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

13 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 - Dec 2011

Fingerprint

autoimmune diseases
Haplotypes
Autoimmune Diseases
haplotypes
gene
cell death
genes
Genes
Cell Death
autoimmunity
Crohn disease
protein products
immunosuppression
Peripheral Tolerance
sclerosis
3' untranslated regions
Immune Tolerance
G-proteins
natural selection
human population

Keywords

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

ASJC Scopus subject areas

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

Cite this

An evolutionary analysis of RAC2 identifies haplotypes associated with human autoimmune diseases. / Sironi, Manuela; Guerini, Franca Rosa; Agliardi, Cristina; Biasin, Mara; Cagliani, Rachele; Fumagalli, Matteo; Caputo, Domenico; Cassinotti, Andrea; Ardizzone, Sandro; Zanzottera, Milena; Bolognesi, Elisabetta; Riva, Stefania; Kanari, Yasuyoshi; Miyazawa, Masaaki; Clerici, Mario.

In: Molecular Biology and Evolution, Vol. 28, No. 12, 12.2011, p. 3319-3329.

Research output: Contribution to journalArticle

Sironi, Manuela ; Guerini, Franca Rosa ; Agliardi, Cristina ; Biasin, Mara ; Cagliani, Rachele ; Fumagalli, Matteo ; Caputo, Domenico ; Cassinotti, Andrea ; Ardizzone, Sandro ; Zanzottera, Milena ; Bolognesi, Elisabetta ; Riva, Stefania ; Kanari, Yasuyoshi ; Miyazawa, Masaaki ; Clerici, Mario. / An evolutionary analysis of RAC2 identifies haplotypes associated with human autoimmune diseases. In: Molecular Biology and Evolution. 2011 ; Vol. 28, No. 12. pp. 3319-3329.
@article{adf5364118144795ad921c944fae4e40,
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.",
keywords = "balancing selection, Crohn's disease, haplotype, multiple sclerosis, RAC2",
author = "Manuela Sironi and Guerini, {Franca Rosa} and Cristina Agliardi and Mara Biasin and Rachele Cagliani and Matteo Fumagalli and Domenico Caputo and Andrea Cassinotti and Sandro Ardizzone and Milena Zanzottera and Elisabetta Bolognesi and Stefania Riva and Yasuyoshi Kanari and Masaaki Miyazawa and Mario Clerici",
year = "2011",
month = "12",
doi = "10.1093/molbev/msr164",
language = "English",
volume = "28",
pages = "3319--3329",
journal = "Molecular Biology and Evolution",
issn = "0737-4038",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - An evolutionary analysis of RAC2 identifies haplotypes associated with human autoimmune diseases

AU - Sironi, Manuela

AU - Guerini, Franca Rosa

AU - Agliardi, Cristina

AU - Biasin, Mara

AU - Cagliani, Rachele

AU - Fumagalli, Matteo

AU - Caputo, Domenico

AU - Cassinotti, Andrea

AU - Ardizzone, Sandro

AU - Zanzottera, Milena

AU - Bolognesi, Elisabetta

AU - Riva, Stefania

AU - Kanari, Yasuyoshi

AU - Miyazawa, Masaaki

AU - Clerici, Mario

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

KW - balancing selection

KW - Crohn's disease

KW - haplotype

KW - multiple sclerosis

KW - RAC2

UR - http://www.scopus.com/inward/record.url?scp=81855199716&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81855199716&partnerID=8YFLogxK

U2 - 10.1093/molbev/msr164

DO - 10.1093/molbev/msr164

M3 - Article

C2 - 21680873

AN - SCOPUS:81855199716

VL - 28

SP - 3319

EP - 3329

JO - Molecular Biology and Evolution

JF - Molecular Biology and Evolution

SN - 0737-4038

IS - 12

ER -