Published on Jan. 1, 2012 in Arch Biochem Biophys volume 7(12).

PubMed ID: 23251365

DOI: PONE-D-12-00728

Abstract:

BACKGROUND: Recent studies showed that polymorphisms in the Fat andObesity-Associated (FTO) gene have robust effects on obesity, obesity-related traitsand endophenotypes associated with Alzheimer's disease (AD). METHODS: We used 1,877Caucasian cases and controls from the NIA-LOAD study and 1,093 Caribbean Hispanicsto further explore the association of FTO with AD. Using logistic regression, weassessed 42 SNPs in introns 1 and 2, the region previously reported to be associatedwith AD endophenotypes, which had been derived by genome-wide screenings. Inaddition, we performed gene expression analyses of neuropathologically confirmed ADcases and controls of two independent datasets (19 AD cases, 10 controls; 176 ADcases, 188 controls) using within- and between-group factors ANOVA of log(10)transformed rank invariant normalized expression data. RESULTS: In the NIALOADstudy, one SNP was significantly associated with AD and three additional markerswere close to significance (rs6499640, rs10852521, rs16945088, rs8044769, FDRp-value: 0.05<p<0.09). Two of the SNPs are in strong LD (D'>0.9) with the previouslyreported SNPs. In the Caribbean Hispanic dataset, we identified three SNPs(rs17219084, rs11075996, rs11075997, FDR p-value: 0.009<p<0.01) that were associatedwith AD. These results were confirmed by haplotype analyses and in a metaanalysis inwhich we included the ADNI dataset. FTO had a significantly lower expresssion in ADcases compared to controls in two independent datasets derived from human cortex andamygdala tissue, respectively (p = 2.18 × 10-5 and p<0.0001). CONCLUSIONS: Our datasupport the notion that genetic variation in Introns 1 and 2 of the FTO gene maycontribute to AD risk.