title: Ancient pathogen-driven adaptation triggers increased susceptibility to non-celiac wheat sensitivity in present-day European populations.
abstract: BACKGROUND
  Non-celiac wheat sensitivity is an emerging wheat-related syndrome showing peak prevalence in Western populations. Recent studies hypothesize that new gliadin alleles introduced in the human diet by replacement of ancient wheat with modern varieties can prompt immune responses mediated by the CXCR3-chemokine axis potentially underlying such pathogenic inflammation. This cultural shift may also explain disease epidemiology, having turned European-specific adaptive alleles previously targeted by natural selection into disadvantageous ones.
  
  
  METHODS
  To explore this evolutionary scenario, we performed ultra-deep sequencing of genes pivotal in the CXCR3-inflammatory pathway on individuals diagnosed for non-celiac wheat sensitivity and we applied anthropological evolutionary genetics methods to sequence data from worldwide populations to investigate the genetic legacy of natural selection on these loci.
  
  
  RESULTS
  Our results indicate that balancing selection has maintained two divergent CXCL10/CXCL11 haplotypes in Europeans, one responsible for boosting inflammatory reactions and another for encoding moderate chemokine expression.
  
  
  CONCLUSIONS
  This led to considerably higher occurrence of the former haplotype in Western people than in Africans and East Asians, suggesting that they might be more prone to side effects related to the consumption of modern wheat varieties. Accordingly, this study contributed to shed new light on some of the mechanisms potentially involved in the disease etiology and on the evolutionary bases of its present-day epidemiological patterns. Moreover, overrepresentation of disease homozygotes for the dis-adaptive haplotype plausibly accounts for their even more enhanced CXCR3-axis expression and for their further increase in disease risk, representing a promising finding to be validated by larger follow-up studies.
authors.affiliation: Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.|Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sazzini
authors.affiliation: Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.|Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: De Fanti
authors.affiliation: Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.|Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cherubini
authors.affiliation: Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.|Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Quagliariello
authors.affiliation: Department of Biological, Biocomputing Group, Geological and Environmental Sciences, University of Bologna, 40126 Bologna, Italy.|CIRI Health Science and Technologies, University of Bologna, 40064 Ozzano dell'Emilia, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Profiti
authors.affiliation: Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.|Department of Biological, Biocomputing Group, Geological and Environmental Sciences, University of Bologna, 40126 Bologna, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Martelli
authors.affiliation: Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.|Department of Biological, Biocomputing Group, Geological and Environmental Sciences, University of Bologna, 40126 Bologna, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Casadio
authors.affiliation: Department of Clinical and Experimental Sciences, Gastroenterology Unit, Spedali Civili, University of Brescia, 25123 Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ricci
authors.affiliation: Department of Medical and Surgical Sciences, Digestive Diseases and Internal Medicine Unit, St. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Campieri
authors.affiliation: Department of Clinical and Experimental Sciences, Gastroenterology Unit, Spedali Civili, University of Brescia, 25123 Brescia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lanzini
authors.affiliation: Department of Medical and Surgical Sciences, Digestive Diseases and Internal Medicine Unit, St. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Volta
authors.affiliation: Department of Medical and Surgical Sciences, Digestive Diseases and Internal Medicine Unit, St. Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Caio
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
authors.affiliation: Department of Biological, Unit of Gut Physiopathology and Nutrition, Geological and Environmental Sciences, University of Bologna, 40126 Bologna, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Spisni
authors.affiliation: Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.|Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, 40126 Bologna, Italy.
authors.forename: Donata
authors.initials: D
authors.lastname: Luiselli
keywords: Evolutionary medicine; Human adaptation; Human dietary shifts; Natural selection; Non-celiac wheat sensitivity