BTK and COVID-19: Both TLR7 and BTK are X-link inactive genes; 84% of TLR7 and 98% BTK expression are inactivated by XCI in females.34 A recent study found a male-biased single-nucleotide polymorphism (SNP) rs2071223 in BTK (p = 0.005).33 Meanwhile, a rare loss-of-function variant (c.2129_2132del) of TLR7 was reported in 4 young men with severe COVID-19, which is associated with impaired type I and II interferon responses.37 We found that TLR7 (q = 8.9 × 10−8) and BTK expression (q = 0.001) in monocytes are significantly elevated in men with severe COVID-19 compared to women (Fig. 5b).