rs4065

This study evaluated variants in seven amyloid-beta degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, TF) for association with Alzheimer's disease (AD) risk and cognitive phenotypes in older adults. In the GERAD1 cohort (3,333 AD cases, 1,225 controls), a four-SNP ECE1 intragenic haplotype (rs212524/rs212525/rs2282714/rs212531) was significantly associated with increased AD risk (OR=1.61, P=0.00035) in APOE ε4 carriers. In the Lothian Birth Cohort 1936 (LBC1936), a two-SNP ECE1 haplotype (rs2282715/rs3026883) was associated with lower non-verbal reasoning scores (β=-0.19, P=0.00036) in APOE ε4 non-carriers. Meta-analysis of four cognitive cohorts confirmed ECE1 promoter region SNPs associated with non-verbal reasoning in APOE ε4 non-carriers. Functional analysis showed the ECE1 rs213045 (338C>A) variant affected promoter activity in neuroblastoma cell lines, suggesting tissue-specific regulation.

Genome-wide linkage and association study of 1,902 individuals from 328 families with late-onset Alzheimer disease (LOAD) and 236 unrelated controls, using ~6,000 SNP markers. The strongest finding was at chromosome 19q13.32 confirming the APOE gene effect on LOAD risk (FBAT Z=8.68, P=1.98×10⁻¹⁸; case-control χ²=150.46, P=1.4×10⁻³⁴). Additional significant loci identified include 7p22.2 (rs798485, LOD=3.77), 7p21.3 (rs719423, LOD=2.89), and 16q21 (rs1482258, LOD=3.32) in linkage analyses, with 7q31.1 and 20q13.33 also showing positive associations in case-control and meta-analysis comparisons.

This paper presents a two-stage analysis approach to identify genetic heterogeneity and gene-gene interactions in late-onset Alzheimer disease (LOAD). Using Bayesian Classification clustering followed by multifactor dimensionality reduction (MDR), the authors identified LRRTM3 as a primary stratification gene and found that markers in PLAU, ACE, and CDC2 were associated with LOAD specifically within distinct LRRTM3-defined subgroups, suggesting complex gene-gene interactions in LOAD etiology.

This association study examined six urokinase gene polymorphisms in 252 European-American patients with infection-associated acute lung injury and 175 healthy controls. While single-marker analyses showed no significant associations, haplotype analysis identified the CGCCCC haplotype (rs1916341-rs2227562-rs2227564-rs2227566-rs2227571-rs4065) as significantly associated with 60-day mortality (p=0.033) and prolonged mechanical ventilation (p<0.001) in ALI patients. The urokinase haplotype was associated with outcome but not susceptibility to ALI.

Association study of four tag SNPs in the urokinase-plasminogen activator (PLAU) gene with Alzheimer's disease in 1,000 cases and 697 controls. The 3'UTR variant rs4065 showed significant protective association with AD risk (OR=0.71, 95% CI: 0.53-0.95, p=0.02) and age-at-onset (p=0.036), while rs2227571 in intron 9 was associated with age-at-onset (p=0.01) and disease duration (p=0.006).