Glucocorticoid-related genetic susceptibility for Alzheimer's disease.
Because glucocorticoid excess increases neuronal vulnerability, genetic variations in the glucocorticoid system may be related to the risk for Alzheimer's disease (AD). We analyzed single-nucleotide polymorphisms in 10 glucocorticoid-related genes in a population of 814 AD patients and unrelated control subjects. Set-association analysis revealed that a rare haplotype in the 5' regulatory region of the gene encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) was associated with a 6-fold increased risk for sporadic AD. Results of a reporter-gene assay indicated that the rare risk-associated haplotype altered HSD11B1 transcription. HSD11B1 controls tissue levels of biologically active glucocorticoids and thereby influences neuronal vulnerability. Our results indicate that a functional variation in the glucocorticoid system increases the risk for AD, which may have important implications for the diagnosis and treatment of this disease.
de Quervain
Dominique J-F
DJ
Division of Psychiatry Research, University of Zürich, Zürich, Switzerland. quervain@bli.unizh.ch
Poirier
Raphael
R
Wollmer
M Axel
MA
Grimaldi
Luigi M E
LM
Tsolaki
Magdalini
M
Streffer
Johannes R
JR
Hock
Christoph
C
Nitsch
Roger M
RM
Mohajeri
M Hasan
MH
Papassotiropoulos
Andreas
A
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000031:analogs & derivatives / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D002478:Cells, Cultured; D005060:Europe; D040461:Gene Components; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005822:Genetic Vectors; D005838:Genotype; D005938:Glucocorticoids / Q000378:metabolism*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008156:Luciferases; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D014162:Transfection
D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D008156:Luciferases