Lehrer Steven, Rheinstein Peter
Icahn School of Medicine Mount Sinai.
Severn Health Solutions.
Res Sq. 2024 Jul 29:rs.3.rs-4798019. doi: 10.21203/rs.3.rs-4798019/v1.
The APOE gene has long been associated with Alzheimer Disease (AD) risk. Emerging research indicates that other genetic loci, including the paired immunoglobulin-like type 2 receptor alpha (PILRA) gene, may play a crucial role. In the current study we used UK Biobank data to assess the relationship between PILRA and AD.
We examined the PILRA polymorphism rs1859788, a single nucleotide missense variant, G > A, minor allele frequency 0.3. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 determined APOE isoform. We used PheWeb to perform a phenome wide association study (phewas) of rs1859788 and identify other conditions that might be related to both AD and rs1859788.
In male subjects homozygous for ApoE isoform ε4/ε4, of the men without AD, 9.7% had AA genotype; of the men with AD, 1.8% had AA genotype. This difference was significant (p = 0.006, two tail Fisher exact test). In female subjects homozygous for ApoE isoform ε4/ε4, of the women without AD, 10.4% had AA genotype; of the women with AD 7.9% had AA genotype. This difference was not significant (p = 0.481). In subjects not homozygous for ApoE isoform ε4/ε4, the effect of PILRA genotype was not significant. A phewas of rs1859788 found an association with megaloblastic anemia.
We have confirmed the previously noted PILRA snp rs1859788 risk reduction of AD, as well as a PILRA link to the ApoE ε4 isoform that has been previously described. We are uncertain why the significant association is only with men who are homozygous for the ε4/ε4 isoform. A phewas indicated that PILRA SNP rs1859788 is associated with megaloblastic anemia, which may explain an observed association between AD and anemia. The identification of PILRA as a potential risk gene for Alzheimer's disease underscores the complexity of the genetic landscape contributing to AD. Alongside APOE, PILRA may play a significant role in modulating key pathological processes such as neuroinflammation and amyloid-beta accumulation.
载脂蛋白E（APOE）基因长期以来一直与阿尔茨海默病（AD）风险相关。新出现的研究表明，其他基因位点，包括配对免疫球蛋白样2型受体α（PILRA）基因，可能起关键作用。在本研究中，我们使用英国生物银行的数据来评估PILRA与AD之间的关系。
我们检测了PILRA基因多态性rs1859788，这是一个单核苷酸错义变体，G>A，次要等位基因频率为0.3。rs429358和rs7412的单核苷酸多态性（SNP）数据确定了APOE异构体。我们使用PheWeb对rs1859788进行全表型关联研究（phewas），并确定其他可能与AD和rs1859788都相关的疾病。
在ApoE异构体ε4/ε4纯合的男性受试者中，无AD的男性中，9.7%具有AA基因型；患有AD的男性中，1.8%具有AA基因型。这种差异具有统计学意义（p = 0.006，双尾Fisher精确检验）。在ApoE异构体ε4/ε4纯合的女性受试者中，无AD的女性中，10.4%具有AA基因型；患有AD的女性中，7.9%具有AA基因型。这种差异无统计学意义（p = 0.481）。在非ApoE异构体ε4/ε4纯合的受试者中，PILRA基因型的影响不显著。对rs1859788的phewas研究发现其与巨幼细胞贫血有关。
我们证实了之前提到的PILRA单核苷酸多态性rs1859788降低AD风险，以及PILRA与先前描述的ApoE ε4异构体之间的联系。我们不确定为何显著关联仅存在于ε4/ε4异构体纯合的男性中。一项phewas研究表明，PILRA单核苷酸多态性rs1859788与巨幼细胞贫血有关，这可能解释了观察到的AD与贫血之间的关联。将PILRA鉴定为阿尔茨海默病的潜在风险基因凸显了导致AD的遗传格局的复杂性。除了APOE之外，PILRA可能在调节神经炎症和β淀粉样蛋白积累等关键病理过程中发挥重要作用。
