Interactive Effects of HLA and GM Alleles on the Development of Alzheimer Disease

OBJECTIVE: We investigated whether particular immunoglobulin GM (γ marker) alleles—individually or epistatically with a known human leukocyte antigen (HLA) risk allele—were associated with the development of Alzheimer disease (AD). METHODS: Using a prospective cohort study design, we genotyped DNA samples from 209 African American (AA) and 638 European American (EA) participants for IgG1 (GM 3 and GM 17), IgG2 (GM 23+ and GM 23−), and HLA-DRB1 rs9271192 (A/C) alleles by TaqMan and rhAMP genotyping assays. RESULTS: In EA subjects, none of the GM or HLA alleles—individually or epistatically—were associated with time to development of AD. In AA subjects, GM and HLA alleles individually were not associated with time to development of AD. However, there was a significant interaction: In the presence of GM 3 (i.e., GM 3/3 and GM 3/17 subjects), the presence of the HLA-C allele was associated with a 4-fold increase in the likelihood of developing AD compared with its absence (hazard ratio [HR] 4.17, 95% CI, 1.28–13.58). In the absence of GM 3 (GM 17/17 subjects), however, the presence of the HLA-C allele was not associated with time to development of AD (HR 1.10, 95% CI, 0.50–2.41). CONCLUSIONS: These results show that particular GM and HLA alleles epistatically contribute to the development of AD.