An evolutionary analysis of RAC2 identifies haplotypes associated with human autoimmune diseases

Manuela Sironi, Franca Rosa Guerini, Cristina Agliardi, Mara Biasin, Rachele Cagliani, Matteo Fumagalli, Domenico Caputo, Andrea Cassinotti, Sandro Ardizzone, Milena Zanzottera, Elisabetta Bolognesi, Stefania Riva, Yasuyoshi Kanari, Masaaki Miyazawa, Mario Clerici

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The human RAC2 gene encodes a small GTP-binding protein with a pivotal role in immune activation and in the induction of peripheral immune tolerance through restimulation-induced cell death (RICD). Different human pathogens target the protein product of RAC2, suggesting that the gene may be subject to natural selection, and that variants in RAC2 may affect immunological phenotypes in humans. We scanned the genomic region encompassing the entire transcription unit for the presence of putative noncoding regulatory elements conserved across mammals. This information was used to select two RAC2 gene regions and analyze their intraspecific genetic diversity. Results suggest that a region covering the 3′ untranslated region has been a target of multiallelic balancing selection (or diversifying selection), and three major RAC2 haplogroups occur in human populations. Haplotypes belonging to one of these clades are associated with increased susceptibility to multiple sclerosis (P = 0.022) and earlier onset of disease symptoms (P = 0.025). This same haplogroup is significantly more common in patients with Crohn's disease compared with healthy controls (P = 0.048). These data reinforce recent evidences that susceptibility alleles/haplotypes are shared among multiple autoimmune disorders and support a causal "role for RAC2" variants in the pathogenesis of autoimmune diseases. Other genes with a role in RICD have previously been associated with autoimmunity in humans, suggesting that this pathway and RAC2 may represent novel therapeutic targets in autoimmune disorders.

Original languageEnglish
Pages (from-to)3319-3329
Number of pages11
JournalMolecular biology and evolution
Volume28
Issue number12
DOIs
Publication statusPublished - 2011 Dec

Keywords

  • Crohn's disease
  • RAC2
  • balancing selection
  • haplotype
  • multiple sclerosis

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics

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  • Cite this

    Sironi, M., Guerini, F. R., Agliardi, C., Biasin, M., Cagliani, R., Fumagalli, M., Caputo, D., Cassinotti, A., Ardizzone, S., Zanzottera, M., Bolognesi, E., Riva, S., Kanari, Y., Miyazawa, M., & Clerici, M. (2011). An evolutionary analysis of RAC2 identifies haplotypes associated with human autoimmune diseases. Molecular biology and evolution, 28(12), 3319-3329. https://doi.org/10.1093/molbev/msr164