P3-270: An association study between progranulin gene polymorphisms and Alzheimer's disease

Abstract

Mutations in the progranulin gene (PGRN) leading to haploinsufficiency of the progranulin protein have been shown to cause tau-negative frontotemporal dementia linked to chromosome 17q21. Although the precise biological function of progranulin in neurons has not yet been determined, the initial findings suggest that progranulin is crucial for the neuronal survival and that the down regulation of this protein leads to neurodegeneration. Here we wanted to investigate whether genetic variability in the PGRN gene influences also the risk of developing the more common neurodegenerative brain disease, Alzheimer's disease (AD). To study the genetic association between PGRN and AD, we genotyped four single nucleotide polymorphisms (SNPs) (rs3785817, rs4792939, rs850713, and rs5848) in clinically well-defined AD patient and control cohort originating from Eastern Finland. Over 500 late onset AD patients were compared to 650 non-demented, age-matched control subjects using single locus and haplotype approaches. After performing allele, genotype and haplotype analyses of SNPs, no significant associations were found. However, upon stratifying the population based on APOE status, a significant association was found in APOE ϵ4 negative subgroup with SNPs rs850713 (p<0.05) and rs5848 (p=0.01), which are located at the 3'-prime end of PGRN gene. Furthermore, the same SNPs showed a significant association among men and the assessment of combined effect of APOE status and gender revealed strong single locus and haplotype association with SNPs rs850713 and rs5848 in men not carrying the APOE ϵ4 allele (p<0.01). Although we did not find any of the studied PGRN SNPs to be associated with AD in the whole case-control cohort, the fact that SNPs rs850713 and rs5848 were associated in APOE and gender stratified subgroups suggests that genetic variability in the PGRN gene may also influence the risk of AD in certain conditions. Further studies are required to corroborate our findings.