Association of the dihydrolipoamide dehydrogenase gene with Alzheimer's disease in an Ashkenazi Jewish population

Abraham M. Brown, Derek Gordon, Hsinhwa Lee, Michael Caudy, John Hardy, Vahram Haroutunian, John P. Blass

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Abundant biochemical evidence links deficient activity of mitochondrial α-ketoglutarate dehydrogenase with neuropathologically confirmed Alzheimer's disease (AD). Reduced α-ketoglutarate dehydrogenase activity has also been associated with anti-mortem measures of clinical disability. One of the genes encoding this complex, namely, DLD, lies within a chromosome 7 region that is in linkage disequilibrium with AD. We therefore examined the hypothesis that variation in DLD is associated with AD risk. Denaturing HPLC was used to search for sequence variations in the coding and flanking regions of all exons of DLD, but no abundant variants that alter protein sequence were found. However, four common SNPs were identified and genotyped in a case-control series of 297 Caucasians from New York City, including 229 residents of a Jewish nursing home. Logistic regression analysis was performed for the four-locus DLD genotype, sex, and ApoE4 status to determine the association of these independent variables with AD. Significant associations with AD were observed for ApoE4 (P < 10-6) and sex combined with DLD genotype (P = 0.013). The association with the DLD genotypes appears only in the male population in both the Caucasian series (P = 0.0009, n = 83) and the Ashkenazi Jewish subseries (P = 0.017, n = 49). The DLD genotype appears to operate independently of APOE in conferring AD risk.

Original languageEnglish
Pages (from-to)60-66
Number of pages7
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume131 B
Issue number1
DOIs
StatePublished - 15 Nov 2004

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