Novel extreme homozygote haplotypes at the human caveolin 1 gene upstream purine complex in sporadic Alzheimer's disease.

Aberrant expression of the caveolin-1 (CAV1) gene is associated with Alzheimer's disease (AD) brain. We have recently reported a polymorphic purine stretch located at between 1.8 and 1.5 kb flanking the CAV1 gene, whose alleles and genotypes are associated with late-onset AD. Extra-short homozygote haplotypes were observed that were present only in the AD cases. Following an independent case/control study, we report alleles at the other extreme of the allele range, haplotypes of which were observed to be homozygous across the region in the AD cases. We propose that there is a window for the length of motifs and haplotypes in the controls. Homozygosity for shorter and longer motifs and haplotypes was linked with AD in our study. Our findings elucidate novel predisposing haplotypes at the CAV1 gene purine complex, and confirm the role of this region in the etiopathophysiology of late-onset AD.

A novel polymorphic purine complex at the 1.5 kb upstream region of the human caveolin-1 gene and risk of Alzheimer's disease; extra-short alleles and accumulated allele homozygosity.

Crucial interaction of caveolin-1 (CAV1) with beta- and gamma-secretases, and aberrant expression of the gene encoding this protein in Alzheimer's disease (AD) support a role for CAV1 in the pathophysiology of this disease. We report a novel polymorphic purine complex stretching approximately 150 bp of genomic DNA at the 1.5 kb upstream region of the human CAV1 gene, alleles and genotypes of which are associated with sporadic late-onset AD. Extra-short alleles were observed in the case group that were absent in the control subjects. Remarkably, 63% of these alleles were observed to be homozygous in length, forming 23.7% of the homozygote length compartment in the AD cases (chi(2) = 19.08, df = 1, P < 0.000007). Increased homozygosity for length was also observed at this region in the Alzheimer's cases, for the allele lengths shared by the case and control groups [(chi(2) = 30.75, df = 1, P < 0.0000000, OR = 4.54, CI 95% (2.56-8.3)]. This region contains GGAA and GAAA motifs, the consensus binding sites for the Ets and IRF family transcription factors, respectively, and is highly conserved in distantly related non-human primates in respect with location and motif sequence. The effect of this complex sequence on the expression of CAV1, and the related mechanisms in the pathophysiology of AD remain to be clarified.