O2‐06–04: Identification of late‐onset Alzheimer's disease (LOAD) susceptibility alleles in the PAI‐1 gene
Year: 2008
Type: article
Study design: Observational Study
Abstract: Given that the plasmin system has been implicated in Aβ degradation and that accumulation of Aβ in the brain has an important role in AD, genes encoding proteins in the plasmin system are obvious Alzheimer's disease functional candidates. In this study we focused on the gene encoding the plasminogen activator inhibitor-1 (PAI1), which inhibits the conversion of plasminogen to plasmin. Previous reports of association of PAI1 with AD are conflicting. To evaluate PAI1's contribution to risk for LOAD, we selected variants within the PAI1 genomic region which met minor allele frequency (MAF) and conservation criteria: MAF 1–45%, and human-mouse identity >70% over 100bp windows. Variants were tested for association with disease status by logistic regression analyses at the level of single variants, haplotypes and multilocus genotypes (MLGs) using gender, age-at-diagnosis and APOE ϵ4 dosage as covariates in our LOAD case-control series (1,646 AD vs. 1,862 CON). All 8 variants that met our criteria for genotyping fall within a haplotype block that encompasses the entire gene. Seven out of 8 variants tag a haplotype, and were tested individually under allelic dosage, recessive and dominant models. The dominant model yielded the most significant results. One of the 8 variants, rs12673157, showed nominal significance (p=0.05). Five others, including rs1799889 reported in 2006 by Shibata et al. to associate with LOAD, showed suggestive association (0.06<p<0.25). The haplotypic global p-value did not achieve significance (p=0.14), however, the multilocus genotypes (MLGs) were highly significant (global p=0.002). There are 43 MLGs present 10 or more times, accounting for 94% of all individuals in our case-control series. Three of these MLGs appear to confer significant risk (OR=5.6, p=9.5 × 10; OR=3.4, p=0.027; OR=1.7, p=0.045) and 8 MLGs showed suggestive evidence (0.05<p<0.25) of either risk (ORs 1.46–1.95) or protection (ORs 0.26–0.82). When an additional 469 AD cases were genotyped and combined with the initial series, the MLG global p-value became more significant (global p=2.4 × 10). Overall, our results strongly suggest that PAI1 has multiple susceptibility alleles warranting further examination of PAI1 as an LOAD susceptibility gene.
Source: Alzheimer s & Dementia
Institutions: Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2038164371