Human genetic factors associated with pneumonia susceptibility, a cue for COVID-19 mortality

Guin, D.; Yadav, S.; Singh, P.; Thakran, S.; Kukal, S.; Kanojia, N.; Paul, P. R.; Pattnaik, B.; Sardana, V.; Grover, S.; Hasija, Y.; Indian Genome Variation Consortium,; Agrawal, A.; Kukreti, R.

The risk for community acquired pneumonia (CAP) is partially driven by genetics. To identify the CAP-associated genetic risk loci, we performed a meta-analysis of clinically diagnosed CAP (3310 individuals) with 2655 healthy controls. The findings revealed CYP1A1 variants (rs2606345, rs4646903, rs1048943) associated with pneumonia. We observed rs2606345 [G vs T; OR=1.49(1.29-1.69); p=0.0001; I2= 15.5%], and rs1048943 [T vs G; OR= 1.31(0.90-1.71); p=0.002; I2=19.3%] as risk markers and rs4646903 [T vs C; OR= 0.79(0.62-0.96); p=0.03; I2=0%] as a protective marker for susceptibility to CAP, when compared with healthy controls. Our meta-analysis showed the presence of CYP1A1 SNP alleles contributing significant risk toward pneumonia susceptibility. Interestingly, we observed a striking difference of allele frequency for rs2606345 (CYP1A1) among Europeans, Africans and Asians which may provide a possible link for observed variations in death due to coronavirus disease 2019 (COVID-19), a viral pneumonia. We report, for the first time, a significant positive correlation for the risk allele (T or A) of rs2606345, with a higher COVID-19 mortality rate worldwide and within a genetically heterogeneous nation like India. Mechanistically, the risk allele 'A' (rs2606345) is associated with lower expression of CYP1A1 and presumably leads to reduced capacity for xenobiotic detoxification. We note that ambient air pollution, a powerful inducer of CYP1A1 gene expression, is globally associated with lower, not higher mortality, as would normally be predicted. In conclusion, we find that CYP1A1 alleles are associated with CAP mortality, presumably via altered xenobiotic metabolism. We speculate that gene-environment interactions governing CYP1A1 expression may influence COVID-19 mortality.