Alzheimer's disease (AD) is a complex disease
involving several genetic and environmental
components. Genetic studies have yet to identify all
the genes involved in the pathogenesis of AD.
Transforming growth factor-beta1 (TGF-beta1) is a
candidate gene for AD. It is a multifunctional
cytokine whose overexpression has been shown to
promote the deposition of amyloid-beta peptide. The
goal of this study was to investigate the association
of three polymorphisms in TGF-beta1 with the risk of
AD. Two of the polymorphisms are located in the 5'
region at positions -800 (G-->A) and -509 (C-->T), and
the third is in exon 5 at codon 263 (Thr-->Ile). We
screened DNA samples from 428 sporadic, late-onset
patients and 421 controls by PCR-based assays. There
was no statistically significant difference in
genotype or allele frequency distributions between
cases and controls for the -800 or codon 263
polymorphisms (P=0.38 and P=0.60, respectively). The
overall genotype distribution at the -509 site was
significantly different between cases and controls.
(P=0.017). The frequency of the -509/TT genotype was
significantly higher in AD patients than controls
(P=0.015). We further tested whether this polymorphism
may alter the regulation of the TGF-beta1 gene using
dual luciferase reporter assay. We subcloned the 5'
flanking region, which contained the -509 C/T
polymorphic sites, in front of the firefly luciferase
reporter gene in pGL-3 basic vector and co-transfected
with the pRL-CMV vector containing Renilla luciferase
gene as a control for transfection efficiency in COS-1
cells. The activity of each promoter allele was
directly measured by the ratio of firefly luciferase
activity to Renilla luciferase activity. The -509 T
allele was associated with marginally higher
transcriptional activity of TGF-beta compared with the
-509 C allele (P=0.051). These data suggest that the
-509 polymorphism of TGF-beta1 may be modestly
associated with the risk of AD. However, these data
should be interpreted with caution as the differences
associated with the -509 alleles in both the genetic
association and the transfection studies were modest.