INTRODUCTION: Recent genome wide association studies (GWAS) on coeliac disease (CD) have identified risk loci harbouring genes that fit the accepted pathogenic model and are considered aetiological candidates. METHODS: Using Taqman single nucleotide polymorphism (SNP) and expression assays, the study genotyped 11 SNPs tagging eight GWAS regions (1q31, 2q11-2q12, 3p21, 3q25-3q26, 3q28, 4q27, 6q25 and 12q24) in a Spanish cohort of 1094 CD patients and 540 controls, and performed expression analyses of candidate genes (RGS1, IL18R1/IL18RAP, CCR3, IL12A/SCHIP1, LPP, IL2/IL21-KIAA1109, TAGAP, and SH2B3) in intestinal mucosa from 29 CD children and eight controls. RESULTS: Polymorphisms in 1q31, 2q11-2q12, and 3q25 showed association in our cohort, and also 3q28 and 4q27 when combined with a previous study. Expression levels of IL12A, IL18RAP, IL21, KIAA1109, LPP, SCHIP1, and SH2B3 were affected by disease status, but the correlation between genotype and mRNA levels was observed only in IL12A, LPP, SCHIP1, and SH2B3. CONCLUSIONS: Expression differences between treated CD patients and controls along with SNP expression associations suggest a possible primary role for these four genes and their variants in pathogenesis. The lack of SNP effect in the remaining genes is probably a consequence of arbitrary candidate gene selection within association signals that are not based on functional studies.
INTRODUCTION: Recent genome wide association studies (GWAS) on coeliac disease (CD) have identified risk loci harbouring genes that fit the accepted pathogenic model and are considered aetiological candidates. METHODS: Using Taqman single nucleotide polymorphism (SNP) and expression assays, the study genotyped 11 SNPs tagging eight GWAS regions (1q31, 2q11-2q12, 3p21, 3q25-3q26, 3q28, 4q27, 6q25 and 12q24) in a Spanish cohort of 1094 CDpatients and 540 controls, and performed expression analyses of candidate genes (RGS1, IL18R1/IL18RAP, CCR3, IL12A/SCHIP1, LPP, IL2/IL21-KIAA1109, TAGAP, and SH2B3) in intestinal mucosa from 29 CDchildren and eight controls. RESULTS: Polymorphisms in 1q31, 2q11-2q12, and 3q25 showed association in our cohort, and also 3q28 and 4q27 when combined with a previous study. Expression levels of IL12A, IL18RAP, IL21, KIAA1109, LPP, SCHIP1, and SH2B3 were affected by disease status, but the correlation between genotype and mRNA levels was observed only in IL12A, LPP, SCHIP1, and SH2B3. CONCLUSIONS: Expression differences between treated CDpatients and controls along with SNP expression associations suggest a possible primary role for these four genes and their variants in pathogenesis. The lack of SNP effect in the remaining genes is probably a consequence of arbitrary candidate gene selection within association signals that are not based on functional studies.
Authors: Gosia Trynka; Karen A Hunt; Nicholas A Bockett; Jihane Romanos; Vanisha Mistry; Agata Szperl; Sjoerd F Bakker; Maria Teresa Bardella; Leena Bhaw-Rosun; Gemma Castillejo; Emilio G de la Concha; Rodrigo Coutinho de Almeida; Kerith-Rae M Dias; Cleo C van Diemen; Patrick C A Dubois; Richard H Duerr; Sarah Edkins; Lude Franke; Karin Fransen; Javier Gutierrez; Graham A R Heap; Barbara Hrdlickova; Sarah Hunt; Leticia Plaza Izurieta; Valentina Izzo; Leo A B Joosten; Cordelia Langford; Maria Cristina Mazzilli; Charles A Mein; Vandana Midah; Mitja Mitrovic; Barbara Mora; Marinita Morelli; Sarah Nutland; Concepción Núñez; Suna Onengut-Gumuscu; Kerra Pearce; Mathieu Platteel; Isabel Polanco; Simon Potter; Carmen Ribes-Koninckx; Isis Ricaño-Ponce; Stephen S Rich; Anna Rybak; José Luis Santiago; Sabyasachi Senapati; Ajit Sood; Hania Szajewska; Riccardo Troncone; Jezabel Varadé; Chris Wallace; Victorien M Wolters; Alexandra Zhernakova; B K Thelma; Bozena Cukrowska; Elena Urcelay; Jose Ramon Bilbao; M Luisa Mearin; Donatella Barisani; Jeffrey C Barrett; Vincent Plagnol; Panos Deloukas; Cisca Wijmenga; David A van Heel Journal: Nat Genet Date: 2011-11-06 Impact factor: 38.330