rs2227564

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.

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.

This study characterized an Ashkenazi Jewish (AJ) population-specific genetic signature using genome-wide SNP data from 1,312 AJ individuals. Using ADMIXTURE and principal components analysis, the authors identified allelic patterns that differentiate AJ from European and Middle Eastern populations. Gene Ontology enrichment analysis of the AJ-specific genetic signature revealed enrichment in genes involved in transepithelial chloride transport (including CFTR with rs213950 showing V158M variant) and equilibrioception (PCDH15, CLRN1), implicating these pathways in the elevated prevalence of cystic fibrosis and Usher syndrome in Ashkenazi Jews. The study also identified disease-relevant alleles including MTHFR C677T (rs1801133), SH2B3 rs3184504 associated with type 1 diabetes/celiac disease, and MC1R rs1805005, and provided a validated set of 103 ancestry informative markers (AIMs) for population stratification correction.

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).

This association study examined the non-synonymous PLAU polymorphism rs2227564 (Pro141Leu) in two independent case-control series (Swiss n=401, Greek n=280) as a positional candidate for Alzheimer's disease susceptibility. The authors found no significant association of rs2227564 with AD (p=0.151-0.986 across populations), cognitive decline, brain amyloid-beta load, or CSF/plasma Aβ42 levels. The findings contradict previous conflicting reports and suggest that common PLAU variants contribute minimally to AD risk.