title: Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection.
abstract: Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.
authors.affiliation: Complex Genetics Section, Department of Medical Genetics, University Medical Centre Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Clara C
authors.initials: CC
authors.lastname: Elbers
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.forename: Jihane
authors.initials: J
authors.lastname: Romanos
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Dubois
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.forename: Donatella
authors.initials: D
authors.lastname: Barisani
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bardella
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Paivi
authors.initials: P
authors.lastname: Saavalainen
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Carlo
authors.initials: C
authors.lastname: Catassi
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000352:Africa, Northern; D001424:Bacterial Infections / Q000235:genetics*; D002446:Celiac Disease / Q000235:genetics*; D004198:Disease Susceptibility; D005060:Europe; D019143:Evolution, Molecular; D005828:Genetics, Population; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011506:Proteins; C490778:SH2B3 protein, human