Identification of common human <i>TMEM173</i> genotypes associated with Alzheimer's disease

BackgroundRecent 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 <i>WT/WT</i>. However, <i>TMEM173</i>, the human gene encodes STING, has 5 common, distinct, sometimes opposite functional alleles that result in 25 <i>TMEM173</i> genotypes. Only ∼50% of whites, 36% of African Americans (AA), 22% of East Asians are <i>WT/WT</i>. Past STING cancer immunotherapy clinic trials, which did not consider human <i>TMEM173</i> 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 <i>TMEM173</i> genotypes and human diseases.MethodsWe conduct a large-scale (∼15,000 individuals) case-control analysis between <i>TMEM173</i> 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.ResultsA common <i>H232/HAQ TMEM173</i> genotype is associated with AD protection across the populations. An AA-specific <i>TMEM173</i> genotype <i>H232/Q293</i> increases the risk for AA males (OR = 17.7148), especially in the <i>APOE</i> ε3/ε3 population.ConclusionsThe findings discovered the first AA-specific high AD risk factor and established an association between human <i>TMEM173</i> and AD, paving the way for STING-targeting effective AD healthcare.