title: Genetic variability of the gene cluster CALHM 1-3 in sporadic Creutzfeldt-Jakob disease.
abstract: Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. mcalero@isciii.es
authors.forename: Olga
authors.initials: O
authors.lastname: Calero
authors.forename: María J
authors.initials: MJ
authors.lastname: Bullido
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.forename: Rafael
authors.initials: R
authors.lastname: Hortigüela
authors.forename: Ana
authors.initials: A
authors.lastname: Frank-García
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez-Martín
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Rey
authors.forename: Isabel
authors.initials: I
authors.lastname: Sastre
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.forename: Jesús
authors.initials: J
authors.lastname: de Pedro-Cuesta
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Miguel
authors.initials: M
authors.lastname: Calero
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics*; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D005810:Multigene Family; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
chemical_list: C530077:CALHM1 protein, human; D015220:Calcium Channels; D008562:Membrane Glycoproteins; D002118:Calcium