Genetic variation in the tau kinases pathway may contribute to the risk of Alzheimer´s disease
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AuthorVázquez Higuera, José Luis; Mateo Fernández, José Ignacio; Sánchez Juan, Pascual; Rodríguez Rodríguez, Eloy; Pozueta, Ana; Calero Lara, Miguel; Dobato Ayuso, José Luis; Frank García, Ana; Valdivieso Amate, Fernando; Berciano Blanco, José Ángel; Bullido, María Jesús; Combarros Pascual, Onofre
Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in Alzheimer´s disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence AD risk. There was an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30-1.77; p = 1.24×10−5 Bonferroni corrected), and the CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE ε4 allele noncarriers (permutation p = 1.0×10-4) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences in susceptibility to AD.
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