Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease |
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Authors: | Kristin K Nicodemus Judith E Stenger Donald E Schmechel Kathleen A Welsh-Bohmer Ann M Saunders Allen D Roses John R Gilbert Jeffery M Vance Jonathan L Haines Margaret A Pericak-Vance Eden R Martin |
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Institution: | (1) Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA;(2) Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA;(3) Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA;(4) Joseph and Kathleen Bryan Alzheimer s Disease Research Center, North Carolina, USA;(5) GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, USA;(6) Program in Human Genetics, Vanderbilt University Medical Center, Nashville, Tennessee, USA;(7) Department of Medicine and Center for Human Genetics, Duke University Medical Center, DUMC Box 3445, Durham, NC 27710, USA |
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Abstract: | Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE-4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the –219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. Despite these findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influenced risk of AD independent of the APOE-4 allele. In addition to risk, we tested for association between the SNPs and age at onset of AD, but found no association in the case-control or family based analyses. In conclusion, SNPs +5361, or a SNP in strong linkage disequilibrium, may confer some additional risk for developing AD beyond the risk due to APOE-4; however, the effect independent of APOE-4 is likely to be small. |
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Keywords: | Alzheimer disease APOE Single nucleotide polymorphisms Haplotype Age at onset |
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