title: An evolutionary analysis of RAC2 identifies haplotypes associated with human autoimmune diseases.
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.
authors.affiliation: Bioinformatics Laboratory, Scientific Institute IRCCS E. Medea, Bosisio Parini (LC), Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.forename: Franca Rosa
authors.initials: FR
authors.lastname: Guerini
authors.forename: Cristina
authors.initials: C
authors.lastname: Agliardi
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Matteo
authors.initials: M
authors.lastname: Fumagalli
authors.forename: Domenico
authors.initials: D
authors.lastname: Caputo
authors.forename: Andrea
authors.initials: A
authors.lastname: Cassinotti
authors.forename: Sandro
authors.initials: S
authors.lastname: Ardizzone
authors.forename: Milena
authors.initials: M
authors.lastname: Zanzottera
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bolognesi
authors.forename: Stefania
authors.initials: S
authors.lastname: Riva
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Kanari
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyazawa
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics*; D005075:Biological Evolution; D003424:Crohn Disease / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D020744:rac GTP-Binding Proteins / Q000235:genetics*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein