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Human Molecular Genetics Advance Access originally published online on December 22, 2004
Human Molecular Genetics 2005 14(3):447-460; doi:10.1093/hmg/ddi041
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Human Molecular Genetics, Vol. 14, No. 3 © Oxford University Press 2005; all rights reserved

Elevated amyloid ß protein (Aß42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene

Nilüfer Ertekin-Taner1, James Ronald1, Lars Feuk3, Jonathan Prince3, Michael Tucker4,5, Linda Younkin1, Maria Hella1, Shushant Jain1, Alyssa Hackett1, Leah Scanlin1, Jason Kelly1, Muthoni Kihiko-Ehman4,5, Matthew Neltner4,5, Louis Hersh5, Mark Kindy5, William Markesbery5, Michael Hutton1, Mariza de Andrade6, Ronald C. Petersen7, Neill Graff-Radford2, Steve Estus4,5, Anthony J. Brookes3 and Steven G. Younkin1,*

1Department of Neuroscience and 2Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA, 3Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden, 4Department of Physiology and 5Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA and 6Department of Health Sciences Research and 7Department of Neurology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA

* To whom correspondence should be addressed. Email: younkin.steven{at}mayo.edu

Received June 11, 2004; Revised October 8, 2004; Accepted December 10, 2004

Plasma amyloid ß protein (Aß42) levels and late onset Alzheimer's disease (LOAD) have been linked to the same region on chromosome 10q. The PLAU gene within this region encodes urokinase-type plasminogen activator, which converts plasminogen to plasmin. Aß aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Aß. We evaluated single nucleotide polymorphisms (SNPs) in PLAU for association with Aß42 and LOAD. PLAU SNP compound genotypes composed of haplotype pairs showed significant association with AD in three independent case–control series. PLAU SNP haplotypes associated significantly with plasma Aß42 in 10 extended LOAD families. One of the SNPs analyzed was a missense C/T polymorphism in exon 6 of PLAU (PLAU_1=rs2227564), which causes a proline to leucine change (P141L). We analyzed PLAU_1 for association with AD in six case–control series and 24 extended LOAD families. The CT and TT PLAU_1 genotypes showed association (P=0.05) with an overall estimated odds ratio of 1.2 (1.0–1.5). The CT and TT genotypes of PLAU_1 were also associated with significant age-dependent elevation of plasma Aß42 in 24 extended LOAD families (P=0.0006). In knockout mice lacking the PLAU gene, plasma—but not brain—Aß42 as well as Aß40 was significantly elevated, also in an age-dependent manner. The PLAU_1 associations were independent of the associations we found among plasma Aß42, LOAD and variants in the IDE or VR22 region. These results provide strong evidence that PLAU or a nearby gene is involved in the development of LOAD. PLAU_1 is a plausible pathogenic mutation that could act by increasing Aß42, but additional biological experiments are required to show this definitively.


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