450 | p.I468V | c.1402A > G | - | - | 1 | 0.0029 | 1 | 0.0029 | 0.0035 | 0.0000 | 0.0000 | 0.0000 | 0.0112 | 0.0000 | 0.0006 | 0.0010 | 0.0007 | |
| chrX: 15589926 | rs774469453 | splice region variant | c.1665-7delT | - | - | - | - | not detected | 0.0159 | 0.0009 | 0.0211 | 0.0000 | 0.0010 | 0.0006 | 0.0014 | 0.0062 | 0.0050 | ||
| chrX: 15589842 | - | p.V581A | c.1742 T > C | 1 | 0.0029 | - | - | 1 | 0.0029 | - | - | - | - | - | - | - | - | - | |
| chrX: 15582333 | rs769062069 | p.R708Q | c.2123 G > A | - | - | 1 | 0.0029 | 1 | 0.0029 | - | - | - | - | - | - | 0.0000 | - | 0.0000 | |
| chrX: 15582298 | rs41303171 | p.N720D | c.2158A > G | - | - | - | - | not detected | - | 0.0032 | 0.0043 | 0.0155 | 0.0000 | 0.0247 | 0.0153 | 0.0140 | 0.0165 | ||
| chrX: 15582250 | - | p.Q736K | c.2206C > A | 1 | 0.0029 | - | - | 1 | 0.0029 | - | - | - | - | - | - | - | - | - | |
| Gene | Position | dbSNP rs# | Amino acid change | CDS | Japanese lung cancer patients (LC-SCRUM-Asia) |
Genome database |
|||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Zygosity |
Total (N = 350) |
freq. |
|||||||||||||||||
| Hetero |
Homo |
ToMMo (JPN) | GnomAD |
TOPMed | ExAC | ||||||||||||||
| N | freq. | N | freq. | N | freq. | AFR | AMR | ASJ | EAS | NFE | Whole | ||||||||
| TMPRSS2 | chr21:42879909 | rs75603675 | p.G8V | c.23 G > T | 3 | 0.0086 | - | - | 3 | 0.0086 | 0.0031 | 0.3279 | 0.2845 | 0.3681 | 0.0141 | 0.4169 | 0.3642 | 0.3516 | 0.3575 |
| chr21:42866439 | rs61735791 | p.A65T | c.193 G > A | 4 | 0.0114 | - | - | 4 | 0.0114 | 0.0073 | 0.0010 | 0.0007 | 0.0003 | 0.0003 | 0.0029 | 0.0017 | 0.0020 | 0.0016 | |
| chr21:42866388 | rs201679623 | p.Y82D | c.244 T > G | 2 | 0.0057 | - | - | 2 | 0.0057 | 0.0010 | 0.0000 | 0.0000 | 0.0000 | 0.0061 | 0.0000 | 0.0002 | 0.0006 | 0.0005 | |
| chr21:42866384 | rs1016773134 | p.P83L | c.248C > T | 1 | 0.0029 | - | - | 1 | 0.0029 | - | 0.0000 | 0.0001 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | - | |
| chr21:42866331 | rs574582815 | p.V101l | c.301 G > A | 1 | 0.0029 | - | - | 1 | 0.0029 | - | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0000 | 0.0001 | |
| chr21:42852497 | rs12329760 | p.V197M | c.589 G > A | 165 | 0.4714 | 49 | 0.1400 | 214 | 0.6114 | 0.3837 | 0.2884 | 0.1722 | 0.1007 | 0.4172 | 0.2474 | 0.2801 | 0.2470 | 0.2502 | |
| chr21:42842591 | rs61735794 | p.G422G | c.1266 G > A | - | - | - | - | not detected | - | 0.0057 | 0.0189 | 0.0196 | 0.0000 | 0.0305 | 0.0203 | - | 0.0206 | ||
Genetic variants are listed if they were detected in a whole-exome sequence or if the AF was more than 0.01 in at least one of the databases.
Position numbers indicate distance from 5′ end of the original exon 1.
ToMMo: The Tohoku Medical Megabank Project, GnomAD: The Genome Aggregation Database, TOPMed: Trans-Omics for Precision Medicine, ExAC: The Exome Aggregation Consortium.
JPN: Japanese, AFR: African-American/African, AMR: Latino, ASJ: Ashkenazi Jewish, EAS: East Asian, NFE: Non-Finnish European.
141 patients have no variant in ACE2 and 127 patients have no vatiant in TMPRSS2. Two patients have two variants in ACE2 and five patients have two variants in TMPRSS2.
As far as we know, the biological significance of these variants in SARS-CoV-2 infection and clinical data for members of these cohorts with COVID-19 are unknown. Although further studies are needed to evaluate this matter, the present data may support our understanding of racial differences in COVID-19 severity and may help to overcome this pandemic.
Transparency document
Declaration of Competing Interest
This work was supported by Japan Agency for Medical Research and Development, AstraZeneca, Bristol-Myers Squibb, Chugai, and Ono.
The sponsors had no control over the interpretation, writing, or publication of this work.
The first author, Yuji Shibata, received honorarium from Pfizer Inc., Bristol-Myers Squibb K.K., AstraZeneca K.K. and Taiho Pharmaceutical Co., Ltd., and research grant from Pfizer Inc., AstraZeneca K.K. and Ono Pharmaceutical Co., Ltd.
Co-responding author, Shingo Matsumoto, received honorarium from Novartis Pharma K.K. and research grant from Pfizer Inc., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Eli Lilly Japan K.K. and Merck Biopharma.
Kiyotaka Yoh received research grant from Eli Lilly, Novartis, MSD, Taiho, Daiichi Sankyo, Bayer, Pfizer and Takeda and received honorarium from Boehringer Ingelheim and Kyowa Kirin.
Research grant which Koich Goto received is written below.
From Bristol-Myers Squibb K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Amgen Astellas BioPharma K.K., Amgen Inc., Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., DAIICHI SANKYO Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Ignyta, Inc., Janssen Pharmaceutical K.K., Kyowa Hakko Kirin Co., Ltd., Loxo Oncology, Inc., MEDICAL ＆ BIOLOGICAL LABORATORIES CO., LTD., Merck Biopharma Co., Ltd., Merck Serono Co., Ltd., MSD K.K., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Pfizer Inc., Sumitomo Dainippon Pharma Co., Ltd., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., Xcoo, Inc. and Takeda Pharmaceutical Co., Ltd.
Honorarium which Koich Goto received is written below.
From Bristol-Myers Squibb K.K., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Amgen Astellas BioPharma K.K., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Guardant Health Inc., Janssen Pharmaceutical K.K., Merck Biopharma Co., Ltd., MSD K.K., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., and Takeda Pharmaceutical Co., Ltd.
Acknowledgements
This work was supported by Japan Agency for Medical Research and Development, AstraZeneca, Bristol-Myers Squibb, Chugai, and Ono.
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