Association of a Functional NOS1 Promoter Repeat with Alzheimer's Disease in the VITA Cohort

Article type: Research Article

Authors: Reif, Andreas^{a; *; 1} | Grünblatt, Edna^{a; b} | Herterich, Sabine^c | Wichart, Ildiko^d | Rainer, Michael K.^e | Jungwirth, Susanne^e | Danielczyk, Walter^e | Deckert, Jürgen^a | Tragl, Karl-Heinz^e | Riederer, Peter^a | Fischer, Peter^{e; f}

Affiliations: [a] Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany | [b] Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland | [c] Central Laboratory, Department of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany | [d] Institute of Clinical Neurobiology, Vienna, Austria | [e] Ludwig Boltzmann Society, L. Boltzmann Institute of Aging Research, Vienna, Austria | [f] Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria

Correspondence: [*] Correspondence to: Andreas Reif, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Füchsleinstr. 15, D-97080 Würzburg, Germany, Tel.: +49 931 201 76402; Fax: +49 931 201 77220; Email: reif_a@klinik.uni-wuerzburg.de.

Note: [1] Both authors contributed equally.

Abstract: NO synthase, type I (NOS-I) has been suggested to play a role in the etiology of Alzheimer's disease (AD). The gene encoding NOS-I harbors at least nine alternative first exons; in the promoter region of exon 1f, a polymorphic repeat (NOS1 ex1f-VNTR) has been described which influences gene expression and neuronal transcriptome. We have shown that short alleles of this repeat are associated with AD. Here, we sought to further explore this finding by investigating a longitudinal cohort sample from the Vienna-Transdanube-Aging (VITA) study consisting of 606 subjects enrolled at the age of 75 (of these, genotypes were available for 574 subjects) and followed up for 60 months. The ex1f-VNTR risk genotype was associated with AD in the total sample and at the second follow-up. Thus, either long alleles of NOS1 ex1f-VNTR are protective against disease or conversely, short alleles predispose to earlier onset of disease. As demonstrated, ex1f-VNTR interacted with the apolipoprotein E ε4 risk allele (OR in the presence of both risk alleles 3.63; 95% CI: 1.45–9.12). These findings provide further evidence for an association of NOS1 with AD.

Keywords: Alzheimer's disease, genetics, neuronal nitric oxide synthase (NOS1), polymorphism, risk factor, VITA study

DOI: 10.3233/JAD-2010-101491

Journal: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 327-333, 2011