Identification of common human TMEM173 genotypes associated with Alzheimer's disease

Background Recent animal studies have revealed STING (Stimulator of interferon genes) as a potential key player in Alzheimer's disease (AD). The actual impact of human STING on AD, however, is unknown. Mouse STING studies were done in WT/WT . However, TMEM173 , the human gene encodes STING, has 5 common, distinct, sometimes opposite functional alleles that result in 25 TMEM173 genotypes. Only ∼50% of whites, 36% of African Americans (AA), 22% of East Asians are WT/WT . Past STING cancer immunotherapy clinic trials, which did not consider human TMEM173 heterogeneity, all failed. Objective (1) Discover new protective and risk AD genetic factors across populations or AA-specific. (2) Establish the physiological significance of common human TMEM173 genotypes and human diseases. Methods We conduct a large-scale (∼15,000 individuals) case-control analysis between TMEM173 genotypes and AD using data from The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site. The data include late-onset AD (LOAD) non-Hispanic White (NHW), early-onset AD (EOAD) NHW, and AA. Results A common H232/HAQ TMEM173 genotype is associated with AD protection across the populations. An AA-specific TMEM173 genotype H232/Q293 increases the risk for AA males (OR = 17.7148), especially in the APOE ε3/ε3 population. Conclusions The findings discovered the first AA-specific high AD risk factor and established an association between human TMEM173 and AD, paving the way for STING-targeting effective AD healthcare.