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

Objective We investigated whether particular immunoglobulin GM (gamma 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.