In contrast to the conclusions drawn by Zeberg & Pääbo 6, our work on ACE2 identified a haplotype frequent among South Asians and East Eurasians 8–10. This haplotype is derived by a polymorphism rs2285666 responsible for elevated expression of ACE2. We have found high inverse correlation of this haplotype with the state-wise cases as well as case fatality ratio among Indian populations 10. This correlation was significant at various timelines of the pandemic in India (Table 1). We verified the statistical tests with the updated data up to December 2020 and found these data to be consistent with previous observations (Fig. 1 and Supplementary Fig. 1). Thus, it is likely that the ACE2 SNP rs2285666 has played a significant role in modulating the susceptibility to the disease among Indian populations.
In our search of the SNPs reported to be associated with high risk by Zeberg & Pääbo 6, we found rs10490770 from genome-wide datasets 14,15,18–20. We applied the same tests done for the ACE2 SNPs (Fig. 1). The state-wise frequency variation of this SNP did not show any association either with the number of cases or the case fatality ratio (Table 1 and Supplementary Figure 1). We repeated these regression tests for the number of cases as well as the case fatality ratio data, obtained during all the three months. However, none of them showed any association with the rs10490770 (p > 0.3) (Table 1). The lack of association is striking and suggests instead a complex susceptibility response among Indian populations.
Zeberg & Pääbo 6 have used the data of higher susceptibility to the disease among the Bangladeshi population living in UK 21 to support their findings. The higher mortality rate for Bangladeshi population in the UK needs more detailed investigation on comorbidity, relative age, genetic admixture as well as local environment and socio-economic circumstances in their particular British context. More importantly, a similar trend has also been observed among African Americans, where some of the same qualifications may apply mutatis mutandis22–24. Furthermore, it is notable that among the Bangladeshi samples analysed by us, the tribal populations of Bangladesh showed almost three times less frequency of rs10490770 (Supplementary Table 1). Therefore, it is advised to explicitly mention the caste and tribal populations while making any statement about South Asian populations. Significantly, our data also show that the incidence of the allele rs2285666 has been found to occur in the highest frequency of 100% in Indian populations such as the Nishi and Kokborok (Tripuri), who represent Trans-Himalayan language communities (Supplementary Fig. 1 and Supplementary Table 1). As a linguistic phylum, the Trans-Himalayan language family is widespread in parts of eastern Eurasia and includes languages such as Tibetan, Burmese, Mandarin, Cantonese and Hokkien.
Thus, our extensive analyses on realtime data did not show any association of the SNP rs10490770 with the state-wise infection rates as well as CFRs, suggesting that the risk allele for COVID-19 in Europe does not play a significant role in COVID-19 severity in India.