TY - JOUR
T1 - Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection
AU - Zhernakova, Alexandra
AU - Elbers, Clara C.
AU - Ferwerda, Bart
AU - Romanos, Jihane
AU - Trynka, Gosia
AU - Dubois, Patrick C.
AU - de Kovel, Carolien G.F.
AU - Franke, Lude
AU - Oosting, Marije
AU - Barisani, Donatella
AU - Bardella, Maria Teresa
AU - Joosten, Leo A.B.
AU - Saavalainen, Paivi
AU - van Heel, David A.
AU - Catassi, Carlo
AU - Netea, Mihai G.
AU - Wijmenga, Cisca
N1 - Funding Information: The study was supported by the Celiac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government, the Netherlands Organization for Scientific Research, EU STREP KP6, SenterNovem (IOP genomics), and the Wellcome Trust. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council and the Wellcome Trust. G.T. was awarded a Ter Meulen Fund travel grant by the Royal Netherlands Academy of Arts and Sciences (KNAW). M.G.N. was supported by a VIDI grant from the Netherlands Organization for Scientific Research (NWO). P.C.D. is an MRC Clinical Training Fellow. We thank all the clinicians and Coeliac UK for their help in recruiting individuals for this study. The Finnish Celiac Disease Study Group is represented by Katri Kaukinen, Kalle Kurppa, and Markku Mäki. This study used data generated by the Wellcome Trust Case-Control Consortium 2 and resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. We thank all the individuals who participated in the study. A full list of personal acknowledgements is given in the Supplemental Data.
PY - 2010/7/11
Y1 - 2010/7/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77953231426&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2010.05.004
DO - https://doi.org/10.1016/j.ajhg.2010.05.004
M3 - Article
C2 - 20560212
SN - 0002-9297
VL - 86
SP - 970
EP - 977
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -