Department of Pharmacology & Immunology, Medical University of South Carolina, Charleston, SC, 29425-2230, USA.
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
Immunogenetics. 2024 Nov 4;77(1):1. doi: 10.1007/s00251-024-01358-4.
Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a large number of susceptibility genes, but most of AD heritability remains unexplained, implying the existence of additional genes. Furthermore, the majority of the GWAS have been conducted in people of European descent, and the genes important for AD susceptibility in people of African descent have been underexplored. In this hypothesis-generating prospective cohort study, we genotyped 191 African Americans (AAs) from three longitudinal cohorts on aging for the IgG3 allotype GM6, which is expressed exclusively in people of African descent, and assessed its interaction with IGHG, FCGRIIB, and HLA-DRB1 genes. Cox proportional hazards modeling showed that GM6 by itself was not significantly associated with AD development. However, there was evidence of epistatic interaction: The risk of developing AD associated with GM6 positivity was significantly different (p = 0.0098) in non-GM17/GM17 participants compared with GM 17/GM17 participants. Specifically, in non-GM17/GM17 participants, the risk of AD was over fourfold higher in GM6-positive participants compared with GM 6-negative participants (HR = 4.63). Similarly, risk of developing AD associated with GM6 positivity was marginally different in non-FCGRIIB TT participants compared with FCGRIIB TT participants. In non-FCGRIIB TT participants, the risk of developing AD was over twofold higher in GM6-positive participants compared with GM6-negative participants (HR = 2.44). This is the first report suggesting that immunoglobulin GM allotypes might play a role in AD etiology among AAs; however, since this was largely a hypothesis-generating study, replication in larger cohorts would be required to confirm this finding.
全基因组关联研究（GWAS）发现了大量的阿尔茨海默病（AD）易感基因，但大部分 AD 的遗传率仍未得到解释，这意味着存在其他基因。此外，大多数 GWAS 都是在欧洲血统的人群中进行的，而非洲血统人群中对 AD 易感性重要的基因则尚未得到充分探索。在这项产生假说的前瞻性队列研究中，我们对来自三个衰老纵向队列的 191 名非裔美国人（AA）进行了 IgG3 同种型 GM6 的基因分型，该同种型仅在非洲裔人群中表达，并评估了其与 IGHG、FCGRIIB 和 HLA-DRB1 基因的相互作用。Cox 比例风险模型显示，GM6 本身与 AD 发展没有显著相关性。然而，存在上位性相互作用的证据：与 GM6 阳性相关的 AD 发病风险在非 GM17/GM17 参与者中与 GM17/GM17 参与者显著不同（p=0.0098）。具体来说，在非 GM17/GM17 参与者中，GM6 阳性参与者的 AD 风险是 GM6 阴性参与者的四倍以上（HR=4.63）。同样，与 GM6 阳性相关的 AD 发病风险在非 FCGRIIB TT 参与者中与 FCGRIIB TT 参与者相比也略有不同。在非 FCGRIIB TT 参与者中，GM6 阳性参与者的 AD 发病风险是 GM6 阴性参与者的两倍以上（HR=2.44）。这是第一项表明免疫球蛋白 GM 同种型可能在非裔美国人 AD 病因学中发挥作用的报告；然而，由于这主要是一项产生假说的研究，需要在更大的队列中进行复制才能证实这一发现。
