Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection |
| |
Authors: | Alexandra Zhernakova Clara C Elbers Bart Ferwerda Jihane Romanos Patrick C Dubois Lude Franke Marije Oosting Donatella Barisani Finnish Celiac Disease Study Group Paivi Saavalainen Carlo Catassi Mihai G Netea Cisca Wijmenga |
| |
Institution: | 1 Complex Genetics Section, Department of Medical Genetics, University Medical Centre Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands 2 Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, 2300RC Leiden, The Netherlands 3 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, the Netherlands 4 Department of Internal Medicine, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands 5 Nijmegen Institute for Infectious Inflammation and Immunity, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands 6 Genetics Department, University Medical Centre Groningen and University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands 7 Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK 8 Department of Experimental Medicine, Faculty of Medicine, University of Milano-Bicocca, Via Cadore 48, 20052 Monza, Italy 9 Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Padiglione Granelli, Via Francesco Sforza 35, 20122 Milan, Italy 10 Department of Medical Sciences, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy 11 University of Tampere and Tampere University Hospital, Medical School, Building Finn-Medi 3, University of Tampere, 33014 Tampere, Finland 12 Department of Medical Genetics and Research Program of Molecular Medicine, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland 13 Department of Pediatrics, Università Politecnica delle Marche, Ancona, Via F Corridoni 11, 60123 Ancona, Italy 14 Center for Celiac Research, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA |
| |
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. |
| |
Keywords: | |
本文献已被 ScienceDirect 等数据库收录! |
|