title: Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia.
abstract: The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.
authors.affiliation: Department of Physiology, Sanders-Brown Center on Aging .
authors.forename: Manasi
authors.initials: M
authors.lastname: Malik
authors.affiliation: Department of Physiology, Sanders-Brown Center on Aging .
authors.forename: Joe
authors.initials: J
authors.lastname: Chiles
authors.affiliation: Computational Sciences Center of Emphasis, Pfizer Inc., Cambridge, MA 02140, USA.
authors.forename: Hualin S
authors.initials: HS
authors.lastname: Xi
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Medway
authors.affiliation: Department of Physiology, Sanders-Brown Center on Aging .
authors.forename: James
authors.initials: J
authors.lastname: Simpson
authors.affiliation: Rinat-Pfizer, South San Francisco, CA 94080, USA.
authors.forename: Shobha
authors.initials: S
authors.lastname: Potluri
authors.affiliation: Department of Internal Medicine.
authors.forename: Dianna
authors.initials: D
authors.lastname: Howard
authors.affiliation: Department of Internal Medicine.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Toxicology.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Paumi
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Shubhabrata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Crane
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA and.
authors.forename: Steven
authors.initials: S
authors.lastname: Younkin
authors.affiliation: Department of Biostatistics, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
authors.affiliation: Department of Physiology, Sanders-Brown Center on Aging , Steve.Estus@uky.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Estus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D002460:Cell Line; D005091:Exons; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C571163:CD33 protein, human; D012333:RNA, Messenger; D063268:Sialic Acid Binding Ig-like Lectin 3; C477390:lintuzumab