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Association of the dihydrolipoamide dehydrogenase gene with Alzheimer's disease in an Ashkenazi Jewish population
Author(s) -
Brown Abraham M.,
Gordon Derek,
Lee Hsinhwa,
Caudy Michael,
Hardy John,
Haroutunian Vahram,
Blass John P.
Publication year - 2004
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30008
Subject(s) - genetics , genotype , biology , linkage disequilibrium , locus (genetics) , population , single nucleotide polymorphism , gene , medicine , environmental health
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 ApoE 4 status to determine the association of these independent variables with AD. Significant associations with AD were observed for ApoE 4 ( 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. © 2004 Wiley‐Liss, Inc.