CD33: increased inclusion of exon 2 implicates the Ig V-set domain in Alzheimer's disease susceptibility

Hum Mol Genet. 2014 May 15;23(10):2729-36. doi: 10.1093/hmg/ddt666. Epub 2013 Dec 30.


We previously demonstrated that the Alzheimer's disease (AD) associated risk allele, rs3865444(C), results in a higher surface density of CD33 on monocytes. Here, we find alternative splicing of exon 2 to be the primary mechanism of the genetically driven differential expression of CD33 protein. We report that the risk allele, rs3865444(C), is associated with greater cell surface expression of CD33 in both subjects of European and African-American ancestry and that there is a single haplotype influencing CD33 surface expression. A meta-analysis of the two populations narrowed the number of significant SNPs in high linkage disequilibrium (LD) (r(2) > 0.8) with rs3865444 to just five putative causal variants associated with increased protein expression. Using gene expression data from flow-sorted CD14(+)CD16(-) monocytes from 398 healthy subjects of three populations, we show that the rs3865444(C) risk allele is strongly associated with greater expression of CD33 exon 2 (pMETA = 2.36 × 10(-60)). Western blotting confirms increased protein expression of the full-length CD33 isoform containing exon 2 relative to the rs3865444(C) allele (P < 0.0001). Of the variants in strong LD with rs3865444, rs12459419, which is located in a putative SRSF2 splice site of exon 2, is the most likely candidate to mediate the altered alternative splicing of CD33's Immunoglobulin V-set domain 2 and ultimately influence AD susceptibility.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • African Americans
  • Alternative Splicing
  • Alzheimer Disease / genetics*
  • Case-Control Studies
  • European Continental Ancestry Group
  • Exons
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Linkage Disequilibrium
  • Polymorphism, Single Nucleotide
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Sequence Analysis, DNA
  • Sialic Acid Binding Ig-like Lectin 3 / genetics*
  • Sialic Acid Binding Ig-like Lectin 3 / metabolism


  • CD33 protein, human
  • Protein Isoforms
  • Sialic Acid Binding Ig-like Lectin 3